Biomedical subjects

F K Ennever

Publications and source records attributed to F K Ennever.

30 records · Page 2Linked to original sources

PubMed1988

The influence of the proportion of carcinogens on the cost-effectiveness of short-term tests.

The cost-effectiveness of using short-term genotoxicity tests to screen unknown chemicals for carcinogenicity depends upon the inherent reliability of the tests (sensitivity, or fraction of carcinogens giving positive results, and specificity, or fraction of non-carcinogens giving negative results) and also upon the proportion of carcinogens in the population of chemicals to be screened. Individual tests may be combined into batteries to improve reliability; however, this requires decision rules to declare the overall result positive or negative. A framework for developing such rules based upon minimizing costs of false-positives and false-negatives was presented in a seminal paper by Lave and Omenn (1986, Nature (London), 324, 29-34). We have extended their work, which is based on logit analysis, to consider, using Bayes' theorem, the influence of the proportion of carcinogens upon the decision rules for declaring a battery result positive or negative. If the proportion of carcinogens is high (20% or greater), then the most effective tests are those with high sensitivity, and if the proportion of carcinogens is low, then the most effective tests are those with high specificity.

Animals↗

PubMed1988

Methodologies for interpretation of short-term test results which may allow reduction in the use of animals in carcinogenicity testing.

Assessment of the risk to humans posed by chemical substances currently relies primarily on experimental exposure of animals in lifetime feeding studies. Short-term tests for genotoxicity are much less costly and use fewer or no animals, but have not replaced the long-term animal bioassay because their results do not coincide completely. We have developed methodologies for interpretation of short-term tests which improve the usefulness of their results, and may allow them to replace the long-term animal bioassay in some circumstances.

Animal Testing Alternatives↗

PubMed1987

Evaluating the potential for genotoxic carcinogenicity of methyl isocyanate.

The carcinogenicity prediction and battery selection method was used to predict the probability of carcinogenicity of methyl isocyanate (MIC) based upon the results of short-term tests. The analysis predicts that MIC has a significant potential for inducing cancer in rodents. However, the pattern of response suggests that the carcinogenic potency would be low. Obviously, the realization of the identified risk would be dependent upon level, duration, and mode of exposure.

Animals↗

PubMed1987

Evaluation of the genotoxicity of theobromine and caffeine.

Published data on the mutagenicity and genotoxicity of theobromine and caffeine were analysed by the Carcinogen Prediction and Battery Section (CPBS) method. In spite of some positive responses, these analyses did not predict for theobromine a potential for causing cancer by virtue of a genotoxic mechanism. Caffeine, on the other hand, clearly has potential for genotoxic carcinogenicity. The predictive performance of cost-effective batteries consisting of selected combinations of four assays was also evaluated. The predictions were similar to those derived when all the available test results were considered.

Bayes Theorem↗

PubMed1987

Prediction of carcinogenic potency by short-term genotoxicity tests.

Past attempts to correlate carcinogenic potencies of chemicals with potencies in causing mutations or other endpoints in short-term genotoxicity tests have found quantitative correlations to be weak except for restricted classes of chemicals. We have classified 379 chemicals on the basis of the rodent carcinogenic potencies calculated by Gold and co-workers as strong carcinogens, moderate carcinogens, weak carcinogens, or non-carcinogens, and have compared the qualitative results of short-term tests (positive or negative) for each of the four classes of chemicals. For most of the short-term tests analyzed, the proportion of positive results increased with carcinogenic potency, being highest for strong carcinogens, lower for moderate carcinogens, lower still for weak carcinogens, and least for non-carcinogens. This differential sensitivity based on carcinogenic potency implies that short-term test responses could be used to predict the carcinogenic potency of unknown chemicals. We have quantified these predictions using Bayesian analysis so that positive or negative results in short-term tests can be interpreted as predicting that a chemical may be a strong carcinogen, a moderate carcinogen, a weak carcinogen, or a non-carcinogen. Possible screening strategies based on these predictions are discussed.

Animals↗

PubMed1987

The predictivity of animal bioassays and short-term genotoxicity tests for carcinogenicity and non-carcinogenicity to humans.

The successful use of surrogate tests to predict whether a chemical may be carcinogenic to humans requires that the tests be both sensitive (few false negatives) and specific (few false positives). To assess specificity, results for non-carcinogens must be compared. Although no chemicals have been definitively shown not to cause cancer in humans, we have identified 29 chemicals for which some evidence of non-carcinogenicity exists in evaluations by the International Agency for Research on Cancer. Twenty of these probable non-carcinogens have been tested for rodent carcinogenicity in animal bioassays; 19 were positive and only one was negative, indicating that the specificity of animal bioassays is low. The sensitivity of animal bioassays, however, is very high: all definite human carcinogens adequately tested were positive. Most short-term tests which measure genotoxicity or transformation also had low specificity; however, four tests gave predominantly negative results for probable human non-carcinogens as well as predominantly positive results for definite human carcinogens. These results are based on comparison of small numbers of chemicals, but do suggest the need for more investigation of the relationships of genotoxicity and rodent carcinogenicity to carcinogenicity in humans.

Animals↗

PubMed1986

Short-term test results for NTP noncarcinogens: an alternate, more predictive battery.

A battery of short-term tests used to predict whether or not a chemical is a carcinogen must be both sensitive (correctly identifying carcinogens) and specific (correctly identifying noncarcinogens). A recent publication [Shelby and Stasiewicz, 1984, Environ Mutagen 6:871-876] of results in four short-term tests for 70 noncarcinogens tested under the aegis of the National Toxicology Program (NTP) indicates that the battery of short-term tests lacked specificity. We have analyzed these results using the Carcinogen Prediction and Battery Selection (CPBS) procedure and calculated that the specificity of the NTP battery is indeed very low, i.e., 0.50. Using published data from NTP, the Gene Tox program of EPA, and the collaborative study of the WHO International Programme on Chemical Safety, we have constructed an alternate battery that has fewer false positives; this battery has a specificity of 0.80. Thus, the lack of specificity of the original NTP battery does not imply that no set of short-term tests is able to predict carcinogenicity accurately.

Mutagenicity Tests↗

PubMed1986

Invited contribution: an objective approach to the development of short-term tests predictive of carcinogenicity.

The Carcinogenicity Prediction and Battery Selection procedure was developed to address two problems: (1) the identification of highly predictive, yet cost-effective, batteries of short-term tests and (2) the objective prediction of the potential carcinogenicity of chemicals based upon the results of short-term tests even when a mixture of positive and negative results is obtained. In the present report the usefulness of the Carcinogenicity Prediction and Battery Selection procedure is demonstrated using benzo[a]pyrene, benzoin and diethylstilbestrol as examples. In addition, its applicability in the analysis of all the possible outcomes of a battery is illustrated together with an analysis of the worth of additional testing.

Animals↗

PubMed1986

Predicting the carcinogenicity of the aromatic amine derivatives tested in the second UKEMS Collaborative Study.

The carcinogenicity prediction and battery selection (CPBS) procedure was used to analyze the short-term in vitro and in vivo genotoxicity results obtained during the Second UKEMS Collaborative Study. In accordance with preliminary animal bioassay results, CPBS predicted correctly the carcinogenicity of benzidine, 4,4"-diaminoterphenyl and 4-dimethylaminoazobenzene. CPBS predicted the non-carcinogenicity of 4-cyanodimethylaniline, a chemical of as yet unknown carcinogenicity. Moreover, CPBS indicated that for the chemicals included in the UKEMS study, highly predictive as well as cost-effective batteries consisting of three short-term assays could be identified.

Aniline Compounds↗

PubMed1986

Evaluating batteries of short-term genotoxicity tests.

Selecting a battery of short-term genotoxicity tests suitable for screening unknown chemicals for carcinogenicity can be a large combinatorial task because of the great number of short-term tests currently available. Biological criteria, such as requirements for different targets and endpoints, can reduce the number of possible combinations. An independent yet potentially complementary approach which we have developed uses Bayes' theorem to predict carcinogenicity from results (positive or negative) in short-term tests. Batteries can be evaluated by their predictivity, calculated with Bayes' theorem from the sensitivities and specificities of the component tests. Our analyses indicate that tests which contribute most to a battery's predictivity are those which are both sensitive and specific, which we call Class I tests. Because few of the currently available tests are Class I, we have extended our analyses to consider when other types of tests must be substituted for Class I tests, the purpose of a particular test program will influence the choice. In order to obtain the best predictions for all chemicals, a battery should include an equal number of Class II tests (i.e. those that are sensitive but are not specific) and Class III tests (i.e. those that are not sensitive but are specific). However, for the purpose of reducing the number of carcinogens erroneously classified as non-carcinogenic, Class II tests contribute about twice as much to the predictivity of a battery as do Class III tests, and for the purpose of reducing the number of non-carcinogens erroneously classified as carcinogenic, Class II tests contribute about half as much as Class III tests.(ABSTRACT TRUNCATED AT 250 WORDS)

Mutagenicity Tests↗

PubMedDate not supplied

Quantifying genotoxicity and non-genotoxicity.

Since the ability to induce genotoxicity is often equated with the potential for initiating the carcinogenic process, a method for quantitating genotoxicity would provide a useful measure for this potential. It is demonstrated herein that CPBS, the Carcinogenicity Prediction and Battery Selection method, provides a useful quantitative measure of genotoxicity as well as allowing for the detailed evaluation of the performance of batteries of short-term tests in order to select those predictive of carcinogenic potential.

Animals↗

PubMedDate not supplied

The ability of plant genotoxicity assays to predict carcinogenicity.

A number of assays have been developed which use higher plants for measuring mutagenic or cytogenetic effects of chemicals, as an indication of carcinogenicity. Plant assays require less extensive equipment, materials and personnel than most other genotoxicity tests, which is a potential advantage, particularly in less developed parts of the world. We have analyzed data on 9 plant genotoxicity assays evaluated by the Gene-Tox program of the U.S. Environmental Protection Agency, using methodologies we have recently developed to assess the capability of assays to predict carcinogenicity and carcinogenic potency. All 9 of the plant assays appear to have high sensitivity (few false negatives). Specificity (rate of true negatives) was more difficult to evaluate because of limited testing on non-carcinogens; however, available data indicate that only the Arabidopsis mutagenicity (ArM) test appears to have high specificity. Based upon their high sensitivity, plant genotoxicity tests are most appropriate for a risk-averse testing program, because although many false positives will be generated, the relatively few negative results will be quite reliable.

Carcinogens↗