Carcinogens and Anticarcinogens in the Human Diet A Comparison of Naturally Occurring and Synthetic Substances (1996) / Chapter Skim
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5 Risk Comparisons
5 Risk Comparisons
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From page 219... ...
Annual Report as known to be or reasonably anticipated to be carcinogenic. The level of risk associated with a carcinogenic agent clepencis on both the potency of the agent and on the level of exposure to that agent Carcinogenic potency can be estimated using clinical and epidemiologic data on humans or toxicologic data clerived from animal bioassays.
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From page 220... ...
Estimates of potential cancer risks associated with low levels of indiviclual food chemicals derived on the basis of labora tory results are highly uncertain. The application of animal cancer test ciata to humans requires extrapolation from the high doses used in laboratory studies to much lower closes corresponding to concentrations in the human diet, and extrapolation from animals to humans.
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From page 221... ...
levels of ingestion of specific dietary carcinogens, both natural and synthetic; and, 3) the carcinogenic potency of these chemicals.
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Because the TDso is often clerived from high dose experimental ciata, it cloes not necessarily provide an appropriate basis for mak ing inferences about cancer risks at low levels of exposure. To ob lain a measure of carcinogenic potency that is closer to human exposure levels, the committee also uses!
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From page 223... ...
that synthetic carcinogens present in the diet might be responsible for a very small fraction of the human cancer burden (Ames et al. 1995, Higginson 1988)
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There is substantial uncertainty in such food consumption data due to a variety of factors, including recall bias, measurement error, and recording errors. The fact that the numbers of people surveyed are relatively small and response rates poor makes generalization to the U.S.
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NFC ant] NHANES surveys deal primarily with nutritional consid orations and are less useful for evaluating ingestion of naturally occurring chemicals and foot!
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Diet and Health provides an in depth discussion of the limitations of NHANES data. A number of factors need to be considered when using food composition and consumption data in estimating dietary cancer risks.
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From page 227... ...
This variability could result in substantial seasonal, geographic, ant! individual variation among food samples and, consequently, among human exposure levels.
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From page 228... ...
, and vegetables are greater for infants than for older children or adults, and should be consiclered in estimating the risk from dietary expo sure to potential human carcinogens. Such age dependent differ ences in dietary patterns need to consiclered when evaluating life time cancer risks (Goddard!
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From page 229... ...
Several million peo pie take cholesterol lowering agents, and new drugs are being devel oped to block lipid absorption. Information on the use of pharma ceutical products that may affect dietary cancer risks is therefore of interest.
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, metabolic intermedi ales in plants (e.g., acetaldehyd;e) , caffeic acid, and natural furocou marine (5 methoxy and 8 methoxypsoralen)
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From page 231... ...
veterinary drugs-estradiol 17p, progesterone, reserpine, testosterone, ii) food packaging materialbenzene, cobalt, ethyl acrylate, formaldehydet', nickelb Direct food additives acetaldehydet', ethyl acrylate, formaldehydeb Traditional foods and beverages alcoholic beverages, betel quid, bracken fern, hot mate, pickled vegetables, salted fish (Chinese style)
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From page 232... ...
USDA food consumption ciata, rough estimates of human intake are obtained and presented in Table 5 2. Table 5 2 reports ranges rather than single values for caffeic acid ntake, to reflect both the uncertainty and variability in caffeic acid exposure.
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The upper bound indicates results assuming complete hydrolysis of caffeic acid conjugates, and the lower bound assumes only 10% hydrolysis. CFrom Herrmann (1978~.
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From page 234... ...
Estimates of average daily intake of caffeic acid from food for the general population were 0.02 0.2 mg/kg. Daily intakes for high consumers of produce can be considerably greater (e.g., the 95th percentile estimates for chit dren aged ~ 6 are 0.2~3 mg/kg)
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(1995) analyzed the consumption of foods containing five of the principal heterocyclic amines by 3,563 persons who provided 3 day dietary records in a USDA sponsored survey conducted in 1989.
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The above calculations do not account for endogenous formation of N-nitroso compounds. Urethane is formed naturally in fermented beverages and foods, such as alcoholic beverages, leavened bread, soy sauce, yogurt, and
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From page 237... ...
items, and using the results from the USDA Continuing Survey of Food Intakes by Individuals (as cacti fled by TAS 1995a,b) , estimates for daily intake of urethane in food were obtained 1.4 x 10 5 mg/kg for the general population, and 4.4 x lO 5 mg/kg for children aged 1 6, with an upper 95th percentile for this group of 9.5 x 105.
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From page 238... ...
for carcinogenicity and fount] to be carcinogenic, myco toxins are predominant and have the greatest human exposure potential.
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From page 239... ...
via feed grains, can be a significant human dietary source of ochratoxin A Pass-Through Inorganic metals and organic contaminants, such as polycyclic aromatic hydrocarbons (PAHs)
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. Intentional Food Additives and Constituents of Spices Intentional food additives are plotted in Figure 5 1 in decreasing order of annual per capita disappearance, which reflects usage in focal.
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RISK COMPARISONS 241 100 kg 10 kg 1 kg 100 9 10 9 1 9 100 mg 10 mg 1 mg 100 p9 10 p9 1 p9 1 00 ng 10 ng (I) Caloric sweeteners (I pH adjusting agents ~rbs, oils E D 7 ~ 3 _ .
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From page 242... ...
Constitutive substances reported to be inhib itors of carcinogenesis are listed in Appendix B The comparative carcinogenic potency of constitutive and nonconstitutive substances is aciciressed later in this chapter.
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From page 243... ...
Synthetic Carcinogens Table 5 3 classifies synthetic carcinogens found in the cliet into six categories pesticide residues, potential animal drug residues, packaging or storage container migrants, residues from food pro ces sin", colors, and direct food aclditives. The chemicals listed under each category have been classified by lARC or NTP as car cinogens.
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From page 244... ...
, toxaphene, 2,4,6 trichlorophenol Potential animal drug residues Diethylstilbesterol (now banned) , ethinyl estradiol, medroxyprogesterone acetate, methylthiouracil, 5 (morpholinomethyl)
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From page 245... ...
bAgents listed in tl~e FDA priority-6ased Assessment of Food Additives data base as indirect food additives (Benz 1994~. Although carcinogenic agents cannot lie used as food additives because of the Delaney Clause, saccharin had a congressional override, and BHA appears to operate by mechanisms where low level exposures are unlikely to pose a risk.
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From page 246... ...
Processing may increase, decrease, or have no effect on the con centration levels of pesticide residues in foods. Washing the raw foocis tends to reduce residues, blanching recluces them further, and canning reduces them even further (Elkins 19891.
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Specifically, it requires analytical methods capable of detecting drug residues in edible meat at concentrations in the human flier that have estimated lifetime cancer risks of less than lob. For some of the hormone residues, FDA prohibits detectable levels in edible tissues.
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From page 248... ...
Methylene chloride residues introduced during the procluc lion of decaffeinated coffee were the subject of considerable con cern. Direct Food Additives A variety of additives are allowed into the final food product to assure its safety in the package.
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From page 249... ...
1986 CSFlls (USDA 1987~. In these surveys, dietary fiber inclucled the insoluble fraction (neu tral detergent fiber)
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Both the 1985 CSFIT and the 1977 NFCS indicated average intakes of this vitamin exceeding the RDA, with intakes positively corre latecI with economic status. RDAs for vitamin D range from 5 to 10 ,ug; however, its intake is only estimated in national surveys monitoring food consumption, because little information is avail able on vitamin D in foods.
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From page 251... ...
Data from the 1985 CSFIl indicate average intakes of 305 ,u/day and 189 ,ug/day for men and women 19 to 50 years of age, respectively. Results for folic acid are limited by the inherent variability in laboratory methods of analysis of folacin in foods, and by the high percentage of folacin concentra lions in foods that were imputed rather than measured.
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From page 252... ...
MEASURES OF CARCINOGENIC POTENCY To estimate cancer risks, information is required on the carcino genie potency of the agent of interest, in acictition to the level of exposure to the agent. Recent developments in measuring carcino genie potency are related to the TDso inclex introduced by Peto et al.
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From page 253... ...
U.S. Population Average High Consumers Constitutive Caffeic acid Food 20 200 Coffees 200 2,000 8 methoxypsora len~xantho toxin)
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From page 254... ...
In this chapter, the TDo~ will also be considered as the basis for comparing the potency of naturally occurring and synthetic carcinogens. The TDo~ is closer to human exposure levels,
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U.S. Population Average High Consumersa Pesticide Residues 000, DDE, and DDT 1954 (DDE and DDT)
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U.S. Population Average High Consumersa Intentional Food Additives Butylated hydroxyanisoleh Potassium bromate' Saccharin 1977j 120 120 350 270 7GO (9Oth percentile intakes for different age groups)
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RISK COMPARISONS 257 . Table 5~5 Continued From the NRC (1979b)
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(1984, 1986, 1987, 1990, 1993, 1995) have tabulated the TD50 values for a large number of chemical carcinogens in their Carcinogenic Potency Database (CPDB)
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From page 259... ...
When data on the clepenclency of cancer risk on age and exposure time are not available, stanciardization of TD50 values in the Carcinogenic Potency Database is done uncler the assumption that risk increases in proportion to time to the seconc! power.
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From page 260... ...
For the one stage model, TDo1 = TD50/69. Correlation Between Cancer Potency and Other Measures of Toxicity Several investigators have notect a strong correlation between the TD50 and the MTD (Bernstein et al.
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From page 261... ...
As indicated in Figure 5 3, there is a strong negative correlation between qua and the MTD. Thus, the MTD has a strong influence on measures of carcinogenic potency at both high and low doses.
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From page 262... ...
between carcinogenic potency anct acute toxicity. Zeise et al.
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Only seven of the 53 carcinogenicity studies reporting positive results exhibited target organ toxicity that could have been the cause of observed carcinogenic effects. Those findings suggested that only a small number of chemical carcinogens that induce tumors in rodents solely by indirect mechanisms may be limited.
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. Interpretation of Carcinogenic Potency Little information is currently available on the relative potencies of various carcinogens ant!
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From page 265... ...
The current animal bioassay was designed as a qualitative screen for carcinogenicity; it was not clesigned to provide information on an agent's biologic mechanisms of action or on its close response characteristics at low doses. Most cancer bioassays use the MTD, which is generally much higher than environmental exposure levels likely to be encountered by humans.
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From page 266... ...
from animal test data, consiclerable uncertainty may remain about the magnitude of the risk. ESTIMATING HUMAN CANCER RISKS Risk-Estimation Methods Estimates of human cancer risks are baser!
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. Quantitative predictions of human cancer risk are generally obtained by fitting a suitable close response model to either toxicologic or epidemiologic data.
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From page 268... ...
If the close response curve is assumed to be linear in the low close region, estimates of human cancer risk at low doses can be obtained using the linear ized multistage moclel describer! by Crump (1984)
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From page 269... ...
For example, both food consumption patterns and concentrations of carcino genie substances present in the diet can vary widely, leacling to appreciable variation in individual intake of dietary chemicals. Uncertainty about the mechanisms of carcinogenic action and the relative sensitivity of animals and humans leads to uncertainty about the risk associates!
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From page 270... ...
They demonstrate`] that uncertainty surrounding the values of the model parameters im pliect considerable uncertainty in tissue doses of the proximate carcinogen.
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From page 271... ...
Therefore, studies of the carcinogenicity of some chemicals at high doses are of limited value in assessing the dose response relation ships occurring at low exposure levels that are likely to be encoun terec! in the human diet (Cohen ant!
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From page 272... ...
Toxicologically Insignificant Exposure Levels The concept of toxicologically insignificant exposures (TIE) in the regulation of certain chemical substances found in food is cur rently receiving considerable attention (Rulis 1986, 1989, 1992; FDA 1993)
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From page 273... ...
of 500 pot, based on his analysis of the Carcinogenic Potency Database clescribecI earlier. However, con lamination by some agents with moderately high carcinogenic activ ity could be a concern at this level.
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From page 274... ...
Cancer potency esti mates differ by approximately a factor of 10 for the two groups (Wu Williams et al.
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From page 275... ...
on the sum of the effective closes of each component. The presence of a chemical in a mixture may increase or decrease the carcinogenic potency of other components through the induc lion of detoxification enzymes or DNA repair, competition for receptors, or saturation of metabolic pathways.
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From page 276... ...
The adclition of a chemical Blat augments the background carcino genie process will increase cancer risk to an extent that is proper tional (linearly related to the chemical close at low doses. In this case, the use of a response additive model is inappropriate, and a close acIditive model shoulc!
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From page 277... ...
For the small, relative risks that would be expected at low doses, estimates of cancer risk for a mixture are approximately additive (NRC 19881. This is readily seen by a simple example.
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From page 278... ...
by naturally occurring constituents. DIETARY CANCER RISKS Overall Impact Of Diet on Cancer The NRC Committee on Diet ant!
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From page 279... ...
Impact of Dietary Constituents on Human Cancer Although only a few individual carcinogens in the flier have been identified through epiclemiologic studies (e.g., aflatoxin and arsen.
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From page 280... ...
Broccoli also contains chlorogenic and neochIorogenic acids; both are metabo lived to caffeic acid, which is found in broccoli at concentrations up to 10 mg/kg. Anticarcinogenic substances fount]
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From page 281... ...
. The committee noted that there was some epidemiologic evidence that alcohol consumption is associated with primary liver cancer and moderate beer drinking with colorectal cancer, and found the association between alcohol con gumption and breast cancer less clear.
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From page 282... ...
Unfortu nately, many early epidemiologic studies of diet and cancer clid not assess total caloric intake, and others clid not acljust for calories when examining the effects of fat or other macronutrients (NRC 1989a)
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From page 283... ...
Men in the age group 15~18 years of age, in contrast, consumed an average of 2,568 kcal per day. Fat Many epidemiologic studies have found a positive association between dietary fat intake and cancer at certain sites, such as the colon, prostate, and breast (NRC 1989a)
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From page 284... ...
can generate potentially carcinogenic polycyclic hyctrocar bons and heterocyclic amines (Sugimura 19851. Thus, a causal relationship between dietary fat ant!
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From page 285... ...
over time. Risk Estimates Derived from Epidemiologic Studies In only a few cases can dietary risks be estimated from human data.
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From page 286... ...
heterocyclic amines formed during the cook ing of food. Cancer potency estimates were derived from roclent data.
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From page 287... ...
cancer risks to hu mans from known animal anct human carcinogens present in the flier. Human exposure estimates were based on average ciaily intake estimates for dietary carcinogens in Switzerland.
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From page 288... ...
Using a TD50 of 16g/kg/d for excess feed in rats, the authors estimate that 60,000 cancer cases in a population of one million coulct be attributed to excess food intake in Switzerland, noting that "this value is provocatively close to the number of can cer cases not explained by the human dietary chemical carcino gens." Scheuplein (1990) examined the contribution of various food categories to overall human cancer risk.
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From page 289... ...
Scheuplein estimated that naturally occurring carcinogens account for approximately 91% of the cancers attributable to the human diet. Scheuplein's attempt to quantitate the contribution of dietary risk factors to human cancers demonstrates the gaps in our present knowledge.
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From page 290... ...
Table 5 8 compares the geometric means of the TDo~ values for various synthetic versus naturally occurring carcinogens fount!
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From page 291... ...
. Table 5~8 Comparison of TDC,I Values for Selected Synthetic and Naturally Occurring Carcinogens in the Diet TDC,1 Geomet Geometric Number of ric Mean (mg/ Standard Occurrence in the Diet Agents kg/day)
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From page 292... ...
292 1 1 Am_ \ \ ~'\ \ : \ \ ~\ \ I'm so U
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From page 293... ...
a number of other pyrolytic products are classified as naturally occurring dietary carcinogens, even though relatively large dietary contributions can result from plant uptake of fossil fuel combustion byproducts.
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From page 294... ...
19911; thus it is improbable that the risks de rived from animal bioassay data using standard techniques are representative of actual risks for human beings. The estimated carcinogenic potency of caffeic acid is therefore unlikely to be inclic alive of its activity under conditions of most human exposures.
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From page 295... ...
1990, 19921. Based on a tabulation of HERP indices for various carcino yens using data from the Carcinogenic Potency Database, these investigators assert that the risks associates!
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From page 296... ...
On the basis of these results, they concluded that dietary exposure to naturally occurring pesticicles, weighted by carcinogenic potency, is greater than dietary exposure to synthetic pesticides. They further noted that a high proportion of "natural pesticicles" were positive in ant mat cancer tests anct concluclect that naturally occurring ant!
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From page 297... ...
by IARC. Consequently, there is an uneven comparison of synthetic agents that have been formally recognized as carcinogens to naturally occurring agents with insuffi cient evidence.
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From page 298... ...
, ant! then ranking HERP inclices from highest to lowest for agents they identify as natural and synthetic pesticides results in the following: caffeic acid, ~ limonene, safrole, mix of hydrazines, catechol, DDT (before ban in 1972)
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From page 299... ...
clefined as the ratio of dietary exposure to carcinogenic potency. Carcinogenic potency is expressed in terms of the TED,, then estimated to induce an excess lifetime cancer risk of I%.
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From page 300... ...
300 CARCINOGENS AND ANTICARCINOGENS IN THE HUMAN DIET Table 5 9 Exposure/Potency Index for Selected Naturally Occurring and Syn thetic Carcinogens in tl~e Diets Carcinogen Exposure Potency Index U.S. Population Average High Consumers Natural Constitutive Caffeic acid Food 0.03 0.3 0.1 1 (average child ser 1 6yr.)
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From page 301... ...
1965 Early 1980's Ethylene thiourea Unsymmetrical dimethyl hydrazine Packaging migrants Diethylhexyl phthalate 1982 report 0.07 1991 report 0.003 Environmental 0.1 0.02 0.001 0.0009; 0.003 0.014 contaminants TCDD equivalents 0.01 0.04 Polychlorinated biphenyls 0.2 Intentional food additives Butylated 0.1 (average intake, non nursing infant) 0.02 0.9 Pursing infant)
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From page 302... ...
potentially carcinogenic to humans if consumed at levels producing cancer in animal bioassays, these simple phenolic compounds are potentially anticarcinogenic at lower levels, operating through an antioxidant mechanism (see Chapter 21. The degree, therefore, that caffeic acid poses a cancer risk to humans is unclear.
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From page 303... ...
Unlike most naturally occurring dietary constituents, synthetic ones such as direct and indirect food adcli fives and pesticide residues are highly regulated, with stringent limits placed on their allowable levels of synthetic chemicals in foods. The risks associated with dietary carcinogens depend on the carcinogenic potency of the substance and its level of ingestion.
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From page 304... ...
Epidemiologic studies provide direct infor mation on cancer risks in humans but are subject to certain limita lions, includinginadequate exposure data and confounding clue to exposure to multiple agents. Toxicological studies can be con ducted under controlled conditions but provide only indirect info r mation on human cancer risks.
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From page 305... ...
In this analysis, carcinogenic potency was expressed in terms of the reciprocal of the TDo~, defined as the close inclucing an excess lifetime cancer risk of 1%. Results of the analysis indicate that the average potency of the naturally occurring carcinogens was some what higher than that of the synthetic carcinogens.
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From page 306... ...
Ames and his colleagues have argued that HERP values for naturally occurring carcinogens often exceed those for synthetic carcinogens, largely because of the greater consumption of a few naturally occurring substances such as caffeic acid, which occurs in high concentrations in commonly consumer! foods such as lettuce, apples, and coffee.
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From page 307... ...
Based on average daily consumption data, HERP inclices for natural and synthetic carcinogens appear to be somewhat comparable. Several investigators have attempted to assess the proportion of the human cancer burden attributable to different sources.
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From page 308... ...
However, excess calories and fat appear to have a substan tial impact on human cancer. The human diet contains both naturally occurring and syn' thetic agents that may affect cancer risk.
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From page 309... ...
fat represent major components of the human diet and play an impor tent role in the dietary contribution towards human cancer. Natu rally occurring chemicals are present in the food supply in much larger quantities than synthetic chemicals.
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From page 310... ...
Similarly, with the exception of a few agents such as caffeic acid, naturally occurring carcinogens, including "natural pesticides," are also present at very low levels. The human diet contains anticarcinogens that reduce cancer risk.
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From page 311... ...
OVERALL CONCLUSIONS Although diet clearly contributes importantly to human cancer, the committee found it difficult to identify the specific components of diet that serve to increase or decrease cancer risk. Although excess calories and fat appear to represent the single most impor tent component of the human diet that increases cancer risk, the epiclemiological evidence in this regarc!
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From page 312... ...
The committee also noted that the fractions of naturally occurring and synthetic substances that are positive in animal cancer tests are comparable, and that the dietary concentrations of many naturally occurring arrival carcinogens such as caffeic acid exceed those of most syn thetic carcinogens present in or on food. These observations sup ported the committee's cor~clusion that natural components of the ctiet may prove to be of greater concern than synthetic components with respect to cancer risk, although aclditional evidence is required before this conclusion can be drawn with certainty.
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From page 313... ...
1985. Some tautologous aspects of the comparison of carcinogenic potency in rats and mice.
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From page 314... ...
1994. Cancer potencies of heterocyclic amines found in cooked foods.
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From page 315... ...
1984. An improved procedure for low dose carcinogenic risk assessment from animal data.
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From page 316... ...
1990. Dietary intakes of some essential and non essential trace elements, nitrate, nitrite and N nitrosoamines, by Dutch adults: Estimated via a 24 hour duplicate portion study.
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From page 317... ...
1987. Estimating carcinogenic potency from a rodent tumorigenicity experiment.
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From page 318... ...
1990. Third chronological supplement to the Carcinogenic Potency Database: Standardized results of animal bioassays published through December 1986 and by the National Toxicology Program through June 1987.
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From page 319... ...
1993a. The fifth plot of the Carcinogenic Potency Database: Results of animal bioassays published in the general [Literature through 1988 and by the National Toxicology Program through 1989.
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From page 320... ...
Modeling the relative risk of hepatocellular carcinoma.
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From page 321... ...
1990. Carcinogenic potency correlations: Real or artifactual?
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From page 322... ...
1993. Correlation between carcinogenic potency and the maximum tolerated dose Implications for risk assessment.
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From page 323... ...
Environmental Factors in Experimental and Human Cancer, H.V. Gelatin, B
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From page 324... ...
1990. Safety assessment procedures for indirect food additives an overview.
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From page 325... ...
1993b. Issues in Risk Assessement: Use of the Maximum Tolerated Dose in Animal Bioassays for Carcinogenicity.
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From page 326... ...
1984a. The TD50: A proposed general convention for the numerical description of the carcinogenic potency of chemicals in chronic exposure animal experiments.
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From page 327... ...
1989. Experimental desing constraints on carcinogenic potency estimates.
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From page 328... ...
1984. Calculation of carcinogenic potency from long term animal experiments.
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From page 329... ...
In Relevance to Human Cancer of N Nitroso Compounds, Tobacco Smoke and Mycotoxins, I.K O'Neill, I
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From page 330... ...
1990a. Prediction of carcinogenic potency from toxicology data.
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From page 331... ...
1991. Quantitative correlation of carcinogenic potency with four different classes of short term test data.
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From page 332... ...
1990. Enhancement of mammary carcinogenesis by high levels of dietary fat: A phenomenon clepenclent on ad libitum beetling.
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From page 333... ...
1982. Use of toxicity to estimate carcinogenic potency.
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