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M D Waters

Publications and source records attributed to M D Waters.

At least 19 recordsLinked to original sources

EC/US workshop report: assessment of genetic risks associated with exposure to ethylene oxide, acrylamide, 1,3-butadiene and cyclophosphamide.

The EC/US Workshop on Risk Assessment: 'Human Genetic Risks from Exposure to Chemicals, Focusing on the Feasibility of a Parallelogram Approach' had as its main objective the identification of the methodology, data requirements and mechanistic research to understand the human health impact of germ cell mutagens. Specifically, it represented an evaluation of current knowledge and the identification of future research needs for a more precise assessment of human genetic risks from exposure to mutagenic chemicals. Four chemicals were selected for review at the Workshop and in this Special Issue: ethylene oxide, 1,3-butadiene, acrylamide, and cyclophosphamide. The first three are important industrial chemicals with substantial use worldwide and, therefore, considerable potential for human exposure. The fourth, cyclophosphamide, is a commonly used cancer chemotherapeutic agent. This Special Issue contains the major scientific reports from the workshop. These include four Introductory Papers (on the parallelogram concept, alternative genetic risk assessment approaches, regulatory data needs, and the research background for risk assessment of ethylene oxide), four Working Group Reports on the specific compounds mentioned above and, finally, three Crosscutting Papers pertinent to the issue of germ-line mutagenesis and genetic risk estimation.

Acrylamide

Meeting report of the EC/US workshop on genetic risk assessment: "human genetic risks from exposure to chemicals, focusing on the feasibility of a parallelogram approach".

This workshop was the concept of Professor Frits Sobels who passed away on the 6th of July 1993. The underlying idea of the Sobels' parallelogram approach is that an estimate (corrected by DNA-adduct dosimetry) of the genetic damage in human germ cells can be obtained by measuring a common endpoint in human and mouse somatic cells (such as gene mutation in lymphocytes) and in germ cells of mice, the desired target tissue inaccessible in humans. The main objective of the workshop was to identify the methodology, data requirements and mechanistic research to understand the human health impact of germ-cell mutagens. 4 chemicals were selected for review at the meeting: ethylene oxide, 1,3-butadiene, acrylamide and cyclophosphamide. The first 3 are important industrial chemicals with substantial use worldwide and, therefore, considerable potential human exposure. The 4th, cyclophosphamide, is a commonly used cancer chemotherapeutic agent. This first EC/US workshop on risk assessment was highly focused on the feasibility of the parallelogram concept to estimate potential germ-cell effects in humans. It represented an evaluation of current knowledge and the identification of future research needs for a more precise assessment of human genetic risks from exposure to mutagenic chemicals.

Animals

Development and impact of the Gene-Tox-Program, genetic activity profiles, and their computerized data bases.

This invited historical review traces the development and impact of two major data bases in the field of genetic toxicology. Discussed from a personal perspective are the Environmental Protection Agency (EPA) Gene-Tox Program and the EPA/International Agency for Research on Cancer Genetic Activity Profiles (GAPs) and their respective data bases. Whereas Gene-Tox was focused on the assessment of short-term tests and their role in predicting carcinogens and mutagens, GAPs and the GAP data base were designed specifically to aid in the evaluation of individual chemicals. Both data bases have been computerized. Gene-Tox is available on TOXNET and GAP is available in a personal computer format from the author. The Gene-Tox and GAP data bases appear to have had substantial impact, particularly on hazard identification activities in cancer risk assessment.

Carcinogenicity Tests

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

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

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

Developmental trends in fetal habituation to vibroacoustic stimulation.

Habituation is a measure of the ability to inhibit responding and is a more mature form of behavior than is persistent responding. We examined the developmental trend in habituation of the fetal startle response to repeated vibroacoustic stimulation in 90 normal human fetuses between 28 and 40 weeks of gestation. Fetal movement was graded according to the nature of the behavioral response: general startle (3), fast limb movement (2), slow rolling movement (1), and no movement (0). A significant developmental difference (p < 0.0004) in the rate of habituation was found, with response decrement occurring faster in fetuses of more than 32 weeks of gestation. Furthermore, by dividing the patients into three gestational age groups, it was determined that the greatest change in the rate of habituation occurred between 28 and 32 weeks and 32 and 36 weeks. We conclude that the rate of fetal habituation may be determined by the degree of maturation of the neural circuitry governing this form of nonassociative learning.

Acoustic Stimulation

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

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

DNA adduct formation by 12 chemicals with populations potentially suitable for molecular epidemiological studies.

DNA adduct formation, route of absorption, metabolism and chemistry of 12 hazardous chemicals are reviewed. Methods for adduct detection are also reviewed and approaches to sensitivity and specificity are identified. The selection of these 12 chemicals from the Environmental Protection Agency list of genotoxic chemicals was based on the availability of information and on the availability of populations potentially suitable for molecular epidemiological study. The 12 chemicals include ethylene oxide, styrene, vinyl chloride, epichlorohydrin, propylene oxide, 4,4'-methylenebis-2-chloroaniline, benzidine, benzidine dyes (Direct Blue 6, Direct Black 38 and Direct Brown 95), acrylonitrile and benzyl chloride. While some of these chemicals (styrene and benzyl chloride, possibly Direct Blue 6) give rise to unique DNA adducts, others do not. Potentially confounding factors include mixed exposures in the work place, as well the formation of common DNA adducts. Additional research needs are identified.

Animals

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

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

Characteristics of the U.S. EPA's Office of Pesticide Programs' toxicity information databases.

The United States Environmental Protection Agency's Office of Pesticide Programs (OPP) requires that data from toxicity testing be submitted to the OPP to support the registration of pesticide chemicals. Once the toxicity data are submitted, they are entered into various toxicity databases. The studies are listed in an archival database to catalog and allow retrieval of the study for review. Reviews of toxicity studies are then placed into a separate database that can be retrieved to support a regulatory position. Toxicity information for health effects other than cancer and gene mutations from chronic exposure is reviewed through a reference dose (RfD) approach, and these decisions and supporting data are entered into an RfD database. Carcinogenicity data are reviewed by a peer review process, and these decisions are entered into a newly developed database to show the regulatory decision with supporting data. The mutagenicity data are reviewed and acceptable data are entered into the Genetic Activity Profile system to catalog and display the submitted information. These databases contain the information used for hazard evaluations as part of the OPP review of pesticide chemicals.

Animals

Genetic activity profiles in the testing and evaluation of chemical mixtures.

Some knowledge of the potential genetic activity of a complex environmental mixture may be gained from an assessment of the genetic activity of its component chemicals. The expanded Genetic Activity Profile (GAP) data base provides a computer-generated graphic representation of genetic bioassay data as a function of dose of the substance tested. In addition, the Atmospheric Chemical Compound (ACC) data-base contains information on chemical structures, properties, detection methods, and sources of chemicals found in ambient air. Using the combined data bases, the quantity of an individual chemical present within a mixture or fraction of a mixture may be related to the quantity (lowest effective dose, LED) of the chemical, by itself, required to demonstrate a positive response in one or more genetic bioassays.

Animals

Antimutagenicity profiles for some model compounds.

The concept of activity profile listings and plots, already applied successfully to the display of mutagenicity data, has been modified for application to antimutagenicity data. The activity profiles are bar graphs that have been organized in two general ways: for antimutagens that have been tested in combination with a given mutagen and for mutagens that have been tested in combination with a given antimutagen. Doses from both the mutagen and the antimutagen are displayed and plotted together with results on enhancement or inhibition of mutagenic activity. The short-term tests that have been used extensively to identify mutagens and potential carcinogens are increasingly being used to identify antimutagens and potential anticarcinogens. Three model mutagens, N-methyl-N'-nitro-N-nitrosoguanidine, aflatoxin B1 and benzo[a]pyrene, and 4 model antimutagens, butylated hydroxyanisole, butylated hydroxytoluene, glutathione and disulfiram, were selected from the data surveyed in the published literature. It is not clear at the present time whether the inhibition of carcinogen-induced mutation is a good indicator of anticarcinogenic properties, and further research is needed. Nevertheless, the activity profiles are useful for the assessment of the available antimutagenesis data by providing rapid visualization of considerable dose information and experimental results.

Biotransformation