Drinking Water and Health, Volume 6 (1986) / Chapter Skim
Currently Skimming:
5. Mechanisms of Carcinogenesis
5. Mechanisms of Carcinogenesis
Pages 139-167
The Chapter Skim interface presents what we've algorithmically identified as the most significant single chunk of text within every page in the chapter.
Select key terms on the right to highlight them within pages of the chapter.
From page 139... ...
(19841. This chapter provides an overview of principles that should be considered when assessing risk of exposure to drinking water.
|
From page 140... ...
initiation Initiators are mutagens that act either directly or indirectly by forming electrophilic species that interact with and modify DNA structure, or otherwise damage the DNA sequence, but do not by themselves induce tumor formation. Initiation is believed to cause a lesion that persists over a long period, as demonstrated by Van Duuren et al.
|
From page 141... ...
Some compounds may be both cocarcinogens and promoters. However, not all tumor promoters are cocarcinogens and not all cocarcinogens are tumor promoters, sug
|
From page 142... ...
Immortalization of cells in culture has been carried out using chemical carcinogens, and these cells have been transformed and promoted by oncogene products and xenobiotic substances. Studies have shown that the DNA from chemically induced tumors contains active oncogenes, and recent research has demonstrated the potential importance of chromosome translocations in oncogene activation (Bishop, 1982; Land et al., 1983; Leder et al., 1983~.
|
From page 143... ...
Although these PMA analogs have less promoting activity, they are important in studies designed to determine the mechanism of action of phorbol ester promoters (Boutwell, 19741. In addition to the phorbol ester tumor promoters, there are other classes of compounds with promoting activity in the mouse skin.
|
From page 144... ...
A number of chemicals that are tumor promoters in mouse skin are also cocarcinogens in mouse skin. The existence of cocarcinogenic substances was inferred from studies of carcinogenesis resulting from exposures to cigarette smoke condensate (CSC)
|
From page 145... ...
Rat and Mouse Liver This model system has in the past involved an invasive procedure (partial hepatectomy) , followed by administration of the initiator [usually 2-acetylaminofluorene (2-AAF)
|
From page 146... ...
Investigations of several organ systems indicate that cells in the process of normal replication are more susceptible to mutagenesis and carcinogenesis than are cells that are relatively dormant and replicate more slowly. For example, synchronized rat liver epithelial cells were shown to be most sensitive to mutation at the phosphoribosyltransferase locus by methyl methane sulfonate or by the gastric carcinogen N-methyl-N'-nitro-N-nitrosoguanidine (MUNG)
|
From page 147... ...
This finding is supported by evidence in humans for tissuespecific promotion by estrogens, cigarette smoking, and asbestos, the latter serving as a promoter of lung cancer development and as an initiator of mesothelioma (NRC, 1984, pp.
|
From page 148... ...
GENETIC TOXICITY Several contaminants in drinking water react chemically with DNA. A few of these are reviewed in Chapter 9.
|
From page 149... ...
In primary genetic toxicity, either the parent compound or its metabolite directly alters or binds to genetic material. For example, both methyl methane sulfonate (MMS)
|
From page 150... ...
have shown that human blood monocytes (phagocytic blood cells that become macrophages in tissue) destroy tumor cells but not normal cells when they are cultured together.
|
From page 151... ...
Tumor-promoting agents such as TPA, DES, TCDD, DMVC, and urethan have been shown to decrease both the cell-mediated immune response and overall resistance to infections (Dean et al., 1983a; Luster et al., 1980a,b, 19821. However, phorbol ester tumor promoters have been reported to activate macrophages and to stimulate reactive oxygen release from macrophages (Laskin and Pilaro, 1985; Laskin et al., 1981; Pilaro and Laskin, 19841.
|
From page 152... ...
to maximize the sensitivity of the bioassay and the validity of this approach (Food Safety Council, 1980; NRC, 1977; NTP, 1984; OSTP, 1985; OTA, 19811. The MTD has been operationally defined as the dose that will neither reduce longevity nor inhibit the maximum growth or weight gain of the experimental animals by more than 10%.
|
From page 153... ...
Some cell culture assays, such as the cell transformation assay, may be useful in detecting promoting activity (Abernethy et al., 1984; Frazelle et al., 1983) , but there is still a need for shortterm tests for promotion (IARC, 1983; NTP, 1984; OSTP, 1985~.
|
From page 154... ...
The weak activity in bacteria bears no resemblance to the complex pattern of activation in the whole animal, which involves the enterohepatic circulation and sequential steps of metabolism by the liver, gut flora, and the liver once again (Rickert et al., 19841. Only when genetic toxicity,
|
From page 155... ...
Whether these negative results reflect the inadequacy of current germ cell mutagenicity assays or the relative mutagenic potency of cigarette smoke in germ cells is not clear. One of the few tests that can be conducted in humans is the sperm morphology assay, which at least provides an indication that the parent compound or its metabolites reach the testes (Wyrobek et al., 19821.
|
From page 156... ...
This was based on data for 60 nitrosamines that had been tested in rats (Druckrey et al., 1967~. The relationship for nitrosamines was extended to include target organ specificity, revealing that specificity is directly associated with molecular structure and a complex interplay between the parent molecule and its metabolites with the exposed organism (Edelman et al., 19801.
|
From page 157... ...
When assessing the risk of exposure to carcinogens in drinking water, one should consider information on metabolism and pharmacokinetics. This information may be used to ascertain the validity of a linear doseresponse assumption, which can misstate the risk because of inadequate information on metabolism.
|
From page 158... ...
1971. Tumour-promoting activity of fatty acid methyl esters in mice.
|
From page 159... ...
Banbury Report 13. Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y.
|
From page 160... ...
1984. Lymphokine-activated human blood monocytes destroy tumor cells but not normal cells under cocultivation conditions.
|
From page 161... ...
1983. Tumor promotion by phorbol esters in skin: Evidence for a memory effect.
|
From page 162... ...
1981. Enhancement of macrophage-induced cytotoxicity by phorbol ester tumor promoters.
|
From page 163... ...
1979. Effects of 12-O-tetradecanoylphorbol-13-acetate and mezerein on epidermal ornithine decarboxylase activity, isoproterenol-stimulated levels of cyclic adenosine 3':5'-monophosphate, and induction of mouse skin tumors in vivo.
|
From page 164... ...
1977. Drinking Water and Health.
|
From page 165... ...
1977. Fluocinolone acetonide: A potent inhibitor of mouse skin tumor promotion and epidermal DNA synthesis.
|
From page 166... ...
1979. Correlation of the inhibition by retinoids of tumor promoter-induced mouse epidermal ornithine decarboxylase activity and of skin tumor promotion.
|
From page 167... ...
1982. Chemical Carcinogenesis.
|
Key Terms
This material may be derived from roughly machine-read images, and so is provided only to facilitate research.
More
information on Chapter Skim is available.