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4 Methods for Evaluating Potential Carcinogens and Anticarcinogens
Pages 181-218

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From page 181...
... How ever, in the absence of testable hypotheses and of well conductec! epidemiologic studies, the role of individual dietary components, inclucling potential carcinogens, remained largely unclear for most organ sites, with few exceptions.
From page 182...
... toxicants as we know them today, and emphasized that they should be further studied. Neither the UICC committee nor the National Research Council committee suggested that naturally occurring compounds posed any unique problems for testing, nor dill they mention any qualitative differences between naturally oc curring and synthetic carcinogens.
From page 183...
... We must also discuss the issues involved in study of complex mixtures in the presence of multiple plausible confounders. When adequate human data are not available, it is often neces sary to base opinions about human risk on results from expert meets in animal models.
From page 184...
... Genetic predisposition to cancer can also be influenced by inherited mutations in tumor suppressor genes, as illustrated by the Li Fraumeni syndrome, in which patients inherit mutations in one allele of the pS3 gene, and in hereditary retina blastoma, which involves the RB gene. Interestingly, inherited mutations in either of these tumor suppressor genes increases the susceptibility of inctivicluals to certain racliation inclucect tumors (Frebourg and Frienc!
From page 185...
... In Chapter 4, the following questions are addressed: What methods are currently being used to identify and evatu ate chemicals as potential carcinogens Should the methods for testing naturally occurring potential carcinogens differ from those used for testing synthetic chemicals' Are existing methods adequate How should naturally occurring compounds be prioritized for evaluation of carcinogenic potential? METHODS FOR EVAEUATING CHEMICAE CARCINOGENESIS Stuclies in Human Populations E· e plC emlO Ogy Epidemiology, a science based on population measurements, can
From page 186...
... Epidemiologic approaches to deter mining cancer risks from chemical constituents of foocis require the assessment of exposure (cliet)
From page 187...
... Disadvantages include the fact that exposure data are obtained retrospectively (dietary recall) , and that differential misclassification between cases ant!
From page 188...
... Although large sample sizes can help to reduce some of the effects of random misclassification, the effects of bias cannot be dealt with so readily. However, the findings from many case control studies, such as those on the effects of fruits and vegetables on cancer risk, have been remarkably consistent, attesting to the strength of this approach (Steinmetz and Potter 1991~.
From page 189...
... 1990~. Cohort studies have often included biochemical measures, such as serum nutrient levels, since data collection occurs prior to the onset of disease.
From page 190...
... Even well designed intervention trials can founder on such obstacles. Examples of intervention studies related to dietary exposures include a trial of ~ carotene supplements to lower risk of skin can cers (Greenberg et al.
From page 191...
... to as molecular epidemiology and is discussed in detail below. Molecular Epidemiology Research on molecular mechanisms of carcinogenesis will likely provable additional methods for identifying human exposures to
From page 192...
... , the definitions of sensitivity and specificity, as related to epidemiologic studies differ from those used in labora tory studies. While laboratory sensitivity refers to the lowest level that can be reliably analyzed, sensitivity in population studies refers to the proportion of cases that the marker correctly identifies.
From page 193...
... carcinogens, as well as repair clamage to DNA. A genetic predisposition to cancer may also be due to mute lions in oncogenes and tumor suppressor genes.
From page 194...
... Another limitation is that levels of carcinogen DNA aciclucts generally reflect recent expo sure rather than cumulative exposure over time and do not inclicate if critical targets in DNA such as oncogenes or tumor suppressor genes are affected. Several methods have been developed for detecting and quanti sating carcinogen DNA adJucts in extracts of human peripheral blood cells and tissues.
From page 195...
... One approach would be to develop assays for biologic markers that assess occur pancy rates of high affinity receptors for specific hormones or TCDD. Because carcinogenesis can involve disturbances in signal transduction and gene expression, the following assays could be incorporated into molecular epidemiology studies in the future: assays to evaluate levels of specific growth factors, growth factor receptors, seconc!
From page 196...
... by errors in dietary recall methods (see previ ous section) , it is essential to identify objective biologic markers of exposure to specific dietary constituents.
From page 197...
... Screening Tests in Mode! Systems Frequently there are insufficient human data to evaluate the potential carcinogenicity of a chemical.
From page 198...
... Commonly used endpoints for genotoxicity assays include gene mutation, chromosomal aberra lion, DNA damage, and mammalian cell transformation. Cell transformation assays can also detect certain nongenoto~c carcino gene.
From page 199...
... The end points considered are all types of DNA damage, mito tic recombine lion, gene mutation, sister chromatic exchange, micronuclei, chro mosomal aberrations, aneuploidy, cell transformation, and the inhibition of intercellular communication. Particular end points can be detected in prokaryotes, in lower eukaryotes, and in animal or human cells in vitro as well as animal cells in vivo.
From page 200...
... Although positive results in these assays suggest that a chemical may be a carcinogen, they are not sufficient to label a chemical as a human carcinogen, and fur ther testing is often required to confirm these data. Rodent Carcinogenicity Assays The evaluation of the carcinogenic potential of chemicals is com manly conducted in rodent bioassays.
From page 201...
... The advantages of these medium term assays are that they take less time than the standard 2 year rodent bioassays and that they can provide useful mechanistic data. These assays can be performed using single agents as well as com plex mixtures.
From page 202...
... in combination with other types of data, to assess the likelihood that the substance in question poses a risk for cancer in humans. While current policy accepts that positive results in rodent bioassays are likely to be predictive of human risk, it has been suggested by the NTP Board of Scien tific Counselors that hypothesis-driven mechanistic research be incorporated into the NTP bioassay to place these results in proper perspective (NTP 19921.
From page 203...
... 1993~. When four chemicals were evaluated under the typical conditions of an NTP bioassay, as well as with dietary restriction protocols, the latter increased survival and decreased tumor incidence in both control and exposed animals (Karl and Abdo 1995~.
From page 204...
... To test mixtures is particularly relevant, since human exposure to both natural carcinogens and most synthetic carcinogens generally occurs as a result of exposure to mixtures of those agents with other chem icals; however, to evaluate the toxicity of chemical mixtures is prob lematic and generally avoided. In a 1988 NRC report, Complex Mixtures reviewed epiclemiologic evidence of effects of exposure to chemical mixtures and proposed strategies for testing mixtures.
From page 205...
... In addition, when complex mixtures are tested, prob lems such as interspecies and high to low dose extrapolation are no different from those encountered when testing single agents. One of the central issues associated with testing mixtures, wheth er synthetic or naturally occurring, is identifying the causative agents.
From page 206...
... 206 CARCINOGENS AND ANTICARCINOGENS IN THE HUMAN DIET Table 41 Criteria for Selecting Agents for Evaluating Carcinogenic or Anticarcinogenic Potential Synthetica Naturally Occurring Environmental occurrence and human exposure Population at risk Extent of occurrence and use patterns Stability and persistence in the environment Structure activity relationship with known carcinogens and/or mutagens Results from short term tests for genetic and nongenetic end points Known human carcinogenicity, but no animal data Availability for testing Occurrence in diet and extent of exposure Population at risk Usual dietary concentrations; use patterns in children versus adults; regional and ethnic or racial dif ferences in consumption Stability and persistence in dietary constituents Structural comparison with known synthetic or naturally oc currlng carcinogens Results from short term tests for genetic and nongenetic end points Suspected human carcinogenicity, but no animal data Availability for testing aAdapted from lARC 1984. these compounds, the presence of an agent in the food and the amount consumed shoulc!
From page 207...
... Short term tests can play a role in prioritizing chemicals for tong term rodent bioassays, and the latter assays can help prioritize chemicals for epidemiologic studies. in turn, epidemiologic and molecular epidemiology studies might highlight dietary constituents that warrant further examination in short term tests and rodent bioassays, thus providing further verification of their carcinogenic potential.
From page 208...
... SUMMARY AND CONCLUSIONS To limit the human risk of cancer, it is necessary to evaluate the carcinogenic potential of chemicals, whether they are synthetic or naturally occurring. Current strategies for identifying and evatuat ing potential naturally occurring carcinogens and anticarcinogens can be grouped into epidemiologic studies and those using expert mental animal and cell models.
From page 209...
... The value of traditional epidemiologic approaches to identify ing dietary carcinogens would be expanded by incorporating into their research designs new biochemical, immunologic, and molecu far assays based on human tissues and biologic fluids. Despite their limitations, experimental models serve as impor tent screening tests to identify potential human carcinogens.
From page 210...
... 1985. Fundamental structural alerts to potential carcinogenicity or noncarcinogenicity.
From page 211...
... Kwan, and the Skin Cancer Prevention Study Group.
From page 212...
... 1984. Chemicals anct Exposures to Complex Mixtures Recommended for Evaluation in IARC Monographs and Chemicals and Complex Mixtures Recommencled for Icing Term Carcinogenicity Testing.
From page 213...
... 1995. The effects of ad libidos overfeeding and moderate dietary restriction on Sprague Dawley rat survival, spontaneous carcinogenesis, chronic disease and the toxicologic response to pharmaceuticals.
From page 214...
... 1982. Molecular epidemiology and carcinogen-DNA abduct detection: new approaches to
From page 215...
... 1994. A follow up study of urinary markers of aflatoxin exposure and liver cancer risk in Shanghai, People's Republic of China.
From page 216...
... 1988. The origins of human cancer: molecular mechanisms of carcinogenesis and their implications for cancer prevention and treatment.
From page 217...
... 1992. Comparison of long term dietary recall between cancer cases and noncases.


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