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3 Synthetic Carcinogens in the Diet
Pages 127-180

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From page 127...
... Instead, it examines how synthetic chemicals have been ac3ciressed by the toxicological and regulatory communities, anti 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.
From page 128...
... 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.
From page 129...
... 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 wale variety of sources, both natural and synthetic.
From page 130...
... Curing and Sodium nitrite, salt, sodium tripolyphosphate, pickling agents and ascorbic acid Nutrient Microemulsified protein (natural) and sucrose replacements polyesters Nutrient All essential nutrients (e.g., vitamin A and supplements other vitamins, iron and other minerals, amino acids, and essential fatty acids)
From page 131...
... , oxidizing and reducing agents (e.g., Solvents, vehicles, bulking agents, dispensing aids Sweeteners Taste and flavor modifiers (except sweeteners, salt, and pH control agents) Texture and consistency control agents hydrogen peroxide)
From page 132...
... Drinking Water Whether consumed directly or used in food processing and prep aration, drinking water is a source of potential exposure to a large
From page 133...
... SYNTHETIC CARCINOGENS IN THE DIET 133 Table 3 2 Selected Indirect Syntl~etic Food Additives tnd AcIditives Usec! in Packaginga Use Category Chemical Class or Broad Catego~ Pesticides Acaricides Algicicles Fungicicles Organosulfur compounds, formamidines, dinitrophenols, and organochlorines (DDT analogs3 Organotins Dicarboximides, chlorinated aromatics, dithiocarbamates, and mercurials Amides, acetamides, bipyridyls, carbamates, thiocarbamates, phenoxy compouncis, dinitrophenols, dinitroanilines, substituted ureas, and triazines Chlorinated hydrocarbons, chlorinated ali cyclics, cycloclienes, chlorinated terpenes, organophosphates, carbamates, thio cyanates, clinitrophenols, fluoroacetates, botanicals (nicotinoids, rotenoicis, and pyrethroicls)
From page 134...
... acljuvants A wide variety of polymers, copolymers, resins, rosins, drying oils, glycerides, fatty acicls, catalysts, colorants, solvents, and ad juncts A wide variety of polymers, copolymers, catalysts, olefins, esters, inorganic compounds, chelating agents, defoaming agents, preservatives, solvents, and adjuncts Polymers, copolymers, resins, fibers, lubricants, colors, and a~djuvants
From page 135...
... GPO 1991. The indirect additive regulations, in general, make no distinction between natu rat and synthetic ingredients, except that at several points a regulation expressly authorizes the synthetic equivalents of certain naturally occurring substances, such as fatty acids.
From page 136...
... 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 non
From page 137...
... The second source of information for assessing potential expo sure 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)
From page 138...
... In extrapolating to the approximately 38,300 community water sys tems employing about 94,600 wells ancI 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 preclictec! to have levels above the Health Advisory Limit (HAL)
From page 139...
... Pesticides have been of more concern to the public and to regula tory 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.
From page 140...
... . Hazard assessment anct epidemiologic studies of pesticides show that many, if not all, have the potential to produce toxicity in hu mans, particularly in studies of occupational or accidental high dose exposures.
From page 141...
... Cell births can be increased by direct mutagenesis or by regeneration following cytotox~city; cell deaths can be increased by inhibiting apoptosis or by altering gene expression and differentiation. Agents that en Lance cell DNA damage or cell replication in appropriate cell pop ulations will increase the cancer risk, whereas agents that decrease cell DNA damage or cell proliferation shoulc!
From page 142...
... Widen enzymes involved in the metabolic activation and inactivation of these chemicals are modi fied, the compounds show consiclerable variability in their potential for mutagenicity ant! carcinogenicity.
From page 143...
... Al though this model was derives! 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 chilc~hooct cancers, Hodg kin's disease, and breast cancer.
From page 144...
... Numerous examples of multiple genetic errors in carcinogenesis have been established in animal moclels and in humans with the use of powerful molecu far biological techniques. Also, it is still unclear which genes are directly involves!
From page 145...
... It is not surprising that the metabolic pathways involved in the biotransformation of both synthetic and naturally occurring chemi cats are similar. It is possible that these pathways clevelopecI in response to naturally occurring chemicals and offered some selective advantage to organisms capable of detoxifying xenobiotics.
From page 146...
... , and pyrethrin, a natural pesticide. Other common, metabolic pathways shared by natural and syn thetic chemicals include epoxidations and dealkylations (Oritz cle Montellano 1985~.
From page 147...
... Dieldrin, the epoxt~e 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 agilely used herbicides in the Unitecl States, which is N clealkylatecl, nicotine, which is dealkylated to nornicotine, and the cirug tamoxi fen, which is also N dealkylated Hansen and cle Fluiter 1992~.
From page 148...
... (benzoclioxole) compounds, sodium salts, aromatic amines and related chemicals, and oc2u globulin binding compounds.
From page 149...
... Nitrosation also occurs in soils, organic waste, and water, where industrial and other discharges contain large amounts of famines. Nitrosamines require metabolic activation for expression of mu tagenic and carcinogenic activity.
From page 150...
... The possibility that traces of ni trosamines 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 ant! possibly others (Magee 1989~.
From page 151...
... Tissue localization depends upon the animal species tested, the route of administra lion, the dose, ancI the hydrazine derivative. The carcinogenic properties of hycirazines may be a result of their enzymatic activation.
From page 152...
... The principal synthetic MDP used as a synergist is piperonyl butoxide (Hocigson and Philpot 1974~. Although it is not widely used on crops, it is frequently incluclec!
From page 153...
... 1981~. Piperonyl butoxide (alpha(2 (2 butoxyethoxy~ethoxy)
From page 154...
... 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 iclentified as pyrolysis products resulting from the cook ing of foods at very high temperatures (Wakabayashi et al.
From page 155...
... strain, these chemicals produce tumors predominantly of liver, mammary gland, bladder, and colon in rodents, the urinary blacider in clogs, and the liver in nonhuman primates. Epidemiologic stud ies have associated them only with the formation of urinary bladcler cancer in humans, but recent animal experimental evidence sug gests that aromatic amines may also be associated with other tumor types, such as colon cancer (Ito et al.
From page 156...
... 19921. A limitecI number of natural products, such as phytol-a clecom position product of chlorophyll have been investigatecI for their potential to incluce peroxisome proliferation (NAlatanabe and Suga 1983, Van den Branden et al.
From page 157...
... the incidence of N hyciroxyN-2 fluor enylacetamide induced hepatomas (in male rats3 and mammary
From page 158...
... For example, catechol in duces cell proliferation and is active as a glandular stomach carcino gen (Stich 1991~. The above discussion documents that synthetic and naturally occurring antioxidants behave similarly when tested at high closes for tumorigenic and antitumorigenic effects.
From page 159...
... However co administration of calcium saccharin with alkalinizing substances results in the appearance of proliferative effects. The proliferative and tumorigenic effects associated with high closes of sodium sac charin appear clue to the formation of a urinary amorphous precipi late.
From page 160...
... 1986, Cohen and Ellwein 1990, 19911. Most sodium salts, administered at high closes, produce uro thelial 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~.
From page 161...
... For example, acimin istration of an AIN-76A semisynthetic diet, which produces acidic urine, completely inhibits the proliferative and tumorigenic effects of sodium saccharin (Okamura et al.
From page 162...
... 1989, Flamm and Lehman-McKee~ man 19911. However, this process has not been observed in female rats (Alden 1986)
From page 163...
... in female rats and mice which, when exposed to a2U globulin binding compounds, do not form renal tumors. Lehman McKeeman and Cauclill note that a2u globulin may be the only member of this lipocalin protein superfamily that binds protein droplet inducing agents (19921.
From page 164...
... The most significant priority will be based on association with, or presence of a chemical in, foods asso ciatecI with diets or life styles believed to be cleleterious; however, refinements are possible based on our knowledge of synthetic car cinogens. For example, naturally occurring chemicals meeting the criteria of association with cleleterious foods could be accorded a higher priority for testing if I)
From page 165...
... A review of unique male rat hydrocarbon nephropathy. Toxicol.
From page 166...
... 1993. Critique of R Melnick's "An alternative hypothesis on the role of chemically induced protein droplet Mu globulin)
From page 167...
... 1993. Relationship between bladder changes procluced in male rats by sodium saccharin treatment and formation of an insoluble, amorphous material in the urine.
From page 168...
... male rats fail to develop renal disease following exposure to agents that induce a 2u globulin (a2u) nephropathy.
From page 169...
... 1991. The human relevance of the renal tumor inducing potential of ~ limonene in male rats: implications for risk assessment.
From page 170...
... tubule neoplasia in the kidneys of male rats. Environ.
From page 171...
... nitroso compounds, and inorganic fluorides used in drinking water and dental preparations, Vol.
From page 172...
... 1987. Characterization of spontaneous and clecalin-induced hyaline droplets in kidneys of adult male rats.
From page 173...
... 1 994. The role of alkalizing and neutral potassium salts in urinary bladder carcinogenesis in rats.
From page 174...
... 1991. Peroxisome proliferation and nongenotoxic carcinogenesis: Commentary on a symposium.
From page 175...
... 1979. The 1977 Survey of Industry on the Use of Food Additives.
From page 176...
... 1990. A comparison of male rat and human urinary proteins Implications for human resistance to hyaline droplet nephropathy.
From page 177...
... . Cancer Causes Control 5 141 14;~.
From page 178...
... 1993. Lack of promotion of N butyl N (4 hyciroxybutyl~nitrosamine initiated urinary bladder carcinogenesis in mice by rat cancer promoters.
From page 179...
... and peroxisome proliferation. Pediatr.
From page 180...
... Pp. 423-428 in NNitroso Compounds Occurrence, Biological Effects and Relevance to Human Cancer.


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