Biological bases for cancer dose-response extrapolation procedures

Journal Article · Tue Jan 01 04:00:00 EST 1991 · Environmental Health Perspectives; (United States)

DOI:https://doi.org/10.2307/3430881· OSTI ID:5010597

Wilson, J D ^[1]

---

1. Monsanto Co., St. Louis, MO (United States)

The Moolgavkar-Knudson theory of carcinogenesis of 1981 incorporates the viable portions of earlier multistage theories and provides the basis for both the linearized multistage and biologically based dose-response extrapolation methodologies. This theory begins with the premise that cancer occurs because irreversible genetic changes (mutations) are required for transformation of normal cells to cancer cells; incidence data are consistent with only two critical changes begin required, but a small contribution from three or higher mutation pathways cannot be rules out. Events or agents that increase the rate of cell division also increase the probability that one of these critical mutations will occur by reducing the time available for repair of DNA lesions before mitosis. The DNA lesions can occur from background causes or from treatment with mutagenic agents. Thus, the equations describing incidence as a function of exposure to carcinogenic agents include two separate terms, one accounting for mutagenic and one for mitogenic stimuli. At high exposures these interact, producing synergism and high incidence rates, but at low exposures they are effectively independent. The multistage models that are now used include only terms corresponding to the mutagenic stimuli and this fail to adequately describe incidence at high dose rates. Biologically based models attempt to include mitogenic effects, as well; they are usually limited by data availability.

• OSTI ID: 5010597
• Journal Information: Environmental Health Perspectives; (United States), Journal Name: Environmental Health Perspectives; (United States) Vol. 90; ISSN 0091-6765; ISSN EVHPA
• Country of Publication: United States
• Language: English

Related Subjects

560300* -- Chemicals Metabolism & Toxicology
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
ADDUCTS
CARCINOGENESIS
CARCINOGENS
DNA
DNA ADDUCTS
DOSE-RESPONSE RELATIONSHIPS
EXTRAPOLATION
GENE MUTATIONS
MATHEMATICAL MODELS
MUTATIONS
NUCLEIC ACIDS
NUMERICAL SOLUTION
ORGANIC COMPOUNDS
PATHOGENESIS