A Carcinogenic Potency Database of the Standardized Results of Animal Bioassays

J Cancer Res Clin Oncol

1986

104

Summary.Investigation of covalent DNA binding in vivo provided evidence for whether a test substance can be activated to metabolites able to reach and react with DNA in an intact organism. Fora comparison of DNA binding potencies of various compounds tested under different conditions, a normalization of the DNA lesion with respect to the dose is useful. A covalent binding index, CBI = (JliDol chemical bound per mol DNA nucleotide )/(mmol chemical administered per kg body weight) can be determined for each compound. Whether covalent DNA binding results in tumor formation is dependent upon additional factors specific to the cell type. Thus far, all compounds which bind covalently to liver DNA in vivo have also proven tobe carcinogenic in a long-term study, although the liver was not necessarily the target organ for tumor growth. With appropriate techniques, DNA binding can be determined in a dose range which may be many orders of magnitude below the dose Ievels required for significant tumor induction in a long-term bioassay. Rat liver DNA bindingwas proportional to the dose of aflatoxin B 1 afteroral administration of a dose between 100 J.Lgfkg and 1 ngfkg. The lowest dose was in the range of generat human daily exposures. Demonstration ofa Iack ofliver DNA binding (CBI<0

Section: Carcinogenic Potency Of Mutagensmentioning

confidence: 99%

Section: Carcinogenic Potency Of Mutagensmentioning

confidence: 99%

Quantitative evaluation of DNA binding data for risk estimation and for classification of direct and indirect carcinogens

J Cancer Res Clin Oncol

1986

104

“…injection of radiolabeled dimethylnitrosamine (DMNA). (Original data from Stumpf et al 1979) value (Gold et al 1984), i.e., the approxirnate daily dose required to induce a tumor in 50% ofthe anirnals treated. With respect to the problern of extrapolation of turnor-inducing doses to lower exposures, those studies are the rnost relevant which cover three Oi' rnore orders of rnagnitude below the TD 50 .…”

Section: Dna-binding At Low Dosesmentioning

confidence: 99%

Quantitative Evaluation of DNA-Binding Data In Vivo for Low-Dose Extrapolations

Mechanisms and Models in Toxicology

1987

Introdu.ctionThe risk oftumor formation from exposure to a chemical carcinogen is dependent on the exposure, the potency of the carcinogen, and the imiividual host reaction. Rumans are exposed to chemical carcinogens at dose levels which are orders of magnitude below the levels used in"animal studies on carcinogenicity. The latter experiments provide significant data only at high-dose levels which lead to tumor incidences on the order ofpercent (Fig.1). For humans, tolerable exposures producing not more than one additional tumor in one million lives should be defined. The extrapolation range therefore covers four to five orders of magnitude. Instead of using purely mathematical models for the extrapolation, it woulä. be desirable to have a biologically relevant indicator which could be investigated in the dose range to be bridged.A large group of chemical carcinogens is known to bind covalently to DNA in the target cell. Under appropriate conditions, this primary DNA lesion can be expressed as a mutation finally leading to cancer. The primary interaction of the · carcinogen with DNA can be investigated with appropriate techniques (radiolabeled test compound, phosphorylation with 32 P, or immunological methods) at low dose levels which would not give rise to a detectable increase in tumor yield with a limited number of animals treated. It is therefore possible to investigate the shape of the dose-response curve in the region of interest. MethodsWith radiolabeled test compound,. the limit of detection is dependent on the specific activity, on the binding potency ( covalent binding index, CBI; Lutz 1979), on the amount of DNA analyzed, and on the radioactivity in a vial considered significant. U nder optimal conditions met, for instance, with tritiated aflatoxin B 1 of 8 Ci/mmol and a CBI of 10 000, a single dose of 1 ng/kg rat was the o bserved limit of detection for liver DNA binding (1 0 dpm net radioactivity in 6 mg DNA).

“…The symbols -, +to+ + + + + , indicating an approximate carcinogenic potency in the tables, were assigned according to TD^ values (17) [expressed in mmol/kg(days)]: -, no significant increase under the bioassay conditions used; + , 10 > TDso > 1; ++, 1 > TDJQ > 0.1; + + + , 0.1 > TD^ > 0.01; + + + +,0.01 > TDJO > 0.0001; + + + + + ,0.0001 > TD50 > 0.000001. For the carcinogenic potency ranking used in our quantitative evaluation the chemicals are therefore specified as carcinogens rather than as promoters.…”

Section: Calculations and Statisticsmentioning

confidence: 99%

Stimulation of DNA synthesis in rat and mouse liver by various tumor promoters

Büsser

1987

Carcinogenesis

'To whom reprint requests should be sentIn order to investigate whether the stimulation of liver DNA synthesis might be used to detect one class of hepatic tumor promoters, the incorporation of orally administered radiolabelled thymidine into liver DNA was determined in rats and mice 24 h after a single oral gavage of test compounds at various dose levels. Three DNA-binding hepatocarcinogens, aflatoxin B,~ benzidine and carbon tetrachloride, did not stimulate but rather inhibited DNA synthesis (not for CC1 4 ). Four hepatic tumor promoters, clofibrate, DDT, phenobarbital and thioacetamide, gave rise to a stimulation in a dosedependent manner. Single oral doses between 0.02 and 0.3 mmol/kg were required to double the level of thymidine incorporation into liver DNA (= doubling dose, DD). Differences between species or sex as observed in long-term carcinogenicity studies were reflected by a different stimulation of liver DNA synthesis. In agreement with the bioassay data, aldrin was positive only in male mice (DD = 0.007 mmol/kg) but not in male rats or female mice. 2,3,7,8-TCDD was positive in male mice (DD = 10 ~6 mmol/kg) and in female rats (DD = 2 x 10~6 mmol/kg) but not in male rats. The assay was also able to distinguish between structural isomers with different carcinogenicities.[alpha] Hexachlorocyclohexane stimulated liver DNA synthesis with a doubling dose of about 0.2 mmol/kg in male rats whereas the [gamma]-isomer was ineffective even at 1 mmol/kg. So far, only one result was inconsistent with carcinogenicity bioassay data. The different carcinogenicity of di(2-ethylhexyl)adipate (negative in rats) and di(2-ethylhexyl)phthalate (positive) was not detectable. Both plasticizers were positive in this short-term system with DD's of 0.7 mmol/kg for DEHA and 0.5 mmol/kg for DEHP. The proposed assay is discussed as an attempt to devise short-term assays for carcinogens not detected by the routine genotoxicity test systems.