Science and Judgment in Risk Assessment (1994) / Chapter Skim
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Appendix H-2: Individual Susceptibility Factors
Appendix H-2: Individual Susceptibility Factors
Pages 505-514
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This section discusses five factors that might be among the most significant. CARCINOGEN METABOLISM Most chemical carcinogens require metabolic activation to exert their oncogenic effects, and the amount of carcinogen produced depends on the action of competing activation and detoxification pathways,.
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activity, which is catalyzed by CYPlAl; some of this variability is under direct genetic control, but variations also result from an enzyme induction process due to maternal exposure to environmental carcinogens, such as tobacco smoke. A genetic polymorphism in CYPlA1 in which an amino acid substitution in the heme-binding region of the protein increases catalytic activity of PAHs has been linked to enhanced susceptibility to squamous cell carcinoma of the lung in cigarette-smokers (Nakachi et al., 1991~.
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. Incipient malignancies Tenfold excess leukemia risk Lymphoma in those infected by Epstein-Barr virus Skin carcinoma associated with chronic infection with human papilloma virus Mutation in APC tumor suppressor gene leads to benign colonic growths that are predisposed to malignant transformation Possible deficiency of enzymes that scavenge active .
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The N-acetylation polymorphism is controlled by two autosomal alleles at a single locus in which rapid acetylation is the dominant trait and slow acetylation the recessive trait. Both slow acetylation and rapid acetylation of carcinogenic aromatic amines have been proposed as cancer risk factors.
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Sol me so: o · 'e ct ~ st son · :> A: 'e o · · c~ o am · so so .
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Although the major DNA adducts are qualitatively similar for the chemical carcinogens so far studied in the in vitro models, quantitative differences have been found among people and among various tissue types. The differences due to interindividual variation and intertissue variation within an individual in formation of DNA adducts have a range of a factor of about 10-150 among humans.
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DNA repair might involve tens of enzymes and cofactors, and genetic polymorphisms of the genes encoding these repair enzymes could be responsible for the variation among both persons and groups. Interindividual variation has been noted in the activity of O6-alkyldeoxyguanine-DNA aLkyltransferase; this enzyme repairs alkylation damage to o6deoxyguanine.
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1989. Lung cancer risk, occupational exposure, and the debrisoquine metabolic phenotype.
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1989. Interindividual variation among humans in carcinogen metabolism, DNA adduct formation,and DNA repair.
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1990. Human debrisoquine hydroxylase gene polymorphisms in cancer patients and controls.
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