Dose-response relationships for carcinogens

Mechanistic Basis for Nonlinearities and Thresholds in Rat Liver Carcinogenesis by the DNA-Reactive Carcinogens 2-Acetylaminofluorene and Diethylnitrosamine

“…We suggest that this is a consequence of carcinogen DNA adducts being converted to mutations at a high frequency because of enhanced cell proliferation and consequent reduced opportunity for repair, as detailed in liver cell culture (33). Thus, at high doses, AAF and DEN exert dual effects that underlie cancer risk (2), as has also been described for formaldehyde (32).…”

“…Human safety is assured if the SEL is greater than human exposure. Humans are not exposed to AAF, a synthetic compound, and humans are exposed to only traces of DEN (14), but the likely environmental exposure to all N-nitroso compounds and to aromatic amines is unlikely to exceed the NEL levels described here, except for the exposures of cigarette smokers, snuff users (24, 31), and individuals who consume exceptionally large quantities of foods that are rich in such compounds, such as some smoked meats and fish (32,38), or those exposed in occupational settings (37). …”

“…Although possible under certain circumstances, the realistic potential for such a mechanism can be questioned (2). To begin with, cancer is a progressive disease, in which somatic cells undergo a series of genetic alterations which culminate in a neoplasm that exhibits multiple gene defects in those genes controlling cell proliferation, cell behavior, and genomic stability (ie, oncogenes, tumor suppressor genes) (4,17,48 (32), which perhaps accounts for the fact that mutagenesis (40,41) and oncogene activation (1,19) (23), which indicates the existence of no-effect levels (NELs) for DNA damage in some tissues. A particularly compelling example of this is provided by the EDo, study of 2-acetylaminofluorene (AAF) in mice, a study that revealed an apparent NEL for urinary bladder neoplasms (6,7), although in this study and in a major study on diethylnitrosamine (DEN) in rats (26,27), the exposure response for liver neoplasms was considered to be linear, with no NEL.…”

Mechanism of 1,N2-Etheno-2′-deoxyguanosine Formation from Epoxyaldehydes

“…Exposure of the C7-hydroxyalkyl-substituted etheno adduct (12) to alkaline conditions results in quantitative loss of the C7 side chain, presumably through the imine intermediate 11 (16). The bicyclic adduct 8, which is uniquely derived from the reaction of dGuo with EHN, arises by trapping of the cyclic imine (11) by the side chain hydroxyl group. A similar mechanism can be envisioned for the formation of the 3-(2-deoxy--D-erythropentofuranosyl)-3H-imidazo[2,1-i]purine ( -dAdo) adducts from the reaction with 2,3-epoxyaldehydes, but to our knowledge, bicyclic dAdo adducts analogous to 8 have not been observed.…”

“…Of particular interest, background levels of etheno adducts have been found in unexposed populations (10)(11)(12)(13). The endogenous C 2 donors were hypothesized to be bis-electrophiles such as 2,3-epoxyaldehydes (6), derived from free radical degradation to polyunsaturated fatty acids initated by reactive oxygen species (14)(15)(16).…”