Risk extrapolation for chlorinated methanes as promoters vs initiators of multistage carcinogenesis

Journal Article · Mon Jan 01 04:00:00 EST 1990 · Fundamental and Applied Toxicology; (United States)

DOI:https://doi.org/10.1016/0272-0590(90)90040-Q· OSTI ID:7302605

Bogen, K T ^[1]

---

1. Lawrence Livermore National Lab., CA (United States)

Cell-kinetic multistage (CKM) models account for clonal growth of intermediate, premalignant cell populations and thus distinguish somatic mutations and cell proliferation as separate processes that may influence observed rates of tumor formation. This paper illustrates the application of two versions of a two-stage CKM model for extrapolating cancer risk potentially associated with exposure to carbon tetrachloride, chloroform, and dichloromethane, three suspect human carcinogens commonly present in trace amounts in groundwater supplies used for domestic consumption. For each compound, the models were used to calculate a daily oral virtually safe dose' (VSD) to humans associated with a cancer risk of 10{sup {minus}6}, extrapolated from bioassay data on increased hepatocellular tumor incidence in B6C3F1 mice. Exposure-induced bioassay tumor responses were assumed first to be due solely to promotion' in accordance with the majority of available data on in vivo genotoxicity for these compounds. Available data were used to model dose response for induced hepatocellular proliferation in mice for each compound. Physiologically based pharmacokinetic models were used to predict the hepatotoxic effective dose as a function of parent compound administered dose in mice and in humans. Key issues and uncertainties in applying CKM models to risk assessment for cancer promoters are discussed.

• DOE Contract Number: W-7405-ENG-48
• OSTI ID: 7302605
• Journal Information: Fundamental and Applied Toxicology; (United States), Journal Name: Fundamental and Applied Toxicology; (United States) Vol. 15; ISSN FAATD; ISSN 0272-0590
• 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.
ANIMAL CELLS
ANIMALS
BODY
CARBON TETRACHLORIDE
CARCINOGEN SCREENING
CARCINOGENESIS
CELL PROLIFERATION
CHLORINATED ALIPHATIC HYDROCARBONS
CHLOROFORM
DIGESTIVE SYSTEM
DISEASES
DOSE-RESPONSE RELATIONSHIPS
GLANDS
HALOGENATED ALIPHATIC HYDROCARBONS
LIVER
MAMMALS
MAN
MATHEMATICAL MODELS
MAXIMUM PERMISSIBLE EXPOSURE
METABOLISM
MICE
MUTATIONS
NEOPLASMS
ORGANIC CHLORINE COMPOUNDS
ORGANIC COMPOUNDS
ORGANIC HALOGEN COMPOUNDS
ORGANS
PATHOGENESIS
PRIMATES
RISK ASSESSMENT
RODENTS
SAFETY STANDARDS
SCREENING
SOMATIC MUTATIONS
STANDARDS
TUMOR CELLS
VERTEBRATES