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R W Tennant

Publications and source records attributed to R W Tennant.

At least 55 records · Page 3Linked to original sources
PubMed1994

Prediction of rodent carcinogenicity for 44 chemicals: results.

Methods by which rodent carcinogenicity can be predicted have been prospectively validated for 40 chemicals evaluated for carcinogenicity by the US National Toxicology Program. It is concluded that a chemical of unknown carcinogenicity can be predicted to be in one of three possible categories--probably carcinogenic, probably non-carcinogenic or of uncertain activity. The last category is unlikely to contain genotoxic trans-species and/or multiple-site carcinogens. The component parameters of such predictions are one or more of several aspects of chemical structure, genotoxicity and rodent toxicity. Each of these parameters requires refinement but all are developed to the point that they can be integrated to make assessment of possible carcinogenicity. Carcinogenicity tends to be overpredicted by this integrated technique, each part of which has already been simulated by computer modelling. Improvements in predictive methodology will flow from three assumptions: (i) that emphasis must be placed equally on the properties of the test chemical and the responses it elicits in tissues for which carcinogenicity is to be predicted, (ii) that the integration of different predictive technique is preferable to the exclusive use of a single technique, and (iii) that the general predictivity of any technique or combination of techniques appears to be limited to < or = 80%, imposed by inadequate knowledge, and uncertainties in the experimental evaluation and classification of carcinogenic responses for diverse chemicals. This last statement does not preclude the attainment of higher accuracy within a congeneric series of chemicals. Foreknowledge of the likely outcome of a rodent carcinogenicity bioassay is now possible and will contribute to the focusing of animal testing resources.

Animals↗
PubMed1994

Gene manipulation and genetic toxicology.

Transgenic mice with recoverable target genes, with genes modified in expression or with ablated gene function provide important tools for defining the biological effects of chemicals. In many cases studies can be conducted with fewer animals and in a shorter timeframe. They also provide important tools for studies of carcinogenesis mechanisms and processes, for early detection of carcinogens and for identification of potential cancer therapies.

Animals↗
PubMed1993

Chemical effects in transgenic mice bearing oncogenes expressed in mammary tissue.

Three transgenic mouse lines carrying v-Ha-ras (TG-SH), c-myc (TG-M) or c-neu (TG-NK) oncogenes under regulatory control of mouse mammary tumor virus (MMTV) long terminal repeat (LTR) sequences were evaluated for responses to two chemical carcinogens. p-Cresidine, a mutagenic urinary bladder carcinogen, increased the incidence of urinary bladder carcinomas in males and females in all three lines, and these tumors occurred at comparable incidences and grade in transgenic and non-transgenic mice. p-Cresidine did not affect the rates of mammary or salivary gland neoplasms in transgenic mice; these tumors did not occur in non-transgenic littermates. No other tumor types were observed in exposed or control animals. Reserpine, a non-mutagenic mammary gland carcinogen, was administered under the same protocol, but the high control rates of mammary gland adenocarcinomas in the TG-M and TG-NK strains made it difficult to detect any tumor-enhancing effect of reserpine. However, the incidences of multiple mammary gland tumors were significantly increased in dosed females from both lines. The incidence of mammary gland adenocarcinomas was significantly increased in TG-SH females receiving 5 p.p.m. reserpine. Reserpine did not induce any carcinogenic effects in non-transgenic mice. These results indicate that the transcriptional regulation of these three transgenes is a major determinant in the response to p-cresidine and reserpine. The use of transgenic models for the general detection of carcinogens may require lines in which appropriate genes are targeted for expression in many tissues, or lines in which critical genes have been inactivated.

Adenocarcinoma↗
PubMed1993

Chemically induced skin carcinogenesis in a transgenic mouse line (TG.AC) carrying a v-Ha-ras gene.

A transgenic mouse line (TG.AC) created in the FVB/N strain, carries a v-Ha-ras gene fused to a zeta-globin promoter gene. These trangenic mice have the properties of genetically initiated skin and have been shown to be sensitive to 12-O-tetradecanoylphorbol-13-acetate (TPA), a well-described promoter of skin papillomas in the two-stage mouse skin tumorigenesis model. It was of interest to determine whether the TG.AC mouse strain was also responsive to other known promoters. Groups of heterozygous or homozygous TG.AC mice were treated topically, 2x/week, for up to 20 weeks with benzoyl peroxide (BPO), 2-butanol peroxide (2-BUP), phenol (PH), acetic acid (AA), TPA and acetone (ACN), the vehicle control. Skin papillomas were induced in all groups treated with TPA, BPO and 2-BUP. Papillomas were observed in some treatment groups as early as 3 weeks. The relative activity of the promoters was TPA > 2-BUP > BPO > PH = AA = ACN. No papillomas were observed in any of the uninitiated FVB/N mice treated in a similar manner and which served as treatment control groups. Studies to determine the sensitivity of TG.AC mice to TPA, indicated that a total dose of 25-30 micrograms of TPA administered in 3 or 10 applications, was sufficient to induce an average incidence of 11-15 papillomas per mouse. The papilloma incidence continued to increase and was maintained up to 15 weeks after TPA treatment was terminated. The short latency period and high incidence of papilloma induction indicate that TG.AC mice have a high sensitivity to known skin promoters. The TG.AC line should prove to be a sensitive model for identifying putative tumor promoters or complete carcinogens.

Acetates↗
PubMed1993

Genetic toxicology: current status of methods of carcinogen identification.

A critical aspect of the efforts to relate the results of short-term genetic toxicity tests with those from long-term rodent tests for carcinogens is the quality and consistency of the studies conducted by the National Toxicology Program. Analysis of the results in relationship to chemical structure has shown that mutagenic potential is a primary risk factor for carcinogen identification. Chemicals positive in the Salmonella assay-generally possess "structural alerts" for electrophilic interactions, are predominantly represented among chemicals producing trans-species carcinogenic effects in rodents, and among those identified as carcinogenic to humans. Current efforts are aimed at defining toxicological, structural, and mechanistic properties of nonmutagens that are carcinogenic in rodents.

Animals↗
PubMed1993

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

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 chemical-induced 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-2H2O, 5-bromo-2'-deoxyuridine, C.I. direct blue 15, trans-cinnamaldehyde, cytosine arabinoside, diphenylnitrosamine, manganese sulfate-H2O, 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.

3T3 Cells↗
PubMed1993

Transformation of BALB/c-3T3 cells: V. Transformation responses of 168 chemicals compared with mutagenicity in Salmonella and carcinogenicity in rodent bioassays.

This report describes the activities of 168 chemicals tested in a standard transformation assay using A-31-1-13 BALB/c-3T3 cells. The data set includes 84 carcinogens, 77 noncarcinogens, and 7 research chemicals. Carcinogens included 49 mutagens and 35 nonmutagens; noncarcinogens included 24 mutagens and 53 nonmutagens. The transformation assay did not use an exogenous activation system, thus, all chemical responses depended on the inherent target cell metabolic capacity where metabolic activation was required. The upper dose limit was 100 milli-osmolar because the assay could not discriminate active and inactive chemicals tested above this concentration. Certain physicochemical properties resulted in technical problems that affected chemical biological activity. For example, chemicals that reacted with plastic were usually nonmutagenic carcinogens. Similarly, chemicals that were insoluble in medium, or bound metals, were usually nonmutagenic and nontransforming. Multifactorial data analyses revealed that the transformation assay discriminated between nonmutagenic carcinogens and noncarcinogens; it detected 64% of the carcinogens and only 26% of the noncarcinogens. In contrast, the transformation assay detected most mutagenic chemicals, including 94% of the mutagenic carcinogens and 70% of the mutagenic noncarcinogens. Thus, transformation or Salmonella typuimurium mutagenicity assays could not discriminate mutagenic carcinogens from mutagenic noncarcinogens. Data analyses also revealed that mutagenic chemicals were more cytotoxic than nonmutagenic chemicals; 88% of the mutagens had an LD50 < 5 mM, whereas half of the nonmutagens had an LD50 > 5 mM. Binary data analyses of the same data set revealed that the transformation assay and rodent bioassay had a concordance of 71%, a sensitivity for carcinogens of 80.0%, and a specificity for detecting noncarcinogens of 60%. In contrast, Salmonella mutagenicity assays and rodent bioassays had a concordance of 63%, a sensitivity of 58%, and a specificity of 69%. The transformation assay complemented the Salmonella mutagenesis assay in the identification of nonmutagenic carcinogens; thus, the two assays had a combined 83% sensitivity for all carcinogens and a 75% specificity for nonmutagenic noncarcinogens.

3T3 Cells↗
PubMed1993

A perspective on nonmutagenic mechanisms in carcinogenesis.

Although there is compelling evidence for multiple mutagenic events in the induction of cancers, there is also substantial evidence in support of nonmutagenic mechanisms. It is proposed that the genetic basis of noninduced or spontaneous tumors, as well as cancers induced by nonmutagens, involves heritable changes in the regulation of gene expression.

Animals↗
PubMed1992

Morphological transformation of Syrian hamster embryo cells by mezerein.

Mezerein (MEZ) has been described as a weak complete tumor promoter but an effective stage II promoter in the mouse skin initiation-promotion tumor model. In this study MEZ produced a strong transformation response when tested under code in the Syrian hamster embryo (SHE) clonal morphological transformation assay. Using a standard 7-day exposure protocol designed to detect complete carcinogens, MEZ was active at non-toxic concentrations, producing a linear response between 0.3-10 ng/ml in a log-log plot of transformation activity versus concentration. These concentrations were in the same range as those which had been shown to elicit promotion activity in several in vitro cell culture systems. Our data suggest that the SHE assay has the ability to detect some tumor promoters under the same conditions used to test for complete carcinogens. The possibility that MEZ may possess in vivo carcinogenic activity cannot be excluded.

Animals↗
PubMed1991

A perspective on measurement of mutations in vivo.

The development of transgenic mouse lines with target genes that are suitable for tissue-specific mutagenesis studies is an important contribution to the field of environmental mutagenesis. These models can accommodate many of the questions relating to metabolism, distribution and relative potency of mutagens as well as providing a more comprehensive system for the identification of mutagens. However, the lesions that the field has learned about methods, development and validation from the use of in vitro systems must be applied to the development and validation of transgenic models.

Animals↗
PubMed1991

Evidence that toxic injury is not always associated with induction of chemical carcinogenesis.

Long-term rodent bioassays with chemicals administered at maximum tolerated doses identify noncarcinogens as well as carcinogens. Thirty-one chemicals recently evaluated for carcinogenic potential by the National Toxicology Program provide unique data on the relationships between mutagenicity, toxicity, and carcinogenicity. Twenty-two substances were classified as carcinogens, and nine showed no evidence of carcinogenicity. Although cellular proliferation does play an intrinsic role in neoplastic processes, the responses associated with chronic toxicity in these studies were not always sufficient to induce neoplasia. Regardless of their mutagenic potential, 19 carcinogens induced toxic effects at sites that did not show neoplastic changes; similar toxic lesions were also seen among the mutagenic and nonmutagenic noncarcinogens. Although many nonmutagens induced neoplasia at sites that showed toxic effects, some of the same chemicals also exhibited toxicity at other sites that showed no neoplastic effect. These results suggest that for some chemicals, properties other than mutagenicity or toxicity may be responsible for their carcinogenic potential.

Animals↗
PubMed1991

Classification according to chemical structure, mutagenicity to Salmonella and level of carcinogenicity of a further 39 chemicals tested for carcinogenicity by the U.S. National Toxicology Program.

This paper is an extension of compilations published previously in this journal. (Ashby and Tennant, 1988; Ashby et al., 1989). A summary of the rodent carcinogenicity bioassay data on a further 39 chemicals tested by the U.S. National Toxicology Program (NTP) is presented. An evaluation of each chemical for structural alerts to DNA-reactivity is also provided, together with a summary of its mutagenicity to Salmonella. Chemicals with an aliphatic nitro group (-C-NO2) have been added to the composite structure of DNA-reactive sub-groups. The 39 chemicals were numbered and evaluated as an extension of the earlier analysis of 264 NTP chemicals. The activity patterns and conclusions derived from the earlier studies are followed by these 39 chemicals, albeit a detailed analysis of the total database of 301 chemicals is reserved for the succeeding paper.

Carcinogenicity Tests↗
PubMed1991

Definitive relationships among chemical structure, carcinogenicity and mutagenicity for 301 chemicals tested by the U.S. NTP.

An analysis is presented in which are evaluated correlations among chemical structure, mutagenicity to Salmonella, and carcinogenicity to rats and mice among 301 chemicals tested by the U.S. NTP. Overall, there was a high correlation between structural alerts to DNA reactivity and mutagenicity, but the correlation of either property with carcinogenicity was low. If rodent carcinogenicity is regarded as a singular property of chemicals, then neither structural alerts nor mutagenicity to Salmonella are effective in its prediction. Given this, the database was fragmented and new correlations sought between the derived sub-groups. First, the 301 chemicals were segregated into six broad chemical groupings. Second, the rodent cancer data were partially segregated by target tissue. Using the previously assigned structural alerts to DNA reactivity (electrophilicity), the chemicals were split into 154 alerting chemicals and 147 non-alerting chemicals. The alerting chemicals were split into three chemical groups; aromatic amino/nitro-types, alkylating agents and miscellaneous structurally-alerting groups. The non-alerting chemicals were subjectively split into three broad categories; non-alerting, non-alerting containing a non-reactive halogen group, and non-alerting chemical with minor concerns about a possible structural alert. The tumor data for all 301 chemicals are re-presented according to these six chemical groupings. The most significant findings to emerge from comparisons among these six groups of chemicals were as follows: (a) Most of the rodent carcinogens, including most of the 2-species and/or multiple site carcinogens, were among the structurally alerting chemicals. (b) Most of the structurally alerting chemicals were mutagenic; 84% of the carcinogens and 66% of the non-carcinogens. 100% of the 33 aromatic amino/nitro-type 2-species carcinogens were mutagenic. Thus, for structurally alerting chemicals, the Salmonella assay showed high sensitivity and low specificity (0.84 and 0.33, respectively). (c) Among the 147 non-alerting chemicals less than 5% were mutagenic, whether they were carcinogens or non-carcinogens (sensitivity 0.04).

Animals↗
PubMed1991

The genetic toxicity database of the National Toxicology Program: evaluation of the relationships between genetic toxicity and carcinogenicity.

The database of the U.S. National Toxicology Program has been developed over approximately two decades, principally focused on substances evaluated for carcinogenicity in rodent bioassays. These assays generally provide data on the relative toxicity and carcinogenicity of chemicals based upon discrete subchronic (13 week) and chronic (104 week) exposures. A major value of these data are that the assay protocols, rodent strains, and technical methodologies have been generally consistent, thus permitting comparisons between assays and chemicals. The genotoxicity data for many of the same chemicals have been developed also using standardized biological systems and protocols. Data for assays including mutagenicity in Salmonella and mouse lymphoma cells, chromosomal aberrations, and sister chromatid exchange in Chinese hamster ovary cells, transformation of Balb/c 3T3 cells, and in vivo cytogenetic effects in rodents have been compiled for many chemicals. The results of all of these assays provide a substantial database for evaluating chemical effects and for defining the complex relationships between mutagenicity and carcinogenicity.

Animals↗
PubMed1990

Evaluation of four in vitro genetic toxicity tests for predicting rodent carcinogenicity: confirmation of earlier results with 41 additional chemicals.

The effectiveness of four in vitro short-term tests (STT) for genetic toxicity, induction of mutations in Salmonella (SAL) and mouse lymphoma L5178Y cells (MLA), and induction of sister chromatid exchanges (SCE) and chromosome aberrations (ABS) in Chinese hamster ovary cells that are used for predicting rodent carcinogenicity were examined. The in vitro results were compared with the results from 41 rodent carcinogenicity studies performed by the National Toxicology Program. The predictive values of, and interrelationships among, the STT for these 41 chemicals were similar to those previously reported for 73 chemicals and confirm those earlier results [Tennant RW, Margolin BH, Shelby MD, Zeiger E, Haseman JK, Spalding J, Caspary W, Resnick M, Stasiewicz S, Anderson B, Minor R (1987): Science 236:933-941]. Because of this similarity among the two datasets, the chemicals were combined into a single dataset of 114. The results with 114 chemicals show that SAL had the lowest sensitivity (.48) and the highest specificity (.91), whereas MLA had the highest sensitivity (.72) and the lowest specificity (.40). The concordances of the test results with rodent carcinogenicity were .66, .61, .59, and .59, for SAL, ABS, SCE, and MLA, respectively. Salmonella was the most predictive for carcinogenicity; 89% of the chemicals mutagenic in SAL were carcinogenic in rodents, however a negative result in any or all of the STT was not indicative of noncarcinogenicity. The STT results reported here show good agreement with the potential electrophilicity of the chemicals, and the majority of carcinogens that are undetected by the STT do not have an electrophilic structure. There was no complementarity among the tests and no combination of the four tests was more effective than any single test for predicting carcinogenicity.

Animals↗