Prediction of Chemical Carcinogenicity in Rodents from in Vitro Genetic Toxicity Assays

Tennant, Raymond W.; Margolin, Barry H.; Shelby, Michael D.; Zeiger, Errol; Haseman, Joseph K.; Spalding, Judson W.; Caspary, William J.; Resnick, Michael A.; Stasiewicz, Stanley; Anderson, Beth; Minor, Robert L.

doi:10.1126/science.3554512

Cited by 791 publications

(315 citation statements)

References 24 publications

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“…Appendix A. 59 (15) 110 (15) 91 (15) 32 (15) 40 (30) 152 (20) 115 (20 127 (20) 75 (20) 6 (12,20) 4 (9,20) 7 (20) 24 (20) 24 (20) 150 (20) 126 (20) 6. 14** (40) 128 (20) 71 (20) .…”

Section: Discussionunclassified

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Transformation of BALB/c-3T3 cells: IV. Rank-ordered potency of 24 chemical responses detected in a sensitive new assay procedure.

Matthews

Spalding

Tennant

1993

Environ Health Perspect

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This report introduces an improved method of detecting chemical-induced morphological transformation of A-31-1-13 BALB/c-3T3 cells. The new procedure uses an increased target cell population to assess chemicalinduced damage by increasing the initial seeding density and by delaying the initiation time of chemical treatment. Furthermore, a newly developed co-culture clonal survival assay was used to select chemical doses for the transformation assay. This assay measured the relative cloning efficiency (RCE) of chemical treatments in high-density cell cultures. In addition, transformation assay sensitivity was enhanced through the use of improved methods to solubilize many chemicals. From a group of 24 chemicals tested in at least two trials, clear evidence of chemical-induced transformation was detected for 12 chemicals (aphidicolin, barium chloride-2H20, 5-bromo-2'-deoxyuridine, C.I. direct blue 15, trans-cinnamaldehyde, cytosine arabinoside, diphenylnitrosamine, manganese sulfate-H20, 2-mercaptobenzimidazole, mezerein, riddelliine, and 2,6-xylidine); 2 chemicals had equivocal activity [C.I. direct blue 218 and mono(2-ethylhexyl)phthalate], 9 chemicals were inactive [carisoprodol, chloramphenicol sodium succinate, 4-chloro-2-nitroaniline, C.I. acid red 114, isobutyraldehyde, mono(2-ethylhexyl)adipate, sodium fluoride, and 12-O-tetradecanoylphorbol-13-acetate), and 1 chemical had an indeterminate response (2,6-dinitrotoluene). All positive responses were detected in the absence of an exogenous activation system and exhibited significant activity at two or more consecutive doses. This report also presents a mathematical method that uses t-statistics for rank-ordering the potency of chemical-induced transformation responses. This model detects sensitivity differences in experiments used to evaluate chemical-induced transformation. Furthermore, it provides a method to estimate a chemical's transformation response in terms of the historical behavior of the assay, as well as its future activity. The most active of the 24 chemicals was mezerein, and the least active chemical was diphenylnitrosamine.

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“…Appendix A. 59 (15) 110 (15) 91 (15) 32 (15) 40 (30) 152 (20) 115 (20 127 (20) 75 (20) 6 (12,20) 4 (9,20) 7 (20) 24 (20) 24 (20) 150 (20) 126 (20) 6. 14** (40) 128 (20) 71 (20) .…”

Section: Discussionunclassified

“…Although this protocol has been demonstrated to detect some carcinogenic chemicals (4,5), it has a low sensitivity (4) for detecting the diverse group of chemicals screened in the NTP/ NCI rodent bioassay (6)(7)(8)(9).…”

Section: Introductionmentioning

confidence: 99%

Transformation of BALB/c-3T3 cells: IV. Rank-ordered potency of 24 chemical responses detected in a sensitive new assay procedure.

Matthews

Spalding

Tennant

1993

Environ Health Perspect

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“…The major conclusions ofthe 73-chemical study (11) were: a) Individual qualitative concordance ofthe four STTs with rodent carcinogenicity did not show significant differences among assays (approximately 60%) and were much lower than previous estimates, b) there was no complementarity among STTs, and c) no battery oftests constructed from these four ST1E improved the carcinogenicity predictivity ofthe SAL assay alone. Initial reaction to these conclusions withinthe genetic toxicology community was mixed.…”

Section: Introductionmentioning

confidence: 91%

“…Specifically, suppose one has a battery of r STTs, whose qualitative (positive/negative) results for a given chemical are denoted by Al, A2, *-* Ar.Then Rosenkranz et al (2) (11). First, standard protocols for the four STTs were shown to yield reproducible results in interlaboratory trials with coded chemicals.…”

Section: Introductionmentioning

confidence: 99%

Predicting carcinogenicity by using batteries of dependent short-term tests.

Kim

Margolin

1994

Environ Health Perspect

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Amnag the various nmehods for predictingcarcinogencity from a battery ofshort-term tests (STlb), thecarciDgenity prediction and battery selection (CPBS) procedure is the most prominent. A major ass pn of CPBS is that the STIs used in the prediction are conditionally independent. Resultsof recent Nationa Tlblcology Program studies offour commonly used in vuvSlb ona t thistsrpebon, ofCPBSto cies. This is accomplished via log-linear ing, which then also yields an important dividend: standard errors for the predicted probabilities of carcinogenicity.

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“…In an analysis of the correlation between positive results in short-term in vitro tests and carcinogenicity, performed by Tennant et al [31] for 73 chemicals tested in 2-year carcinogenicity studies, the positive predictivity was 83% for the Ames test, 73% for the chromosomal aberrations Table 5. Correlation between the results of genotoxicity and carcinogenicity assays of bronchodilators and antiasthma drugs.…”

Section: Discussionmentioning

confidence: 99%

Genotoxicity and Carcinogenicity Studies of Bronchodilators and AntiAsthma Drugs

Brambilla

Mattioli

Robbiano

et al. 2013

Basic Clin Pharma Tox

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This survey is a compendium of genotoxicity and carcinogenicity information of bronchodilators and antiasthma drugs. Data from 46 marketed drugs were collected. Of these 46 drugs, 25 (54.3%) did not have retrievable genotoxicity or carcinogenicity data. The remaining 21 (45.7%) had at least one genotoxicity or carcinogenicity test result. Of these 21 drugs, 10 had at least one positive finding: three tested positive in at least one genotoxicity assay, eight in at least one carcinogenicity assay, and one of them gave positive results in both genotoxicity assay and carcinogenicity assay. Concerning the predictivity of genetic toxicology findings for the result(s) of long-term carcinogenesis assays, 15 drugs had both genotoxicity and carcinogenicity data: seven of them (46.6%) were neither genotoxic nor carcinogenic, 6 (40.0%) were carcinogenic in at least one sex of mice or rats but tested negative in genotoxicity assays, 1 (6.7%) tested positive in genotoxicity assay but was non-carcinogenic, and 1 (6.7%) gave positive responses in both genotoxicity and carcinogenicity assay. Only 11 (23.9%) of the 46 drugs considered had all data required by current guidelines for testing of pharmaceuticals, but a large fraction of them were developed and marketed prior to the present regulatory climate.Bronchodilators and antiasthma drugs are continuously or frequently used in the treatment for chronic airways diseases. Among the various adverse reactions of concern that these pharmaceuticals might cause, genotoxic and carcinogenic effects cannot be excluded. Therefore, we deemed useful to verify to what extent the drugs of this family have been tested for their potential genotoxic and carcinogenic risk to human beings.The regulatory authorities of USA, Europe and Japan recommend th at genotoxicity and carcinogenicity assays are performed before application for marketing approval of pharmaceuticals. Present guidelines for genotoxicity testing of pharmaceuticals [1-3] indicate a standard test battery that consists of (i) a test for gene mutation in bacteria; (ii) an in vitro test with cytogenetic evaluation of chromosomal damage with mammalian cells or an in vitro mammalian cells gene mutation assay and (iii) an in vivo test for chromosomal damage performed with rodent hematopoietic cells. Guidelines for carcinogenicity testing of pharmaceuticals [4,5] indicate that long-term carcinogenicity studies in rodents should be performed for all pharmaceuticals whose expected clinical use is continuous for at least 6 months as well as for pharmaceuticals used frequently in an intermittent manner in the treatment for chronic recurrent conditions. In long-term carcinogenicity assays, the highest dose should be at least 25 times higher, on a mg/m 2 basis, than the maximum recommended human daily dose or represent a 25-fold ratio of rodent to human AUC. In the chapter bronchodilators and antiasthma drugs of the 2007 edition of Martindale: The Complete Drug Reference [6] are included 46 drugs still on the market, the majority of wh...

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Prediction of Chemical Carcinogenicity in Rodents from in Vitro Genetic Toxicity Assays

Cited by 791 publications

References 24 publications

Transformation of BALB/c-3T3 cells: IV. Rank-ordered potency of 24 chemical responses detected in a sensitive new assay procedure.

Transformation of BALB/c-3T3 cells: IV. Rank-ordered potency of 24 chemical responses detected in a sensitive new assay procedure.

Predicting carcinogenicity by using batteries of dependent short-term tests.

Genotoxicity and Carcinogenicity Studies of Bronchodilators and AntiAsthma Drugs

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