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Suggested Citation:"3 Synthetic Carcinogens in the Diet." National Research Council. 1996. Carcinogens and Anticarcinogens in the Human Diet: A Comparison of Naturally Occurring and Synthetic Substances. Washington, DC: The National Academies Press. doi: 10.17226/5150.
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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

Suggested Citation:"3 Synthetic Carcinogens in the Diet." National Research Council. 1996. Carcinogens and Anticarcinogens in the Human Diet: A Comparison of Naturally Occurring and Synthetic Substances. Washington, DC: The National Academies Press. doi: 10.17226/5150.
×

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.

Suggested Citation:"3 Synthetic Carcinogens in the Diet." National Research Council. 1996. Carcinogens and Anticarcinogens in the Human Diet: A Comparison of Naturally Occurring and Synthetic Substances. Washington, DC: The National Academies Press. doi: 10.17226/5150.
×

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.

Suggested Citation:"3 Synthetic Carcinogens in the Diet." National Research Council. 1996. Carcinogens and Anticarcinogens in the Human Diet: A Comparison of Naturally Occurring and Synthetic Substances. Washington, DC: The National Academies Press. doi: 10.17226/5150.
×

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)

Suggested Citation:"3 Synthetic Carcinogens in the Diet." National Research Council. 1996. Carcinogens and Anticarcinogens in the Human Diet: A Comparison of Naturally Occurring and Synthetic Substances. Washington, DC: The National Academies Press. doi: 10.17226/5150.
×

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

Suggested Citation:"3 Synthetic Carcinogens in the Diet." National Research Council. 1996. Carcinogens and Anticarcinogens in the Human Diet: A Comparison of Naturally Occurring and Synthetic Substances. Washington, DC: The National Academies Press. doi: 10.17226/5150.
×

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

Suggested Citation:"3 Synthetic Carcinogens in the Diet." National Research Council. 1996. Carcinogens and Anticarcinogens in the Human Diet: A Comparison of Naturally Occurring and Synthetic Substances. Washington, DC: The National Academies Press. doi: 10.17226/5150.
×

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

Suggested Citation:"3 Synthetic Carcinogens in the Diet." National Research Council. 1996. Carcinogens and Anticarcinogens in the Human Diet: A Comparison of Naturally Occurring and Synthetic Substances. Washington, DC: The National Academies Press. doi: 10.17226/5150.
×

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

Suggested Citation:"3 Synthetic Carcinogens in the Diet." National Research Council. 1996. Carcinogens and Anticarcinogens in the Human Diet: A Comparison of Naturally Occurring and Synthetic Substances. Washington, DC: The National Academies Press. doi: 10.17226/5150.
×

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.

Suggested Citation:"3 Synthetic Carcinogens in the Diet." National Research Council. 1996. Carcinogens and Anticarcinogens in the Human Diet: A Comparison of Naturally Occurring and Synthetic Substances. Washington, DC: The National Academies Press. doi: 10.17226/5150.
×

Table 3-3 Sources of Nonintentional Food Additives of Possible Toxicological Significance

During Production

  1.  

Antibiotics and other agents used for prevention and control of disease

  1.  

Growth-promoting substances

  1.  

Microorganisms of toxicologic significance

  1.  

Parasitic organisms

  1.  

Pesticide residues (insecticides, fungicides, herbicides, etc.)

  1.  

Toxic metals and metallic compounds

  1.  

Radioactive compounds

During Processing

  1.  

Microorganisms and their toxic metabolites

  1.  

Processing residues and miscellaneous foreign objects

  1.  

Radionuclides

During Packaging and Storage

  1.  

Labeling and stamping materials

  1.  

Microorganisms and their toxic metabolites

  1.  

Migrants from packaging materials

  1.  

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,

Suggested Citation:"3 Synthetic Carcinogens in the Diet." National Research Council. 1996. Carcinogens and Anticarcinogens in the Human Diet: A Comparison of Naturally Occurring and Synthetic Substances. Washington, DC: The National Academies Press. doi: 10.17226/5150.
×

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

Suggested Citation:"3 Synthetic Carcinogens in the Diet." National Research Council. 1996. Carcinogens and Anticarcinogens in the Human Diet: A Comparison of Naturally Occurring and Synthetic Substances. Washington, DC: The National Academies Press. doi: 10.17226/5150.
×

water from wells and did not study drinking water from ground and surface water sources.

In the survey the number of wells found to contain any particular pesticide was low. Of the 127 analytes, only 17 were detected and only 13 of these exceeded the minimum reporting limits (MRL) established by the primary laboratories involved in the study. In extrapolating to the approximately 38,300 community water systems employing about 94,600 wells and 10.5 million rural domestic wells, EPA estimated that about 10.4% of the community wells and 4.2% of the rural domestic wells contained at least one pesticide at a level above the MRL. None of the community water system wells were predicted to have levels above the Health Advisory Limit (HAL) or the Maximum Contaminant Level (MCL). For the rural wells, 0.2% were expected to exceed the HAL and 0.6% the MCL. The most common findings were acid metabolites of dimethyl tetrachloroterephthlate (DCPA) and atrazine. All DCPA metabolite detections were at a small fraction (0.2% or less) of the HAL. The median atrazine levels were also low. Five pesticides (alachlor, atrazine, dibromochloropropane, ethylene dibromide, and -hexachlorohexane [lindane]) were detected in a small number of samples at levels above their MCLs. In contrast, over half the community water system wells and rural domestic wells exceeded the MRL for nitrate, with 1.2% of the community wells and 2.4% of the rural domestic wells exceeding the MCL. It is estimated that community wells serve about 3 million people and rural wells serve about 1.5 million people. EPA cautions that the data represent a one-time snapshot of the wells, and the results would be expected to vary with season and location.

In considering each of these surveys, it should be emphasized that they examine only a select group of chemicals, i.e., select volatile organic compounds or pesticides.

Suggested Citation:"3 Synthetic Carcinogens in the Diet." National Research Council. 1996. Carcinogens and Anticarcinogens in the Human Diet: A Comparison of Naturally Occurring and Synthetic Substances. Washington, DC: The National Academies Press. doi: 10.17226/5150.
×

Foods

In comparing the possible carcinogenic risks associated with dietary exposure to natural and to synthetic chemicals, it is important that the consumption of both types be put into perspective. Scheuplein (1990) divided food chemicals into seven categories, and reported estimates of the amounts ingested per day in a typical U.S. diet (see Table 5-7). Traditional foods (e.g., grains, fruits, vegetables, and meat) comprise the bulk of the diet. Items such as sugar and salt are the most frequently used direct food additives; these are GRAS (generally recognized as safe) items. Used in much smaller amounts are other direct additives (e.g., artificial sweeteners, colors, and preservatives), spices and flavors (e.g., mustard, pepper, cinnamon, poppy seed, and vanilla). Indirect food additives, such as those chemicals that migrate into food from pesticides and packaging materials, represent over 2,000 other chemicals, many of which may be present in food below the level of detection.

Pesticides have been of more concern to the public and to regulatory agencies than any other indirect food additives. Pesticides in food are generally derived from agricultural residues that remain on foodstuffs but may also be derived from chemicals used in storage facilities or from water used in food preparation. Several previous NRC studies have considered the effect of pesticides in the diet, including: Diet, Nutrition and Cancer (1982); Diet, Nutrition and Cancer, Directions for Research (1983); and Pesticides in the Diets of Infants and Children (1993). These studies should be consulted for an in-depth analysis.

It is clear from these and other reports that pesticide residues are common, but below allowable tolerances, on many foodstuffs in the U.S. diet. Federal agencies concerned with residues in food include the EPA, USDA (Food Safety and Inspection Service and Agricultural Marketing Service), and the FDA. Most of the data about residues is generated by FDA in connection with enforcement of

Suggested Citation:"3 Synthetic Carcinogens in the Diet." National Research Council. 1996. Carcinogens and Anticarcinogens in the Human Diet: A Comparison of Naturally Occurring and Synthetic Substances. Washington, DC: The National Academies Press. doi: 10.17226/5150.
×

tolerance levels. However, there is no single, comprehensive, reliable source of information on pesticide residues in foods. This is due in part to analytical and sampling problems. For example, sampling for compliance emphasizes suspected high samples. Also, the effect of post-harvest processing is seldom adequately investigated. In addition to data from federal agencies, data generated by states are subject to the same uncertainties.

An FDA survey covering the period from 1988 to 1989 (FDA 1994) studied the frequency of occurrence of 46 pesticides (primarily insecticides, with a very small number of herbicides and fungicides). This survey found that occurrence varied from 0.1% (dichlorvos, ethoprop, carbophenothion) to 24.3% (for daminozide) and 28.5% (for benomyl). It should be noted that chemicals were eliminated from the survey if the sample size was too small to be representative (less than 100 samples, compared with more than 45,000 for the most sampled chemical, chlopyrifos).

Hazard assessment and epidemiologic studies of pesticides show that many, if not all, have the potential to produce toxicity in humans, particularly in studies of occupational or accidental high- dose exposures. In addition to cancer (Blair et al. 1985, 1993; Blair and Zahm 1990, 1991; Brown et al. 1990), toxic effects may include neurological ones (Deapen and Henderson 1986, Ecobichon et al. 1990, Tanner and Langston 1990, Rosenstock et al. 1991) and reproductive ones (Gordon and Shy 1981, Schwartz and Logerfo 1988). Despite this potential, accurate estimations of risk from pesticides in the diet are subject to many uncertainties. Epidemiologic studies, almost without exception, involve occupational exposure and are complicated by multiple, sequential exposures as well as routes of exposure other than dietary. The use of tolerance levels in risk estimates is a further complication, since these levels are seldom approached, and even less often exceeded. Extrapolation from rodent assays is also problematic in part because the levels of pesticides in foods are frequently at or below the level of detection. Nevertheless, results from epidemiologic studies of farm

Suggested Citation:"3 Synthetic Carcinogens in the Diet." National Research Council. 1996. Carcinogens and Anticarcinogens in the Human Diet: A Comparison of Naturally Occurring and Synthetic Substances. Washington, DC: The National Academies Press. doi: 10.17226/5150.
×

families and farm workers occupationally exposed to pesticides suggest that the risk of cancer and other illnesses such as Parkinson's disease (Tanner and Langston 1990) should be further studied.

Mechanisms of Carcinogenesis

Although detailed molecular mechanisms of carcinogenesis are not known, several factors involved in the process have been determined (Cohen and Ellwein 1990, 1991; Stanbridge 1990; Bishop 1991; Weinstein et al. 1995). It has become increasingly clear that cancer arises as a result of genetic alterations, either inherited or resulting from the mutation of somatic cells. It is also apparent that more than one genetic error is required for the expression of the malignant phenotype. For genetic errors to become permanent, cell replication is required. The defect must occur in a stem cell (variably defined, but basically a pluripotential cell) population. On the basis of these premises, it is apparent that the likelihood of cancer development in a given cell population can be increased by directly damaging DNA during cell replication or by increasing the number of replication cycles taking place in the cells. Cell births can be increased by direct mutagenesis or by regeneration following cytotoxicity; cell deaths can be increased by inhibiting apoptosis or by altering gene expression and differentiation. Agents that enhance cell DNA damage or cell replication in appropriate cell populations will increase the cancer risk, whereas agents that decrease cell DNA damage or cell proliferation should decrease the risk.

Chemicals can generally be divided into those that directly affect DNA (genotoxic) and those that do not (nongenotoxic), although the genotoxicity of some chemicals remains poorly defined (Williams and Weisburger 1986, Tennant et al. 1987, Rosenkrantz and Klopman 1990). Some chemicals can exert both types of activities, and some chemicals may lead to indirect damage to DNA via, for example, the formation of oxygen radicals.

Suggested Citation:"3 Synthetic Carcinogens in the Diet." National Research Council. 1996. Carcinogens and Anticarcinogens in the Human Diet: A Comparison of Naturally Occurring and Synthetic Substances. Washington, DC: The National Academies Press. doi: 10.17226/5150.
×

Genotoxic chemicals, either directly or after metabolic activation, form DNA adducts, some of which lead to mutations (Williams and Weisburger 1986, Tennant et al. 1987, Reitz et al. 1988, Harris 1990, Rosenkrantz and Klopman 1990). A spectrum of mutation patterns in specific genes has been ascertained for some carcinogens, such as aflatoxin (Harris 1993). Several methods have been developed for assessing exposure of individuals to chemicals based on their formation of specific DNA adducts (Choy 1993, Weinstein et al. 1995). These methods, which include 32P-postlabeling, immunochemical assays, and mass spectroscopy, have led to the quantitation of potency in animals and in humans. In addition, surrogate markers have also been used to estimate exposures of individuals to various chemicals. Examples of these markers include adduct formation with various proteins, particularly hemoglobin and to a lesser extent albumin. When enzymes involved in the metabolic activation and inactivation of these chemicals are modified, the compounds show considerable variability in their potential for mutagenicity and carcinogenicity. This variability has been specifically defined in only limited cases and is a major area for continued investigation (Sipes and Gandolfi 1986).

Nongenotoxic chemicals may affect the carcinogenic process by modifying the number of cell divisions per unit time, but other mechanisms may also play a role. This modification can be accomplished by any of several mechanisms, including direct mitogenesis, cytotoxicity followed by regenerative hyperplasia, inhibiting apoptosis, inhibiting differentiation, or a combination of these processes (Cohen and Ellwein 1990, 1991, 1992). The DNA errors arising during cell replication can occur secondarily to a variety of possible endogenous mechanisms, including oxidative damage, depurination and depyrimidination, deamination, formation of exocyclic adducts (possibly secondary to oxidative damage or lipid peroxidation), defects in DNA repair, indirect chromosomal aberrations, and other mechanisms yet to be defined. Nongenotoxic chemicals can be more broadly divided into those that interact with specific receptors

Suggested Citation:"3 Synthetic Carcinogens in the Diet." National Research Council. 1996. Carcinogens and Anticarcinogens in the Human Diet: A Comparison of Naturally Occurring and Synthetic Substances. Washington, DC: The National Academies Press. doi: 10.17226/5150.
×

on cells, such as hormones, dioxin, and phorbol esters, and those that interact with cells through nonreceptor-mediated processes, such as phenobarbital, sodium saccharin, or d-limonene (Cohen and Ellwein 1990). Many of the nongenotoxic chemicals, especially those acting through specific receptors, alter signal transduction and gene expression. Chemicals that alter gene expression tend to be tissue-specific and frequently species-specific. Chemicals can clearly have more than one of the effects described above.

Because multiple genetic errors are required before malignancy will develop, several multistage models of carcinogenesis have been developed. The first of these models was the initiation-promotion model of Berenblum and Shubik (1947), which was later modified to include the stage of progression (Boutwell 1964). On the basis of this model, the effects of a chemical have been classified in terms of initiation, promotion, or progression. However, when they are completely evaluated, chemicals usually exhibit more than one of these effects, and even single doses of potent carcinogens, such as aflatoxin B1 or diethylnitrosamine, can induce cancer in rodent models. Although the terms initiation, promotion, and progression continue to be used in the field of carcinogenesis, it is difficult to define these stages in many model systems, in studies involving chemical mixtures, or in human carcinogenesis. Nevertheless, numerous authors use the term initiation to mean genotoxicity and promotion to mean nongenotoxic events.

Other multistage models of carcinogenesis have been presented. Armitage and Doll (1954) postulated a sequence of multiple genetic events occurring over time, with the incidence increasing proportionally to an exponent of time, the exponent being defined by one less than the number of stages in the carcinogenic process. Although this model was derived from epidemiologic studies and fits well with most human cancer types, it does not fit the age-specific mortality data for some cancers, such as childhood cancers, Hodgkin's disease, and breast cancer.

To account for these latter anomalies, models involving not only

Suggested Citation:"3 Synthetic Carcinogens in the Diet." National Research Council. 1996. Carcinogens and Anticarcinogens in the Human Diet: A Comparison of Naturally Occurring and Synthetic Substances. Washington, DC: The National Academies Press. doi: 10.17226/5150.
×

genetic errors but cell populations and replication have been developed (Knudson 1971, Moolgavkar and Knudson 1981, Greenfield et al. 1984, Cohen and Ellwein 1990, 1991). Numerous examples of multiple genetic errors in carcinogenesis have been established in animal models and in humans with the use of powerful molecular biological techniques. Also, it is still unclear which genes are directly involved in carcinogenesis and which are related to increased susceptibility to the development of the critical DNA mistakes that occur in carcinogenesis (Cohen and Ellwein 1990, 1991, 1992).

The evidence to date suggests that the processes of carcinogenesis are similar for natural and synthetic chemicals. A combination of approaches used in cell and molecular biology, pharmacokinetics, biochemistry, and in chemistry should continue to provide insight into the overall carcinogenic process in animals and in humans. The committee accepts the concept of multistage carcinogenesis, but because of the difficulties associated with the initiation-promotion-progression model, especially in applying it to human carcinogenesis, we have chosen to use the terms genotoxic and nongenotoxic in referring to specific agents.

Metabolism

The biotransformation of xenobiotics involves phase I (oxidation, reduction, and hydrolysis) or phase II (conjugative) reactions (Bridges and Chasseaud 1976, Testa and Jenner 1976, Jenner and Testa 1981). In many cases, the parent compound may not undergo phase I biotransformation if it has a functional group available for conjugation. For example, glucuronidation is the major metabolic pathway for acetaminophen and naturally occurring morphine. Similarly, reactions such as mercapturic acid formation and sulfation are common in humans. It should be noted that interspecies variations are extensive, as are interindividual variations,

Suggested Citation:"3 Synthetic Carcinogens in the Diet." National Research Council. 1996. Carcinogens and Anticarcinogens in the Human Diet: A Comparison of Naturally Occurring and Synthetic Substances. Washington, DC: The National Academies Press. doi: 10.17226/5150.
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particularly in humans. Furthermore, it has been apparent for many years that metabolism of xenobiotics may be a detoxication event or, through the production of reactive intermediates, an activation event that increases toxicity.

Cytochrome P450 is the principal enzyme involved in the phase I metabolism of xenobiotics. It is located in the endoplasmic reticulum and is found in many living organisms. Over two hundred isozymes have been identified (Degtyarenko and Archakov 1993, Nelson et al. 1993). These isozymes have broad but different specificities that frequently overlap. Isozyme distribution differs between species, organs, and developmental stages. A unique feature of the cytochrome system is its induction by specific chemicals. Other phase I enzymes include the flavin-containing mono-oxygenase, also located in the endoplasmic reticulum, the molybdenum hydroxylases (e.g., aldehyde oxidase and xanthine oxidase), alcohol and aldehyde dehydrogenases, esterases and amidases, and peroxidases and epoxide hydrolase. Xenobiotics may also be cooxidized by prostaglandin synthetase (Hodgson and Levi 1994). It should be noted that Phase I reactions may result in the formation of free radical and other reactive intermediates.

Phase II reactions involve the conjugation of endogenous intermediates with phase I metabolites or the conjugation of the parent compound itself. Phase II enzymes include UDP-glucuronyltransferase, UDP-glucosyltransferase, sulfotransferase, acetyltransferase, methyltransferase, acyltransferases (which affect amino acid conjugation) and glutathione S-transferase (Dauterman 1994).

It is not surprising that the metabolic pathways involved in the biotransformation of both synthetic and naturally occurring chemicals are similar. It is possible that these pathways developed in response to naturally occurring chemicals and offered some selective advantage to organisms capable of detoxifying xenobiotics. However, it must be stressed that biotransformation reactions may lead to bioactivation, especially to the formation of reactive metabolites that may alkylate DNA, thereby initiating the carcinogenic process.

Suggested Citation:"3 Synthetic Carcinogens in the Diet." National Research Council. 1996. Carcinogens and Anticarcinogens in the Human Diet: A Comparison of Naturally Occurring and Synthetic Substances. Washington, DC: The National Academies Press. doi: 10.17226/5150.
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An example of a reaction leading to both detoxication and activation is the metabolism of ethanol, a natural product of fermentation, to acetaldehyde by alcohol dehydrogenase. This metabolism terminates the action of ethanol on the central nervous system. However, the metabolite acetaldehyde may cause some of the other toxic effects associated with ethanol before it, in turn, is metabolically detoxified to acetate. This same enzyme, alcohol dehydrogenase, is involved in the metabolism of other simple alcohols and glycols such as the antifreeze ethylene glycol. A variety of esterases are also important in the metabolism of both natural and synthetic compounds, including drugs (e.g., aspirin, meperidine, acetanilide, and procaine), and pesticides (e.g., permethrin, malathion, and paraoxon) (Hayes and Laws 1991), chemicals of environmental concern such as plasticizers (e.g., diethylhexylphthalate), and natural compounds (e.g., the alkaloid arecoline) (Testa and Jenner 1976).

Most phase I metabolic reactions involve microsomal mono-oxygenases. Ring hydroxylations, such as those associated with benzene and its derivatives (e.g., the moth repellent p-dichlorobenzene), and with drugs like the barbiturate phenobarbital and the antipyretic acetanilide, are extremely common. Side chain oxidations are also common phase I reactions. Examples include the hydroxylation of the N-methyl group of the pesticide carbaryl and the metabolic schemes for pentobarbital, riboflavin (vitamin B2), and pyrethrin, a natural pesticide.

Other common, metabolic pathways shared by natural and synthetic chemicals include epoxidations and dealkylations (Oritz de Montellano 1985). With respect to the first, epoxides may subsequently be metabolized to diols by epoxide hydrolases. A number of epoxides or diol epoxides have been shown to bind to DNA to form adducts. For example, aflatoxin B1 undergoes metabolic activation to an epoxide that can bind to DNA or protein, or can react with glutathione, a detoxification process (IARC 1993). Naphthalene is an example of another aromatic compound that undergoes

Suggested Citation:"3 Synthetic Carcinogens in the Diet." National Research Council. 1996. Carcinogens and Anticarcinogens in the Human Diet: A Comparison of Naturally Occurring and Synthetic Substances. Washington, DC: The National Academies Press. doi: 10.17226/5150.
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metabolic activation to a reactive intermediate. Epoxidations can also occur with double bonds in non-aromatic rings such as with the marihuana constituent 9-tetrahydrocannabinol (Testa and Jenner 1976). Other chemicals that undergo side chain or alkene epoxidations include the synthetic chemicals 4-vinylcyclohexene (Smith et al. 1990), butadiene (Malvoisin and Roberfroid 1982), and naturally occurring d-limonene (IARC 1993). In addition, resulting epoxides may then undergo further phase II conjugation reactions. It should be noted, however, that not all epoxides are reactive. Dieldrin, the epoxide metabolite of aldrin, is quite stable.

Examples of dealkylations, the other common reaction shared by natural and synthetic compounds, include atrazine, one of the most widely used herbicides in the United States, which is N-dealkylated, nicotine, which is dealkylated to nornicotine, and the drug tamoxifen, which is also N-dealkylated (Jansen and de Fluiter 1992). O-Dealkylations encompass a wide range of compounds, including synthetics such as p-nitroanisole, phenacetin, and the pesticide methoxychlor, and the naturally occurring compounds scoparone (6,7-dimethylcoumarin), rotenone, and thebaine (Testa and Jenner 1976).

Less common reactions include deamination and dehydroxylation. Chemicals that undergo deamination include amphetamine and mescaline (Testa and Jenner 1976). Dehydroxylation is postulated to occur in vivo by gut bacteria. Such reactions are important in the metabolism of catechols such as the naturally occurring caffeic acid (IARC 1993), which can also be detoxified via glucuronide conjugation. Many other reactions can occur but are of lesser importance and are not covered here.

One of the factors that tends to make chemicals resistant to metabolism by mammalian organisms is the presence of chlorine groups. However, dechlorination can occur (such as with the pesticide DDT or with the herbicide atrazine), even in mammalian systems. Of particular concern are highly halogenated synthetic chemicals such as hexachlorobenzene and the PCBs (polychlorinated

Suggested Citation:"3 Synthetic Carcinogens in the Diet." National Research Council. 1996. Carcinogens and Anticarcinogens in the Human Diet: A Comparison of Naturally Occurring and Synthetic Substances. Washington, DC: The National Academies Press. doi: 10.17226/5150.
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biphenyls). Dechlorination of these chemicals can be very slow. Structure-activity relationships indicate that PCBs with vicinal-substituted carbons are highly resistant to epoxidation by metabolizing enzymes. Similar arguments can be made for other chlorinated chemicals, such as the dibenzo-p-dioxins and dibenzofurans.

A number of halogenated compounds are natural products (Neidleman and Geigert 1986, Gribble 1992, Willes et al. 1993). Over 1500 halogenated compounds have been identified in marine organisms, more than 250 in red algae alone. Chlorinated compounds are formed in bacteria, algae, fungi, ferns, higher plants, and even lower animals. These compounds, chlorinated via chloroperoxidases, may be quite complex (e.g., chlortetracycline), but the degree of chlorination and, therefore, resistance to metabolism is generally not as great as for synthetic chemicals.

Toxicological Comparisons

In this section, toxicological comparisons are made between chemically related synthetic and naturally occurring chemicals, some of which are known to be carcinogenic. Classes of related compounds discussed include peroxisome proliferators, nitrosamines, hydrazines, phenolic antioxidants, methylene dioxyphenyl (benzodioxole) compounds, sodium salts, aromatic amines and related chemicals, and 2u-globulin binding compounds.

Nitrosamines

Several nitrosamines occur naturally in our environment. Others can be formed endogenously (IARC 1978, 1982). For example, ingested nitrites interact with amines in the acid conditions of the mammalian stomach to form nitrosamines (Sander et al. 1968). Nitrates are reduced to nitrites by bacteria, especially in saliva.

Suggested Citation:"3 Synthetic Carcinogens in the Diet." National Research Council. 1996. Carcinogens and Anticarcinogens in the Human Diet: A Comparison of Naturally Occurring and Synthetic Substances. Washington, DC: The National Academies Press. doi: 10.17226/5150.
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Nitrites from swallowed saliva or from the diet can produce nitrosamines in the stomach (NRC 1981, Kyrtopoulos 1989, Leaf et al. 1989). Because of this, the use of nitrites and nitrates as additives to foods such as meat and fish is strictly regulated. Secondary and tertiary amines, N-alkylamides (including peptides), ureas, carbamates, and guanidines can all be nitrosated (Mirvish 1975, Shepherd and Lutz 1989). Some of these compounds occur ubiquitously in nature, while others are synthetic agricultural chemicals and drugs. For example, the drug aminopyrine reacts readily with traces of nitrosating agents, including gaseous nitrogen oxides, resulting in the formation of dimethylnitrosamine, traces of which have been found in the drug itself (Eisenbrand et al. 1978). The amount of N-nitroso compounds (nitrosamines and nitrosamides) formed by nitrosation depends upon nitrite concentration, the concentration and basicity of the amine or amide, and pH. The presence of nucleophilic ions such as thiocyanates increases the rate of N-nitrosamine formation (Fan and Tannenbaum 1973, NRC 1981). In contrast, ascorbic acid, -tocopherol, and various phenolic compounds inhibit the formation of N-nitrosamines (Mirvish 1975, 1981, 1994; Morgens et al. 1978). Nitroso compounds are also contaminants in foodstuffs, alcoholic beverages, and cosmetics (Tricker et al. 1989). Tobacco contains several nitrosamines and nitrosatable amines, which are formed during the curing and burning of the product. These compounds appear to be significant carcinogens in the induction of various cancers in humans exposed to tobacco smoke and other tobacco products (Hecht and Hoffman 1989). Nitrosation also occurs in soils, organic waste, and water, where industrial and other discharges contain large amounts of amines.

Nitrosamines require metabolic activation for expression of mutagenic and carcinogenic activity. The cytochrome P-450s are responsible for this activation by hydroxylation at the -carbon of the alkyl substituents (Okada 1984, Yang et al. 1984, Archer 1989). The alkyldiazohydroxide intermediates that are formed readily alkylate

Suggested Citation:"3 Synthetic Carcinogens in the Diet." National Research Council. 1996. Carcinogens and Anticarcinogens in the Human Diet: A Comparison of Naturally Occurring and Synthetic Substances. Washington, DC: The National Academies Press. doi: 10.17226/5150.
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proteins and nucleic acids. The possibility that traces of nitrosamines pose a cancer risk for humans has yet to be proved, but certain correlations suggest that target N-nitroso compounds are involved in the etiology of gastric, esophageal, and nasopharyngeal cancers and possibly others (Magee 1989). Childhood leukemia and brain cancer were recently associated with nitrite-preserved hot dogs consumed by children or their parents, but it was unclear whether hot dogs were the primary factor or merely a factor indicative of a low socio-economic status (Bunin et al. 1994, Peters et al. 1994, Sarasua and Savitz 1994). Many target organs in a variety of animal species are susceptible to the carcinogenic action of N-nitroso compounds. Human tissues and cytochrome P-450s can bioactivate nitrosamines to mutagenic intermediates that form adducts with tissue constituents (Hoffman and Hecht 1985). Of the variety of alkyl products formed, the O-alkylations of guanine and thymine are mutagenic, and their formation is associated with the carcinogenic potential of the compound or with the mutagenic susceptibility of the specific organ (Singer 1985).

Although certain nitrosamines have been synthesized for commercial use, they may also occur naturally. For example, dimethylnitrosamine was used in the synthesis of dimethylhydrazine, but it has also been found in a variety of food products (as discussed above). There is no evidence to suggest differences in the properties of naturally occurring versus synthetic nitrosamines.

Hydrazines

Humans are exposed to naturally occurring and synthetic hydrazines with known mutagenic and carcinogenic potential (Toth 1975). Exposure to these chemicals occurs because of their widespread use by the agricultural, pharmaceutical, aerospace and petroleum industries, and because a number of hydrazine derivatives occur naturally. For example, Toth (1991) reported on 11 hydrazine analogs that were identified in 22 species of mushrooms, one

Suggested Citation:"3 Synthetic Carcinogens in the Diet." National Research Council. 1996. Carcinogens and Anticarcinogens in the Human Diet: A Comparison of Naturally Occurring and Synthetic Substances. Washington, DC: The National Academies Press. doi: 10.17226/5150.
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of which is cultivated. Another natural source of hydrazine is tobacco and tobacco smoke, which have been shown to contain hydrazine and 1,1-dimethylhydrazine.

The carcinogenic properties of natural and synthetic hydrazines are similar with respect to organotropism (Toth 1980). For example, when administered orally to mice, phenylhydrazine (synthetic) and 4-methylphenylhydrazine (natural) produce tumors of the lungs and blood vessels. Methylhydrazine, which is produced synthetically but also occurs naturally, produces pulmonary adenocarcinomas in Swiss mice and histiocytomas of the liver and tumors of the cecum in Syrian golden hamsters (Toth 1984). Tissue localization depends upon the animal species tested, the route of administration, the dose, and the hydrazine derivative.

The carcinogenic properties of hydrazines may be a result of their enzymatic activation. A number of enzyme systems have been shown to metabolize hydrazine derivatives. These include cytochrome P450, the flavin-containing mono-oxygenase, and monoamine oxidase. The substituents on the hydrazine moiety determine its metabolic fate. For example, monosubstituted hydrazines and 1,2-disubstituted hydrazines are predominantly metabolized by cytochrome P450 (Prough and Maloney 1985). The metabolism of 1,1-disubstituted hydrazines is catalyzed largely by the flavin-containing mono-oxygenase (Prough and Maloney 1985).

The metabolism of hydrazine derivatives can lead to a variety of chemically reactive species, including diazines, diazonium ions, and carbon-centered radicals (Gannett et al. 1991, Albano et al. 1993). It has been postulated that radicals formed during the enzymatic activation of hydrazine and hydrazine derivatives may subsequently bind to DNA to form adducts (Gannett et al. 1991). Such alterations can result in miscoding upon DNA replication. The enzymatic activation of N-methyl-N-formylhydrazine, a naturally occurring hydrazine, results in the formation of such radicals (Gannett et al. 1991). Thus the formation of DNA adducts may be the initial event in the carcinogenicity of N-methyl-N-formylhydrazine.

Like synthetic hydrazines, naturally occurring hydrazines have

Suggested Citation:"3 Synthetic Carcinogens in the Diet." National Research Council. 1996. Carcinogens and Anticarcinogens in the Human Diet: A Comparison of Naturally Occurring and Synthetic Substances. Washington, DC: The National Academies Press. doi: 10.17226/5150.
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been shown to be mutagenic. The role of metabolic activation in the mutagenicity of hydrazines (natural or synthetic) is questionable, since many hydrazines are mutagenic in the absence of S-9 mix. In fact, the mutagenicity of many hydrazines is inhibited by the presence of S-9 mix or bovine serum albumin (Matsushita et al. 1993).

Methylenedioxyphenyl Compounds

Methylenedioxyphenyl (benzodioxole) compounds (MDPs) occur widely in plants. Among the dietary sources of MDPs are parsnips, carrots, nutmeg, sesame seeds (and sesame seed oil), pepper, and sassafras. Synthetic derivatives of these compounds are used commercially for insecticide synergists. The principal synthetic MDP used as a synergist is piperonyl butoxide (Hodgson and Philpot 1974). Although it is not widely used on crops, it is frequently included in aerosol preparations for household use.

In mammals, MDPs affect multiple enzyme pathways; the effect on the cytochrome P450 system has been the most studied (Goldstein et al. 1973, Hodgson and Philpot 1974). MDPs have been shown to inhibit P450-mediated metabolism and to induce several P450 isozymes (Fujii et al. 1970, Wagstaff and Short 1971, Hodgson and Philpot 1974, Thomas et al. 1983, Yeowell et al. 1985, Lewandowski et al. 1990). As inhibitors of P450 activity, MDPs have been used extensively with the pyrethroid and carbamate insecticides; the metabolism of these insecticides is, in large part, P450-mediated (Haley 1978). It has been postulated that inhibition of P450 activity leads to the formation of a stable inhibitory complex between the heme iron of P450 and the carbene species formed when water is cleaved from the hydroxylated methylene carbon of the MDP (Dahl and Hodgson 1979). While the 3,4-methylenedioxyphenyl group is essential for activity, the relative effectiveness varies with the nature of the side chains in the 1 and

Suggested Citation:"3 Synthetic Carcinogens in the Diet." National Research Council. 1996. Carcinogens and Anticarcinogens in the Human Diet: A Comparison of Naturally Occurring and Synthetic Substances. Washington, DC: The National Academies Press. doi: 10.17226/5150.
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6 positions, a long, lipophilic side chain favoring the formation of a more stable inhibitory complex. Thus the development of commercial synergists involves the addition of a lipophilic side chain to naturally occurring MDPs.

Naturally occurring MDPs and their synthetic derivatives induce various isozymes of the P450 system. In studies conducted with mice, MDPs have been shown to induce P450 1A2 by an Ah receptor-independent mechanism as well as P450 2B10. They also induce P450 1A1, but only at doses higher than those necessary for the first two inductions named. Although extensive structure-activity studies have not been carried out, it appears that the MDP group is essential for this particular pattern of induction; however, the extent of induction varies with other molecular characteristics (Cook and Hodgson 1985, 1986; Murray et al. 1985; Adams et al. 1994).

Some naturally occurring and synthetic MDPs are known to be carcinogenic at high-dose levels. Safrole (5-(2-propenyl)-1,3-benzodioxole), a naturally occurring MDP found in black pepper and oil of sassafras, has been used in flavoring and perfume. It has been shown to be a hepatocarcinogen in animal studies, causing liver tumors at a dietary concentration of 0.5 percent. The active metabolite appears to be the sulfate ester of the 1'-hydroxy derivative (Homberger et al. 1961, Long et al. 1963, Ioannides et al. 1981).

Piperonyl butoxide (alpha(2-(2-butoxyethoxy)ethoxy)-4,5-methyl-enedioxy-2-propyltoluene) tested negative in early tests for carcinogenicity and mutagenicity, but recent long-term feeding studies have demonstrated hepatocellular carcinoma in both male and female F344 rats. However, the lowest effective dose was 1.2% of the diet, some 400,000 times the ADI for humans (Takahashi et al. 1994).

In summary, naturally occurring and synthetic MDPs appear to be attractive models for comparing natural and synthetic carcinogens. There are, however, significant data gaps and unanswered questions. These include the following: 1) Is the MDP group irrelevant to the carcinogenicity of safrole and piperonyl butoxide,

Suggested Citation:"3 Synthetic Carcinogens in the Diet." National Research Council. 1996. Carcinogens and Anticarcinogens in the Human Diet: A Comparison of Naturally Occurring and Synthetic Substances. Washington, DC: The National Academies Press. doi: 10.17226/5150.
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with side chain substituents being of greater, or sole, importance? 2) Is suitability for metabolism to a sulfate ester the critical parameter? 3) Does rendering the molecule more lipophilic and, therefore, more persistent, make the potential for carcinogenicity greater? 4) Do the high-dose levels required make this an inappropriate model? 5) Given the wide distribution of MDP compounds and the potential for additive effects, are high doses likely to be reached in any case? In spite of these data gaps and unanswered questions, two factors suggest that these compounds require further study: one, the potential for human exposure to naturally occurring and synthetic MDPs and two, MDPs induce and inhibit P450 isozymes, which are often involved in the early stages of carcinogeneses.

Aromatic Amines and Related Chemicals

Aromatic amines are among the earliest class of chemicals suggested to be potential human carcinogens. This idea was based on observations by Rehn in 1895 that workers in the aniline dye industry in Germany had an increased risk of developing bladder cancer (Miller and Miller 1983). Subsequently, several aromatic amines were identified as human bladder carcinogens, including 2-naphthylamine, benzidine, and 4-aminobiphenyl, as well as related chemicals such as benzidine dyes and phenacetin. Much of what is known today about the metabolic activation and inactivation of chemical carcinogens is the result of investigations conducted on 2-acetylaminofluorene.

More recently, numerous polycyclic, heterocyclic aromatic amines have been identified as pyrolysis products resulting from the cooking of foods at very high temperatures (Wakabayashi et al. 1992). Aromatic amines, such as 4-aminobiphenyl and o-toluidine, have also been detected in cigarette smoke (Vineis et al. 1994).

The metabolism of the synthetic and naturally occurring aromatic amines are similar (Miller and Miller 1983, Wakabayashi et

Suggested Citation:"3 Synthetic Carcinogens in the Diet." National Research Council. 1996. Carcinogens and Anticarcinogens in the Human Diet: A Comparison of Naturally Occurring and Synthetic Substances. Washington, DC: The National Academies Press. doi: 10.17226/5150.
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al. 1992, Snyderwine et al. 1993, Vineis et al. 1994). Enzymatic activation occurs through N-hydroxylation. The metabolic intermediates thus formed may then undergo phase II conjugation to form various esters, such as sulfates, glucuronides, and acetyl derivatives, and they may covalently bind to DNA (usually to C8 of guanine) to form adducts.

The mutagenic potential of many aromatic amines has been demonstrated in vitro using prokaryotic assays, and several amines have subsequently been shown to be carcinogenic in rodent bioassays and in nonhuman primates. Among the pyrolysis products are included 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP).

Depending on the chemical, route of administration, species, and strain, these chemicals produce tumors predominantly of liver, mammary gland, bladder, and colon in rodents, the urinary bladder in dogs, and the liver in nonhuman primates. Epidemiologic studies have associated them only with the formation of urinary bladder cancer in humans, but recent animal experimental evidence suggests that aromatic amines may also be associated with other tumor types, such as colon cancer (Ito et al. 1991). Evidence indicates that naturally occurring and synthetic aromatic amines have similar potencies in both in vitro assays and rodent carcinogenicity bioassays.

Peroxisome Proliferators

Several compounds of diverse chemical structure (Reddy and Rao 1992, Gibson 1993) are known to induce peroxisome proliferation. These include fibric acid derivatives such as clofibrate, gemfibrizol, and ciprofibrate which are used as hypolipidemic agents; other unrelated drugs such as valproic acid and chlorcyclizine; phthalate ester plasticizers, notably di-2-ethylhexylphthalate; herbicides such as 2,4-dichlorophenoxyacetic acid; and simple compounds such as

Suggested Citation:"3 Synthetic Carcinogens in the Diet." National Research Council. 1996. Carcinogens and Anticarcinogens in the Human Diet: A Comparison of Naturally Occurring and Synthetic Substances. Washington, DC: The National Academies Press. doi: 10.17226/5150.
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trichloroacetic acid (Moody et al. 1991). While these agents cause morphological effects in a number of tissues, the primary target organ is the liver, where they cause hypertrophy, hyperplasia, and peroxisome proliferation. The latter is preceded by an increase in the enzymes involved in fatty acid -oxidation and, to a lesser extent, in catalase (Lock et al. 1989). In addition, peroxisomal proliferators also induce drug metabolizing enzymes (most notably glucuronyl transferase, epoxide hydrolase, and cytochrome P450 4A1), stimulate growth factors, and activate oncogenes (Bieri 1993).

Hepatocarcinogenicity is the primary toxicity of concern associated with peroxisomal proliferators, especially in rodents such as rats and mice. The mechanism responsible for hepatocarcinogenicity is not clear because these chemicals are routinely negative in genotoxicity tests. The pleiotropic response following the administration of peroxisome proliferators appears to be related to their activation of a novel steroid hormone receptor, the peroxisome proliferator-activated receptor (PPAR). Tumorigenicity may ultimately be related to the oxidative stress that results from the enhanced peroxisomal fatty acid oxidation and the concomitant hydrogen peroxide synthesis. Alternatively, these chemicals may enhance cellular replication of hepatocytes, especially cells in foci, since in some studies the degree of sustained DNA replication has been found to be highly correlated with tumorigenicity rather than with peroxisome proliferation (Green et al. 1992).

A limited number of natural products, such as phytol—a decomposition product of chlorophyll—have been investigated for their potential to induce peroxisome proliferation (Watanabe and Suga 1983, Van den Branden et al. 1986). High fat diets, vitamin E deficiency, and diabetes can also produce peroxisome proliferation in rodents (Moody et al. 1991). The role of peroxisomal proliferators in human carcinogenesis is not clear, since peroxisome proliferation does not occur in humans (Blumcke et al. 1983, Hanefeld et al. 1983). Nevertheless, humans do respond to these agents (e.g., with hypolipidemia following treatment with the fibric acid derivatives)

Suggested Citation:"3 Synthetic Carcinogens in the Diet." National Research Council. 1996. Carcinogens and Anticarcinogens in the Human Diet: A Comparison of Naturally Occurring and Synthetic Substances. Washington, DC: The National Academies Press. doi: 10.17226/5150.
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and they, like rodents, possess PPARs that are sensitive to activation.

Phenolic Antioxidants

Butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) are synthetic chemicals used as food antioxidants. They have been widely used to preserve foods, particularly oils, fats, and shortenings, which are subject to oxidative deterioration and rancidity (Verhagen et al. 1991). Although BHA and BHT are compounds with low acute toxicity, they are known to alter the activities of enzymes involved in the activation/detoxification of xenobiotics. For example, the activities of glutathione-S-transferase, epoxide hydrolase, glucuronyl transferase, and cytochrome P-450 are all increased in rats and/or mice after BHA or BHT is administered. Because these enzymes are often involved in the activation and detoxification of chemicals, it is not surprising that they have been shown to modify the toxicological response of a variety of chemicals. BHA reduces liver damage caused by bromobenzene, acetaminophen, and CCl4 in mice, and protects the rat adrenal gland from dimethylbenz[a]anthracene-induced necrosis (Kahl 1984, Stich 1991). Many similar types of protective effects have been observed in other tissues. Most relevant to this discussion are the tumorigenic and antitumorigenic actions of these antioxidants.

BHA suppresses the development of DMBA-initiated tumors of the lung, forestomach, and mammary gland (Kahl 1984, Stich 1991). It has also been shown to suppress skin tumors initiated by DMBA and promoted by TPA. In several studies, BHA and BHT have been shown to be effective against other carcinogens. For example, both chemicals inhibited the hepatocarcinogenesis of concurrently-administered aflatoxin B1 (Williams et al. 1986). BHT also reduced the incidence of N-hydroxy-N-2-fluor-enylacetamide-induced hepatomas (in male rats) and mammary

Suggested Citation:"3 Synthetic Carcinogens in the Diet." National Research Council. 1996. Carcinogens and Anticarcinogens in the Human Diet: A Comparison of Naturally Occurring and Synthetic Substances. Washington, DC: The National Academies Press. doi: 10.17226/5150.
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cancer (in female rats) (Ulland et al. 1973). However, these potentially beneficial effects of BHA and other synthetic antioxidants became questionable when it was reported that they induced carcinomas of the forestomach in rats and hamsters (Ito et al. 1983, 1985). A subsequent study showed that feeding of high-dose levels of BHA to rats enhanced the development of N-methyl-N'-nitro-N-nitrosoguanidine-initiated squamous cell neoplasms of the forestomach (Ito et al. 1985).

Naturally occurring antioxidants produce similar types of effects. Caffeic acid, a phenolic antioxidant found in several fruits and vegetables, is both tumorigenic and antitumorigenic, as discussed in Chapter 2 (IARC 1993, Stich 1991). Dietary administration of caffeic acid at doses comparable to those used with BHA resulted in squamous cell papillomas and carcinomas of the forestomachs of mice and rats. Caffeic acid also increased the incidence of papillomas of the forestomach in rats treated with DMBA as an initiating agent (Hirose et al. 1988). In another study, when caffeic acid was administered before and with benzo(a)pyrene, it decreased the incidence of forestomach tumors induced by benzo[a]pyrene (Wattenberg et al. 1980). Similar effects have been reported for other naturally occurring antioxidants. For example, catechol induces cell proliferation and is active as a glandular stomach carcinogen (Stich 1991).

The above discussion documents that synthetic and naturally occurring antioxidants behave similarly when tested at high doses for tumorigenic and antitumorigenic effects. The ultimate outcome depends on the amount of exposure the animals received. However, it is clear that synthetic and naturally occurring phenolic antioxidants are tumorigenic in rodents, when given at high doses. The implications for human risk, however, remain poorly defined, although a recent expert panel questioned the relevance of the BHA rodent carcinogenesis results to humans (FASEB 1994).

Suggested Citation:"3 Synthetic Carcinogens in the Diet." National Research Council. 1996. Carcinogens and Anticarcinogens in the Human Diet: A Comparison of Naturally Occurring and Synthetic Substances. Washington, DC: The National Academies Press. doi: 10.17226/5150.
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Sodium Salts and Rodent Urinary Tract Carcinogenesis

Sodium saccharin (Ellwein and Cohen 1990) is an artificial sweetener which was found to produce urothelial carcinomas in rats when high doses were given beginning at birth or earlier. It did not produce cancer when administration started at 6-8 weeks of age (as in a standard 2-year bioassay). The male rat appeared to be more susceptible than the female and no proliferative or tumorigenic effects were found in mice, hamsters, guinea pigs, or monkeys. IARC has found the evidence for carcinogenicity to animals for saccharin sufficient; however, the evidence for effects in humans is inconclusive (IARC 1987) and is consistent with two possibilities, first that it does not cause human bladder cancer, and second that it is a very weak cause cause of human bladder cancer (Armstrong 1985)

Research on saccharin (Ellwein and Cohen 1990) indicates that it is not metabolized, is nucleophilic rather than electrophilic (pKa of approximately 2.0), and is absorbed and largely excreted in the urine within hours of consumption. At the level of approximately 1.0% of the diet, it has been shown to have no effect on proliferation, tumor enhancement, or carcinogenicity. Acidification of the urine below pH 6.5 results in inhibiting the proliferative and tumorigenic effects of saccharin. Similarly, administration of certain forms of saccharin, such as calcium or acid saccharin, which produce acidic urine, has no effect on the rat urothelium. However coadministration of calcium saccharin with alkalinizing substances results in the appearance of proliferative effects. The proliferative and tumorigenic effects associated with high doses of sodium saccharin appear due to the formation of a urinary amorphous precipitate. This precipitate is largely calcium phosphate, but it also contains saccharin, protein, silicates, potassium, chloride, and acidic mucopolysaccharides (Cohen et al. 1991, 1993). It is not clear how

Suggested Citation:"3 Synthetic Carcinogens in the Diet." National Research Council. 1996. Carcinogens and Anticarcinogens in the Human Diet: A Comparison of Naturally Occurring and Synthetic Substances. Washington, DC: The National Academies Press. doi: 10.17226/5150.
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the precipitate is formed or how it causes its toxic effect. In addition, studies of how sodium saccharin acts in the rat have raised questions about the underlying assumptions of cancer risk assessment, including the basic assumptions of high to low-dose extrapolation and interspecies extrapolation from rodents to humans (Fukushima et al. 1986, Cohen and Ellwein 1990, 1991).

Most sodium salts, administered at high doses, produce urothelial proliferative and tumorigenic effects in the male rat similar to those of sodium saccharin, providing that the urinary pH is approximately 6.5 or greater (Ellwein and Cohen 1990, Cohen and Ellwein 1992). For example, sodium ascorbate, which has been extensively studied, produces effects similar to those produced by sodium saccharin at comparable doses (approximately 5% of the diet), including effects of urinary acidification and alkalinization (Ellwein and Cohen 1990). Other sodium salts which have produced similar effects in male rats at comparably high doses include glutamate (DeGroot et al. 1988), aspartate, citrate, erythorbate, succinate, phosphate, bicarbonate (Lina et al. 1994), and to a limited extent, chloride. All produce a urinary amorphous precipitate similar to that seen with sodium saccharin (Cohen et al. 1995). Lack of effects can also be similar.

Like sodium saccharin, sodium ascorbate does not affect the urothelium of the mouse (Tamano et al. 1993). It should be noted that all these substances other than saccharin are naturally occurring, and several are essential to human survival. Several are also generated endogenously as part of intermediary metabolism. Urinary concentrations of the anion when the salt is administered as 5% of the diet are approximately 200 mM. Under normal circumstances, these ions are present in the urine at lower, though still substantial, amounts. For example, serum bicarbonate is normally approximately 26 mM and tightly regulated, whereas urinary concentration can range from less than 1 mM to greater than 100 mM depending on pH (Thier 1981). Urinary chloride can range from 10 to 100 mM in rats and 40 to 250 mM in humans. Urinary

Suggested Citation:"3 Synthetic Carcinogens in the Diet." National Research Council. 1996. Carcinogens and Anticarcinogens in the Human Diet: A Comparison of Naturally Occurring and Synthetic Substances. Washington, DC: The National Academies Press. doi: 10.17226/5150.
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sodium ranges from 10 to 250 mM in rats compared with 1 to 300 mM in humans, depending on degree of hydration and numerous other factors (Cohen 1995). It is not surprising that diet greatly influences responsiveness to these chemicals. For example, administration of an AIN-76A semisynthetic diet, which produces acidic urine, completely inhibits the proliferative and tumorigenic effects of sodium saccharin (Okamura et al. 1991).

An apparent exception to the urothelial effects of the sodium salts is sodium hippurate. When administered at high levels in the diet, it produces no urothelial proliferative or tumorigenic effects in any of the species tested, including the rat (Fukushima et al. 1983, Schoenig et al. 1985). However, this lack of effect may be due to the fact that the urinary pH is consistently below 6.5 in rats fed diets high in sodium hippurate.

It also appears that potassium salts produce similar effects as the sodium salts when administered at high doses, although they are somewhat less potent (Ellwein and Cohen 1990). Most notably, potassium bicarbonate was recently shown to be carcinogenic to the rat bladder in a 30-month bioassay (Lina et al. 1994).

All of the substances discussed above are nongenotoxic and appear to produce their tumorigenic effects on the rat urothelium secondary to increased proliferation. Several other substances are known to produce bladder tumors in rats, and occasionally in mice, when administered at high doses in the diet, by causing calculi in the urine (Cohen and Ellwein 1990, 1991, 1992). The calculi cause an erosive toxicity of the urothelium with prominent regenerative hyperplasia. Calculus-forming substances that produce cancer in rodents include numerous synthetic compounds, such as melamine, but they also include numerous, common, naturally occurring substances. Many of the latter are nutritionally essential or are products of intermediary metabolism, such as calcium phosphate, calcium oxalate, glycine, and uracil (Clayson 1974; Cohen and Ellwein 1990, 1991, 1992; Clayson et al. 1995, in press). All these compounds must be administered at doses sufficiently high to generate

Suggested Citation:"3 Synthetic Carcinogens in the Diet." National Research Council. 1996. Carcinogens and Anticarcinogens in the Human Diet: A Comparison of Naturally Occurring and Synthetic Substances. Washington, DC: The National Academies Press. doi: 10.17226/5150.
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calculus formation in the urine and ultimately increase cell proliferation and tumorigenicity. A weak association between calculi and bladder tumors has also been suggested in humans (Burin et al. 1995, in press). The implication is that there is a threshold dose below which calculi, on precipitate, will not form in the urine. Because of physical-chemical and physiologic determinants, there is a threshold for tumorigenicity for all nongenotoxic sodium salts, whether they are naturally occurring or synthetic.

a2u-Globulin Binding Compounds

a2u-Globulin interacts with certain chemicals, resulting in protein droplet formation, and ultimately in renal carcinogenesis and nephropathy. This low molecular weight protein is synthesized under androgenic control in high amounts in the liver of male rats (Borghoff et al. 1990). It also forms a reversible binding complex with certain chemicals, thus inhibiting the hydrolysis of the protein by lysosomal degradation in the proximal convoluted tubule cells of the kidney. The protein is thus accumulated and causes cellular necrosis. It is postulated that this cell death leads to a compensatory cell division and subsequently to renal tumor formation (Borghoff et al. 1990, Swenberg et al. 1989, Flamm and Lehman-McKeeman 1991). However, this process has not been observed in female rats (Alden 1986), male NCI-Black-Reiter rats (Dietrich and Swenberg 1991), mice, guinea pigs, dogs, or monkeys (Alden 1986), all of which are known to be deficient in the production of the a2u-globulin.

Chemicals, both synthetic and naturally occurring, which some have hypothesized act through this mechanism include unleaded gasoline (Olson et al. 1987) and 2,2,4-trimethylpentane as a surrogate (Charbonneau et al. 1987), p-dichlorobenzene (Charbonneau et al. 1989), decalin (Kanerva et al. 1987), pentachloroethane (Goldsworthy et al. 1988), perchloroethylene (Green et al. 1990),

Suggested Citation:"3 Synthetic Carcinogens in the Diet." National Research Council. 1996. Carcinogens and Anticarcinogens in the Human Diet: A Comparison of Naturally Occurring and Synthetic Substances. Washington, DC: The National Academies Press. doi: 10.17226/5150.
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isophorone (Strasser et al. 1988), and tetralin (Serve et al. 1988). Of particular interest is the monoterpene d-limonene, which is found in high amounts in citrus fruits, is the major component of oil of orange, and has been used extensively as a flavoring agent. In a two-year bioassay, it was found to cause renal tumors in male F344 rats but not in female rats or mice of either sex (NTP 1990). It has been shown to be metabolized to d-limonene-1,2-oxide which binds reversibly with a2u-globulin (Lehman-McKeeman et al. 1989). However, since it has been recognized that the formation of the a2u-globulin is specific to the male rat, these results cannot extrapolated to humans (Borghoff et al. 1990, Olson et al. 1990, Flamm and Lehman-McKeeman 1991, Borghoff et al. 1993, Hard et al. 1993). Although a number of proteins have been identified in the serum and urine of humans which share some amino acid homology with a2u-globulin, they are produced in comparatively small amounts. Furthermore, they are similar to those found in female rats and mice which, when exposed to a2u-globulin binding compounds, do not form renal tumors. Lehman-McKeeman and Caudill note that a2u-globulin may be the only member of this lipocalin protein superfamily that binds protein droplet-inducing agents (1992). An alternate hypothesis on the role of chemically induced protein droplet a2u-globulin nephropathy in renal carcinogenesis has been proposed by Melnick (1992).

Summary And Conclusions

The principles and techniques developed to evaluate the carcinogenic potential of synthetic chemicals can serve as a guide for evaluating naturally occurring chemicals found in the human diet.

Overall, the mechanisms involved in the entire process of carcinogenesis, from exposure of the organism to the expression of tumors, are similar, if not identical, between synthetic and naturally occurring carcinogens. Similar too are problems associated with

Suggested Citation:"3 Synthetic Carcinogens in the Diet." National Research Council. 1996. Carcinogens and Anticarcinogens in the Human Diet: A Comparison of Naturally Occurring and Synthetic Substances. Washington, DC: The National Academies Press. doi: 10.17226/5150.
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extrapolation between species and extrapolation between high and low doses.

Although there are differences between specific groups of synthetic and naturally occurring chemicals with respect to properties such as lipophilicity, degree of conjugation, recalcitrance to metabolism, and persistence in the body and environment, it is unlikely that information on these properties, if available, will enable predictions to be made of the degree of carcinogenicity of a naturally occurring or synthetic chemical in the diet. Both categories of chemicals—naturally occurring and synthetic—are large and diverse. Predictions based on chemical or physical properties are problematic, due to the likely overlap of values between the categories.

Given the vast number of naturally occurring chemicals, it is clear that if evaluation for carcinogenicity is to be carried out, priorities must be established. The most significant priority will be based on association with, or presence of a chemical in, foods associated with diets or life styles believed to be deleterious; however, refinements are possible based on our knowledge of synthetic carcinogens. For example, naturally occurring chemicals meeting the criteria of association with deleterious foods could be accorded a higher priority for testing if 1) they fall in the same chemical class as known carcinogens; 2) they contain chemical groups also found in known carcinogens; 3) based on structural comparisons with known carcinogens, they are likely to form reactive intermediates, in vivo; or 4) based on structural comparisons with known carcinogens, they are likely to be stable in vivo. It should be noted that all of the above aspects are susceptible to evaluation by modern QSAR (Quantitative Structure-Activity Relationship) techniques.

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Suggested Citation:"3 Synthetic Carcinogens in the Diet." National Research Council. 1996. Carcinogens and Anticarcinogens in the Human Diet: A Comparison of Naturally Occurring and Synthetic Substances. Washington, DC: The National Academies Press. doi: 10.17226/5150.
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Despite increasing knowledge of human nutrition, the dietary contribution to cancer remains a troubling question. Carcinogens and Anticarcinogens assembles the best available information on the magnitude of potential cancer risk--and potential anticarcinogenic effect--from naturally occurring chemicals compared with risk from synthetic chemical constituents. The committee draws important conclusions about diet and cancer, including the carcinogenic role of excess calories and fat, the anticarcinogenic benefit of fiber and other substances, and the impact of food additive regulation. The book offers recommendations for epidemiological and diet research. Carcinogens and Anticarcinogens provides a readable overview of issues and addresses critical questions: Does diet contribute to an appreciable proportion of human cancer? Are there significant interactions between carcinogens and anticarcinogens in the diet? The volume discusses the mechanisms of carcinogenic and anticarcinogenic properties and considers whether techniques used to evaluate the carcinogenic potential of synthetics can be used with naturally occurring chemicals. The committee provides criteria for prioritizing the vast number of substances that need to be tested. Carcinogens and Anticarcinogens clarifies the issues and sets the direction for further investigations into diet and cancer. This volume will be of interest to anyone involved in food and health issues: policymakers, regulators, researchers, nutrition professionals, and health advocates.

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