High- to low-dose extrapolation: critical determinants involved in the dose response of carcinogenic substances

Journal Article · Tue Dec 01 04:00:00 EST 1987 · Environ. Health Perspect.; (United States)

DOI:https://doi.org/10.1289/ehp.877657· OSTI ID:5129738

Swenberg, J A; Richardson, F C; Boucheron, J A; Deal, F H; Belinsky, S A; Charbonneau, M; Short, B G

Recent investigations on mechanisms of carcinogenesis have demonstrated important quantitative relationships between the induction of neoplasia, the molecular dose of promutagenic DNA adducts and their efficiency for causing base-pair mismatch, and the extent of cell proliferation in target organ. These factors are involved in the multistage process of carcinogenesis, including initiation, promotion, and progression. The molecular dose of DNA adducts can exhibit supralinear, linear, or sublinear relationships to external dose due to differences in absorption, biotransformation, and DNA repair at high versus low doses. In contrast, increased cell proliferation is a common phenomena that is associated with exposures to relatively high doses of toxic chemicals. As such, it enhances the carcinogenic response at high doses, but has little effect at low doses. Since data on cell proliferation can be obtained for any exposure scenario and molecular dosimetry studies are beginning to emerge on selected chemical carcinogens, methods are needed so that these critical factors can be utilized in extrapolation from high to low doses and across species. The use of such information may provide a scientific basis for quantitative risk assessment.

• Research Organization: Chemical Industry Institute of Toxicology, Research Triangle Park, NC (USA)
• OSTI ID: 5129738
• Journal Information: Environ. Health Perspect.; (United States), Journal Name: Environ. Health Perspect.; (United States) Vol. 76; ISSN EVHPA
• Country of Publication: United States
• Language: English

Related Subjects

550301 -- Cytology-- Tracer Techniques
560300* -- Chemicals Metabolism & Toxicology
59 BASIC BIOLOGICAL SCIENCES
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
ADDUCTS
ALDEHYDES
ALKYLATING AGENTS
AMINES
ANIMAL CELLS
AZINES
BIOLOGICAL RECOVERY
BIOLOGICAL REPAIR
CARCINOGENESIS
CARCINOGENS
CELL PROLIFERATION
DNA ADDUCTS
DNA REPAIR
DOSE-RESPONSE RELATIONSHIPS
EXTRAPOLATION
FORMALDEHYDE
FUELS
GASOLINE
HETEROCYCLIC COMPOUNDS
LABELLED COMPOUNDS
LIQUID FUELS
LIVER CELLS
NITROSAMINES
NITROSO COMPOUNDS
NUCLEOSIDES
NUCLEOTIDES
NUMERICAL SOLUTION
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
PATHOGENESIS
PETROLEUM PRODUCTS
PYRIMIDINES
RADIOASSAY
RECOVERY
REPAIR
RIBOSIDES
RISK ASSESSMENT
SOMATIC CELLS
THYMIDINE
TRITIUM COMPOUNDS
UNLEADED GASOLINE