Biomedical subjects

H F Stack

Publications and source records attributed to H F Stack.

At least 19 recordsLinked to original sources

PubMed2000

A review of the genetic and related effects of 1,3-butadiene in rodents and humans.

In this paper, the metabolism and genetic toxicity of 1,3-butadiene (BD) and its oxidative metabolites in humans and rodents is reviewed with attention to newer data that have been published since the latest evaluation of BD by the International Agency for Research on Cancer (IARC). The oxidative metabolism of BD in mice, rats and humans is compared with emphasis on the major pathways leading to the reactive intermediates 1,2-epoxy-3-butene (EB), 1,2:3, 4-diepoxybutane (DEB), and 3,4-epoxy-1,2-butanediol (EBdiol). Results from recent studies of DNA and hemoglobin adducts indicate that EBdiol may play a more significant role in the toxicity of BD than previously thought. All three metabolites are capable of reacting with macromolecules, such as DNA and hemoglobin, and have been shown to induce a variety of genotoxic effects in mice and rats as well as in human cells in vitro. DEB is clearly the most potent of these genotoxins followed by EB, which in turn is more potent than EBdiol. Studies of mutations in lacI and lacZ mice and of the Hprt mutational spectrum in rodents and humans show that mutations at G:C base pairs are critical events in the mutagenicity of BD. In-depth analyses of the mutational spectra induced by BD and/or its oxidative metabolites should help to clarify which metabolite(s) are associated with specific mutations in each animal species and which mutational events contribute to BD-induced carcinogenicity. While the quantitative relationship between exposure to BD, its genotoxicity, and the induction of cancer in occupationally exposed humans remains to be fully established, there is sufficient data currently available to demonstrate that 1,3-butadiene is a probable human carcinogen.

Air Pollutants, Occupational↗

PubMed1999

A survey of EPA/OPP and open literature on selected pesticide chemicals. II. Mutagenicity and carcinogenicity of selected chloroacetanilides and related compounds.

With this effort, we continue our examination of data on selected pesticide chemicals and their related analogues that have been presented to the U.S. Environmental Protection Agency's (USEPA's) Office of Pesticide Programs (OPP). This report focuses on a group of selected chloroacetanilides and a few related compounds. As part of the registration process for pesticidal chemicals, interested parties (registrants) must submit toxicity information to support the registration including both mutagenicity and carcinogenicity data. Although this information is available to the public via Freedom of Information (FOI) requests to the OPP, publication in the scientific literature allows greater dissemination and examination of the data. For this Special Issue, graphic profiles have been prepared of the mutagenicity and carcinogenicity data available in the submissions to OPP. Also, a discussion is presented about how toxicity data are used to help establish tolerances (limits of pesticide residues in foods). The mutagenicity results submitted by registrants are supplemented by data on these chemicals from the open literature to provide a full perspective of their genetic toxicology. The group of chloroacetanilides reviewed here display a consistent pattern of mutagenic activity, probably mediated via metabolites. This mutagenic activity is a mechanistically plausible factor in the development of tumors seen in experimental animals exposed to this class of chemicals.

Acetamides↗

PubMed1999

Genetic toxicology data in the evaluation of potential human environmental carcinogens.

In 1969, the International Agency for Research on Cancer (IARC) initiated the Monographs Programme to evaluate the carcinogenic risk of chemicals to humans. Results from short-term mutagenicity tests were first included in the IARC Monographs in the mid-1970s based on the observation that most carcinogens are also mutagens, although not all mutagens are carcinogens. Experimental evidence at that time showed a strong correlation between mutagenicity and carcinogenicity and indicated that short-term mutagenicity tests are useful for predicting carcinogenicity. Although the strength of these correlations has diminished over the past 20 years with the identification of putative nongenotoxic carcinogens, such tests provide vital information for identifying potential human carcinogens and understanding mechanisms of carcinogenesis. The short-term test results for agents compiled in the EPA/IARC Genetic Activity Profile (GAP) database over nearly 15 years are summarized and reviewed here with regard to their IARC carcinogenicity classifications. The evidence of mutagenicity or nonmutagenicity based on a 'defining set' of test results from three genetic endpoints (gene mutation, chromosomal aberrations, and aneuploidy) is examined. Recommendations are made for assessing chemicals based on the strength of evidence from short-term tests, and the implications of this approach in identifying mutational mechanisms of carcinogenesis are discussed. The role of short-term test data in influencing the overall classification of specific compounds in recent Monograph volumes is discussed, particularly with reference to studies in human populations. Ethylene oxide is cited as an example.

Animals↗

PubMed1999

Short-term tests for defining mutagenic carcinogens.

The results of short-term tests for mutagenicity were first included in the IARC Monographs in the mid-1970s on the basis of the observation that most carcinogens are also mutagens, although not all mutagens are carcinogens. The experimental evidence at that time showed a strong correlation between mutagenicity and carcinogenicity and indicated that the short-term tests were useful for predicting carcinogenicity. Although the correlations have become weaker over the past 20 years, and with them the predictive value of short-term tests, such tests still provide vital information for identifying and understanding mechanisms involved in carcinogenicity. The results of short-term tests compiled in the US Environmental Protection Agency-IARC Genetic Activity Profile database over the past 12 years are summarized and reviewed here in relation to the classification of agents for carcinogenicity within the system used at IARC. The role of the information from short-term tests in making overall classifications of specific compounds in recent Monographs is discussed. The usefulness of data on three genetic end-points, gene mutation, chromosomal aberrations and aneuploidy, and the criteria for mutagenicity and lack of mutagenicity based on a 'defining set' of test results are examined. Recommendations are made for assessing chemicals on the basis of the strength of the evidence from short-term tests, and the implications of this approach for identifying putative mutational mechanisms of carcinogenicity are discussed.

Aneuploidy↗

PubMed1998

Inhibition of genotoxic effects of mammalian germ cell mutagens.

Germ cell mutagens are among the most important chemicals for which chemopreventive agents should be sought and mechanistically defined. These mutagens may include environmental chemicals as well as drugs. In this investigation, the literature was reviewed for substances antimutagenic (or anticlastogenic) to compounds identified as mutagens in at least two germ cell studies. A complete matrix of test results was prepared to identify commonly tested pairs of germ cell mutagens and antimutagens. The categories of antimutagens most tested included vitamins, fatty acids, thiols, tannins and other phenolics. The most frequently studied mutagens were benzo[a]pyrene, cyclophosphamide, mitomycin C, and bleomycin. Based on the availability of the most relevant data, the analysis presented here focused on in vivo tests, specifically on bone marrow cytogenetics. The results indicated that antimutagens commonly found in the diet or endogenously in the body effectively antagonized the cytogenetic damage induced in the bone marrow by most of the germ cell mutagens studied to date. Bone marrow micronucleus and chromosomal aberration assays, which detect systemically active mutagens, may be predictive of similar mitigating effects in germ cells. Test results from antimutagenicity studies in germ cells, though limited, were comparable to the results from studies in the mouse bone marrow micronucleus test.

Animals↗

PubMed1998

Heritable and cancer risks of exposures to anticancer drugs: inter-species comparisons of covalent deoxyribonucleic acid-binding agents.

In the past years, several methodologies were developed for potency ranking of genotoxic carcinogens and germ cell mutagens. In this paper, we analyzed six sub-classes of covalent deoxyribonucleic acid (DNA) binding antineoplastic drugs comprising a total of 37 chemicals and, in addition, four alkyl-epoxides, using four approaches for the ranking of genotoxic agents on a potency scale: the EPA/IARC genetic activity profile (GAP) database, the ICPEMC agent score system, and the analysis of qualitative and quantitative structure-activity and activity-activity relationships (SARs, AARs) between types of DNA modifications and genotoxic endpoints. Considerations of SARs and AARs focused entirely on in vivo data for mutagenicity in male germ cells (mouse, Drosophila), carcinogenicity (TD50s) and acute toxicity (LD50s) in rodents, whereas the former two approaches combined the entire database on in vivo and in vitro mutagenicity tests. The analysis shows that the understanding and prediction of rank positions of individual genotoxic agents requires information on their mechanism of action. Based on SARs and AARs, the covalent DNA binding antineoplastic drugs can be divided into three categories. Category 1 comprises mono-functional alkylating agents that primarily react with N7 and N3 moieties of purines in DNA. Efficient DNA repair is the major protective mechanism for their low and often not measurable genotoxic effects in repair-competent germ cells, and the need of high exposure doses for tumor induction in rodents. Due to cell type related differences in the efficiency of DNA repair, a strong target cell specificity in various species regarding the potency of these agents for adverse effects is found. Three of the four evaluation systems rank category 1 agents lower than those of the other two categories. Category 2 type mutagens produce O-alkyl adducts in DNA in addition to N-alkyl adducts. In general, certain O-alkyl DNA adducts appear to be slowly repaired, or even not at all, which make this kind of agents potent carcinogens and germ cell mutagens. Especially the inefficient repair of O-alkyl-pyrimidines causes the high mutational response of cells to these agents. Agents of this category give high potency scores in all four expert systems. The major determinant for the high rank positions on any scale of genotoxic of category 3 agents is their ability to induce primarily structural chromosomal changes. These agents are able to cross-link DNA. Their high intrinsic genotoxic potency appears to be related to the number of DNA cross-links per target dose unit they can induce. A confounding factor among category 3 agents is that often the genotoxic endpoints occur close to or at toxic levels, and that the width of the mutagenic dose range, i.e., the dose area between the lowest observed effect level and the LD50, is smaller (usually no more than 1 logarithmic unit) than for chemicals of the other two categories. For all three categories of genotoxic agents, strong correlations are observed between their carcinogenic potency, acute toxicity and germ cell specificity.

Animals↗

PubMed1997

Activity profiles of carcinogenicity data: application in hazard identification and risk assessment.

Animal cancer data play a primary role in human risk assessment due to the limited epidemiological data. The current database of test results from the NCI/NTP rodent bioassays provide valuable information concerning the carcinogenic potential of hundreds of environmental agents. An approach is presented to reduce and graphically display these data as activity profiles to allow visualization and assessment of tumor response trends across multiple parameters, e.g. species, sex, target site, and route of exposure. Spreadsheet graphics are used to construct the profiles organized on the multiple parameters of carcinogenicity in a format that enables comparative analysis among chemicals. Several example applications are described to illustrate the value of activity profiles in hazard identification and risk assessment. The NCI/NTP data used in developing this concept are from the Carcinogen Potency Database (CPDB) complied by Gold et al. (Environ. Health Perspect. 103 (Suppl. 8) (1995) 3-122). Computer links to the underlying details in the CPDB are maintained such that specific histopathologies at individual tumor sites, duration of the study, dose-response data, and notes related to diet, survival, treatments, and the authors evaluation are available to aid in the assessment process. The profiles display carcinogen potency based on the tumorigenic dose rate 50 (TD50), i.e. the chronic dose rate that would induce tumors in half of the test animals at the end of their standard lifespan adjusting for spontaneous tumors. The TD50 values provide an index for establishing a relative potency ranking of the chemicals for any specific parameter, such as species or target site. An example ranking of hepatocarcinogens is presented to illustrate relative potencies for chemical analogs. The rank order indicates that the degree and type of halogenation of alkanes has a direct bearing on the carcinogenic potency of these compounds.

Administration, Oral↗

PubMed1996

Genetic activity profiles of anticancer drugs.

The results from short-term tests for genetic and related effects, abstracted from the open literature for 36 anticancer drugs, are examined in this review. Data for 27 of these agents are available in the EPA/IARC Genetic Activity Profile (GAP) database. Data summaries, including data listings and activity profiles, are presented for nine anticancer drugs added to the GAP database for this analysis. Genetic toxicity data from the recent literature are included for the additional agents to provide a broader representation of the categories of drugs being evaluated. These categories, based on the chemical mode of action, are covalent and noncovalent DNA-binding drugs, topoisomerase II inhibitors, antimetabolites, mitotic spindle inhibitors, and drugs which affect endocrine function. The qualitative data for all 36 drugs are summarized in this report and findings are presented from pair-wise matching of genetic activity profiles, based on test results in common, for some chemical analogs. The significance of germ cell test results for some of these drugs and their implication in assessing risk of heritable genetic disease are discussed.

Animals↗

PubMed1996

Activity profiles of antimutagens: in vitro and in vivo data.

In this review, retinol, chlorophyllin, and N-acetylcysteine are examined and compared with regard to their antimutagenic activity against some promutagens and a group of direct-acting alkylating agents. The promutagens included aflatoxin B1, certain polycyclic aromatic hydrocarbons (e.g., benzo[a]pyrene), and certain heterocyclic amines (e.g., food pyrolysates). Results of antimutagenicity testing selected from data surveyed in the published literature are displayed graphically as activity profiles of antimutagens showing both the doses tested and the extent of inhibition or enhancement of mutagenic activity. All three antimutagens are discussed in terms of their putative mechanisms of action in vitro and in vivo with emphasis on the xenobiotic metabolizing enzyme systems.

Acetylcysteine↗

PubMed1996

Human exposures to mutagens--an analysis using the genetic activity profile database.

The Genetic Activity Profile (GAP) database was used to identify and compare agents showing genotoxic activity in humans. The database revealed several substances for which both human and rodent cytogenetic data existed. Based on the ratio of the lowest effective doses (LEDs) in rodents versus human studies, humans appear to be at least 10 times more sensitive than rodents to the majority of the genotoxic substances examined. Several caveats are discussed which may be responsible, in part, for the apparent differences in sensitivity. Some of these differences could be due to variations in the test protocols or they may, in fact, reflect real differences between human and rodent cells. However, in contrast to the in vivo comparison, the LEDs for human data from in vitro studies were not uniformly lower than for comparable studies in rodents. The in vitro comparison suggests that the apparent differences in human versus rodent cell sensitivity seen in vivo must be viewed with a degree of caution. Nevertheless, the overall GAPs for these agents, and particularly the human in vivo data, underscore the concern for adequate protection of humans exposed to these environmental mutagens.

Animals↗

PubMed1996

Interpretation of short-term test data: implications for assessment of chemopreventive activity.

The same short-term tests that have been used extensively to identify mutagens and potential carcinogens are increasingly being used to identify antimutagens and potential anticarcinogens. It is not yet known whether the inhibition of carcinogen-induced mutation is a good indicator of anticarcinogenicity, as the available data on the inhibition of both carcinogenicity and mutagenicity In vivo are still quite incomplete. Furthermore, in vitro tests will detect only those compounds that show an effect that is demonstrable in vitro, such as direct inhibition of the metabolism of the carcinogen or inactivation of the carcinogen by direct reaction. Thus it is essential to confirm putative antimutagenic activity observed in vitro through the use of animal models. Indeed, the interpretation of antimutagenicity data from short-term tests must be subjected to all of the considerations that apply in the interpretation of mutagenicity test results. Moreover, the experimental variable of the antimutagens used must be considered in addition to the variables of the mutagens and short-term tests used. To analyse published results on antimutagens in short-term tests, we have developed the concept of activity profile listings and plots for antimutagens - an approach already used successfully for mutagenicity data. The activity profiles permit rapid visualization of considerable data and experimental parameters, including the inhibition as well as enhancement of mutagenic activity. Here we focus on the use of this methodology to interpret antimutagenicity data for retinol and chlorophyllin against several classes of mutagens in short-term tests.

Anticarcinogenic Agents↗

PubMed1994

The performance of short-term tests in identifying potential germ cell mutagens: a qualitative and quantitative analysis.

A retrospective analysis was undertaken to assess the performance of selected short-term tests in the discrimination of mammalian germ cell mutagens and nonmutagens using data derived from the U.S. Environmental Protection Agency/International Agency for Research on Cancer Genetic Activity Profile (EPA/IARC GAP) and EPA GENE-TOX databases. The short-term tests selected were gene mutation in Salmonella (S. typhimurium), cultured mammalian cell gene mutation and chromosomal aberrations, and mammalian bone marrow cytogenetics (micronucleus and chromosomal aberrations). These are the first level tests used in the EPA mutagenicity testing guidelines. The results of this analysis showed good sensitivity of short-term in vitro tests for mammalian cell gene mutation (96%) or chromosomal aberrations (92%) in identifying germ cell mutagens, while the sensitivity of tests for gene mutation in S. typhimurium was lower (79%). Bone marrow micronucleus or chromosomal aberration assays in vivo each displayed a sensitivity of 96%. Thus, both the in vitro and in vivo tests may be used effectively to screen chemicals for potential germ cell mutagenicity. In contrast, the in vitro tests mentioned above performed poorly in discriminating putative germ cell nonmutagens, giving results for specificity at or below what is expected due to chance alone (50-11%). The bone marrow assays were more efficient in this regard, the micronucleus test yielding a specificity of 63% and the chromosomal aberrations assay 64%. The mouse bone marrow micronucleus test also performed well on a quantitative basis, responding at or below the lowest effective doses tested in the mouse dominant lethal assay. Regression analysis of the mean lowest effective doses of chemicals evaluated in vivo showed approximately 1:1 linear correlations for mouse germ cell assays (heritable translocation vs dominant lethal or specific locus tests) as well as for mouse bone marrow assays (micronucleus vs chromosomal aberration). The results suggest the value of the bone marrow micronucleus test as an assay for potential germ cell mutagenicity and the dominant lethal test as a relatively inexpensive choice for confirmation of germ cell damage. The sensitivity of the in vitro assays investigated and the discriminatory capability of the in vivo bone marrow assay affirmed the utility of these tests within the framework of the EPA mutagenicity testing guidelines.

Animals↗

PubMed1993

The genetic toxicology of putative nongenotoxic carcinogens.

This report examines a group of putative nongenotoxic carcinogens that have been cited in the published literature. Using short-term test data from the U.S. Environmental Protection Agency/International Agency for Research on Cancer genetic activity profile (EPA/IARC GAP) database we have classified these agents on the basis of their mutagenicity emphasizing three genetic endpoints: gene mutation, chromosomal aberration and aneuploidy. On the basis of results of short-term tests for these effects, we have defined criteria for evidence of mutagenicity (and nonmutagenicity) and have applied these criteria in classifying the group of putative nongenotoxic carcinogens. The results from this evaluation based on the EPA/IARC GAP database are presented along with a summary of the short-term test data for each chemical and the relevant carcinogenicity results from the NTP, Gene-Tox and IARC databases. The data clearly demonstrate that many of the putative nongenotoxic carcinogens that have been adequately tested in short-term bioassays induce gene or chromosomal mutations or aneuploidy.

Aneuploidy↗

PubMed1993

A survey of EPA/OPP and open literature data on selected pesticide chemicals tested for mutagenicity. I. Introduction and first ten chemicals.

Parties interested in registering a pesticide chemical with the U.S. Environmental Protection Agency's (USEPA's) Office of Pesticide Programs (OPP) must submit toxicity information to support the registration. Mutagenicity data are a part of the required information that must be submitted. This information is available to the public via Freedom of Information requests to the OPP. However, it is felt that this information would be more effectively and widely disseminated if presented in a published medium. Beginning with this publication, sets of mutagenicity data on pesticide chemicals will be periodically published in the Genetic Activity Profile (GAP) format. In addition, mutagenicity data extracted from the currently available open literature is also presented to provide a more complete database and to allow comparisons between the OPP-submitted data and other publicly available information.

Animals↗

PubMed1993

Hazard identification: efficiency of short-term tests in identifying germ cell mutagens and putative nongenotoxic carcinogens.

For more than a decade, mutagenicity tests have had a clearly defined role in the identification of potential human mutagens and an ancillary role in the identification of potential human carcinogens. The efficiency of short-term tests in identifying germ cell mutagens has been examined using a combined data set derived from the U.S. Environmental Protection Agency/International Agency for Research on Cancer Genetic Activity Profile (EPA/IARC GAP) and EPA Gene-Tox databases. Our review of these data indicates adequate sensitivity of batteries of in vitro short-term mutagenicity tests in identifying germ cell mutagens. The analysis also supports the inclusion of an in vivo assay as suggested in proposed regulatory testing guidelines. In the context of carcinogenicity testing, the ability of short-term bioassays to detect genotoxic or mutagenic carcinogens is well established. Such tests are not considered to be as sensitive to nongenotoxic or nonmutagenic carcinogens. However, analyses presented in this report using the EPA/IARC GAP database demonstrate that many putative nongenotoxic carcinogens that have been adequately tested in short-term genetic bioassays induce gene or chromosomal mutation or aneuploidy. Further investigation should reveal whether the mutagenicity of these agents plays an important mechanistic role in their carcinogenicity.

Animals↗

PubMed1992

Antimutagenicity profiles of some natural substances.

Selected antimutagenicity listings and profiles have been prepared from the literature on the antimutagenicity of retinoids and the carotenoid beta-carotene. The antimutagenicity profiles show: (1) a single antimutagen (e.g., retinol) tested in combination with various mutagens or (2) antimutagens tested against a single mutagen (e.g., aflatoxin B1). Data are presented in the profiles showing a dose range for a given antimutagen and a single dose for the corresponding mutagen; inhibition as well as enhancement of mutagenic activity is indicated. Information was found in the literature on the testing of selected combinations of 16 retinoids and carotenoids vs. 33 mutagens. Of 528 possible antimutagen-mutagen combinations, only 82 (16%) have been evaluated. The most completely evaluated retinoids are retinol (28 mutagens), retinoic acid and retinol acetate (7 mutagens each), and retinal and retinol palmitate (6 mutagens each). beta-Carotene is the most frequently tested carotenoid (15 mutagens). Of the remaining retinoids and carotenoids, 8 were evaluated in combination with a single mutagen and the other 2 were tested against only 2 or 3 mutagens. Most of the data on antimutagenicity in vitro are available for S. typhimurium strains TA98 and TA100. Substantial data also are available for sister-chromatid exchanges in vitro and chromosome aberrations in vitro and in vivo. This report emphasizes the metabolic as well as the antimutagenic effects of retinoids in vitro and in vivo.

Aflatoxin B1↗

PubMed1991

Activity profiles of developmental toxicity: design considerations and pilot implementation.

The available literature was searched for quantitative test results from both in vitro and in vivo assays for developmental toxicity for five model compounds: cyclophosphamide, methotrexate, hydroxyurea, caffeine, and ethylenethiourea. These compounds were chosen on the basis of their extensive utilization in a variety of assay systems for developmental toxicity as evidenced by their representation in the ETIC database (each generally has 100-500 citations encompassing multiple test systems). Nine cellular-based assays, six assays using whole embryos in culture, as well as Segment II and abbreviated exposure tests for mammalian test species are included in the database. For each assay, the critical endpoints were identified, each of which was then provided a three-letter code, and the criteria for extraction of quantitative information were established. The extracted information was placed into a computerized reference file and subsequently plotted such that the qualitative (positive/negative) and quantitative (e.g., IC50, highest ineffective dose (HID), lowest effective dose (LED] results across all test systems could be displayed. The information contained in these profiles can be used to compare qualitative and quantitative results across multiple assay systems, to identify data gaps in the literature, to evaluate the concordance of the assays, to calculate relative potencies, and to examine structure-activity relationships.

Animals↗

PubMed1991

The Genetic Activity Profile database.

A graphic approach termed a Genetic Activity Profile (GAP) has been developed to display a matrix of data on the genetic and related effects of selected chemical agents. The profiles provide a visual overview of the quantitative (doses) and qualitative (test results) data for each chemical. Either the lowest effective dose (LED) or highest ineffective dose (HID) is recorded for each agent and bioassay. Up to 200 different test systems are represented across the GAP. Bioassay systems are organized according to the phylogeny of the test organisms and the end points of genetic activity. The methodology for the production and evaluation of GAPs has been developed in collaboration with the International Agency for Research on Cancer. Data on individual chemicals have been compiled by IARC and by the U.S. Environmental Protection Agency. Data are available on 299 compounds selected from volumes 1-50 of the IARC Monographs and on 115 compounds identified as Superfund Priority Substances. Software to display the GAPs on an IBM-compatible personal computer is available from the authors. Structurally similar compounds frequently display qualitatively and quantitatively similar GAPs. By examining the patterns of GAPs of pairs and groups of chemicals, it is possible to make more informed decisions regarding the selection of test batteries to be used in evaluating chemical analogs. GAPs have provided useful data for the development of weight-of-evidence hazard ranking schemes. Also, some knowledge of the potential genetic activity of complex environmental mixtures may be gained from assessing the GAPs of component chemicals. The fundamental techniques and computer programs devised for the GAP database may be used to develop similar databases in other disciplines.

Animals↗