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PubMedDate not supplied

Chemical carcinogens. A review and analysis of the literature of selected chemicals and the establishment of the Gene-Tox Carcinogen Data Base. A report of the U.S. Environmental Protection Agency Gene-Tox Program.

The literature on 506 selected chemicals has been evaluated for evidence that these chemicals induce tumors in experimental animals and this assessment comprises the Gene-Tox Carcinogen Data Base. Three major sources of information were used to create this evaluated data base: all 185 chemicals determined by the International Agency for Research on Cancer to have Sufficient evidence of carcinogenic activity in experimental animals, 28 selected chemicals bioassayed for carcinogenic activity by the National Toxicology Program/National Cancer Institute and found to induce tumors in mice and rats, and 293 selected chemicals which had been evaluated in genetic toxicology and related bioassays as determined from previous Gene-Tox reports. The literature data on the 239 chemicals were analyzed by the Gene-Tox Carcinogenesis Panel in an organized, rational and consistent manner. Criteria were established to assess individual studies employing single chemicals and 4 categories of response were developed: Positive, Negative, Inconclusive (Equivocal) and Inconclusive. After evaluating each of the individual studies on the 293 chemicals, the Panel placed each of the 506 chemicals in an overall classification category based on the strength of the evidence indicating the presence or absence of carcinogenic effects. An 8-category decision scheme was established using a modified version of the International Agency for Research on Cancer approach. This scheme included two categories of Positive (Sufficient and Limited), two categories of Negative (Sufficient and Limited), a category of Equivocal (the evidence of carcinogenicity from well-conducted and well-reported lifetime studies had uncertain significance and was neither clearly positive nor negative), and three categories of Inadequate (the evidence of carcinogenicity was insufficient to make a decision, however, the data suggested a positive or negative indication). Of the 506 chemicals in the Gene-Tox Carcinogen Data Base, 252 were evaluated as Sufficient Positive, 99 as Limited Positive, 40 as Sufficient Negative, 21 as Limited Negative, 1 as Equivocal, 13 as Inadequate with the data suggesting a positive indication, 32 as Inadequate with the data suggesting a negative indication, and 48 Inadequate with the data not suggesting any indication of activity. This data base was analyzed and examined according to chemical class, using a 29 chemical class scheme.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2006

Improving radioactive waste management: an overview of the Environmental Protection Agency's low-activity waste effort.

Radioactive waste disposal in the United States is marked by a fragmented regulatory system, with requirements that often focus on the origin or statutory definition of the waste, rather than the hazard of the material in question. It may be possible to enhance public protection by moving toward a system that provides disposal options appropriate for the hazard presented by the waste in question. This paper summarizes aspects of an approach focusing on the potential use, with appropriate conditions, of Resource Conservation and Recovery Act Subtitle-C hazardous waste landfills for disposal of "low-activity" wastes and public comments on the suggested approach.

Decision Making↗
PubMed1985

Current status of bioassays in genetic toxicology--the dominant lethal assay. A report of the U.S. Environmental Protection Agency Gene-Tox Program.

The term dominant lethal may be defined as death of the heterozygote arising through multiple chromosomal breaks. The assay is generally conducted by treating male animals, usually mice or rats, acutely (1 dose), subacutely (5 doses), or over the entire period of spermatogenesis. Animals treated acutely or subacutely are mated at weekly intervals to females for a sufficient number of weeks to cover the period of spermatogenesis. Those treated for the entire spermatogenic cycle are mated for 1 or 2 successive weeks at the termination of treatment. Females usually are killed at 14 days of pregnancy and examined for the number of total implantations in the uterus, the number of implantations classified as early deaths, and, in some cases, the number of corpora lutea. The category of early death is the most significant index of dominant lethality. A total of 249 papers were reviewed and 140 chemicals were evaluated. Of the 140 chemicals, 65 were positive by the criteria used by the Work Group in evaluating each publication. The category of "positive" includes those responses of a borderline nature. 99 chemicals were declared negative. There is considerable overlap of chemicals in both categories, which accounts for the incongruity in the total number of chemicals tested and the number considered positive and negative. A total of 44 animal carcinogens have been tested in the dominant lethal assay, 26 of which were positive and 18 negative for a correlation of 59%. The role of the assay should be that of confirming positive results from lower tier chromosomal aberration-detecting systems (confirming in the sense of indicating the ability of the chemical to penetrate gonadal tissue and to produce cytogenetic damage). The dominant lethal assay should not be used as a risk assessment method.

Animals↗
PubMed1984

Mutation tests in Neurospora crassa. A report of the U.S. Environmental Protection Agency Gene-Tox Program.

Many mutation tests have been developed in Neurospora crassa during the almost 40 years of its use in mutation research. These tests detect two major classes of mutation: gene mutation and meiotic nondisjunction. Within the first class, forward- and reverse-mutation tests have been used. The forward-mutation tests include those that detect mutations at many loci and at specific loci. Both kinds of forward-mutation tests have been done in homokaryons (n) and heterokaryons (n + n'). From the publications that were not rejected by our pre-established criteria, data were extracted for 166 chemicals that had been tested for mutagenicity. Only 6 of the 166 chemicals have been tested in one or more gene mutation test and the meiotic nondisjunction test; these 6 chemicals were positive in the first and negative in the second. Of the 102 chemicals tested in one or more gene mutation tests, 94 were positive and 8 were negative. Of the 70 chemicals tested in the meiotic nondisjunction test, 7 were positive and 63 were negative. Two tests, the ad-3 forward-mutation test and the meiotic nondisjunction test, have been used most frequently. These two tests are especially important for hazard evaluation, because each detects a class of mutations that is likely to be deleterious or lethal in the F1 - disomics by the meiotic nondisjunction test and multilocus deletions by the ad-3 forward-mutation test in heterokaryons. Generally, direct-acting chemicals are mutagenic in the gene mutation tests, but few chemicals that required metabolic activation have been tested. Only 31 of the 166 chemicals tested in N. crassa have been tested for carcinogenicity. Among these chemicals, there is a good association between mutagenicity in gene mutation tests and carcinogenicity but a poorer association between meiotic nondisjunction and carcinogenicity; however, only a small number of chemicals has been tested in the meiotic nondisjunction test. Further use and development of certain mutation tests in N. crassa are desirable.

Alleles↗
PubMedDate not supplied

A report of the U.S. Environmental Protection Agency Gene-Tox Program. Evaluation of mutagenicity assays for purposes of genetic risk assessment.

For the vast majority of chemicals, mammalian germ-line (MG) mutation data do not exist. The question was examined of how best to utilize results of non-MG genotoxicity assays that are included in the Gene-Tox data base to provide information of the likelihood that genetic damage might be induced in and transmitted by the reproductive cells of exposed human beings. Two approaches were used to assess the relative value of different assays for genetic hazard identification. (1) Test results were weighted according to parameters by which conditions of an assay resemble those encountered in the potential induction of transmitted genetic damage in mammals. For this purpose, 35 assays were grouped into 16 categories that were assigned weights ranging from 1 to 15; there were 2367 chemicals in the data base. This system was evaluated by comparing the sum of weighted test results for each chemical with the outcome of MG-standard (MGst) tests where such had been reported. (MGst tests used were the specific-locus and heritable-translocation assays [SLT and HTT] for gene mutations and chromosome aberrations, respectively.) The weighting system produced a few false positives with respect to the MGst results. It produced no false negatives, but the available evidence is limited by the circumstance that MGst test have evidently been preferentially performed with chemicals that had already been shown to be positive in several other assays. (2) Findings from each MGst test were compared with those from each of the other assays in turn, provided that at least 10 chemicals had been tested in both of the assays. There were 11 such comparisons involving the SLT, and 14 such comparisons involving the HTT. The observed concordance was above random expectation in several comparisons, particularly those involving certain mammalian in vivo tests, but in only one case (HTT vs. unscheduled DNA synthesis in the testis) did the degree of elevation approach statistical significance.

Animals↗
PubMed1984

Chromosome mutation tests for mutagenesis in Drosophila melanogaster. A report of the U.S. Environmental Protection Agency Gene-Tox Program.

The term 'chromosome mutations' was chosen and defined for this review to refer to alterations of chromosome structure (reciprocal, heritable translocations), of chromosome number (loss or gain of a whole chromosome), or of chromosome content (loss or gain of a part of a chromosome). Chromosome mutations may result from chromosome breakage (clastogenesis) and its consequences or from disruption of chromosome behavior during cell division (nondisjunction). State-of-the-art protocols are outlined to test for heritable translocations, for whole-or partial chromosome loss (clastogenesis), and for whole chromosome loss or gain (nondisjunction). The literature up to 1980 was reviewed and 106 papers were selected for the evaluation of 116 chemicals for one or more chromosome mutation end points. The criteria used for acceptance of data from the literature were not stringent, as most of this work was done some time ago and for purposes other than testing. The main criterion was that germ cell stage sampling was correct. For the evaluation of the accepted data, numerical requirements were set up, using as a guide the control data from all the papers. Compounds were classified, when possible, as mutagenic (+) or nonmutagenic (-). Those not classifiable, usually due to insufficient numbers of chromosomes tested, were listed as inconclusive (inc). Of 61 compounds tested for heritable translocations, 27 were positive, 8 were negative, and 26 were inconclusive. Of the 35 with conclusive data, only 21 also have definitive carcinogenesis classifications (all positive). Of these, 19 were deemed mutagenic, which gives agreement of 90.5%. Of the 76 compounds tested for clastogenesis by the chromosome loss test, 26 were positive, 13 were negative, and 37 were inconclusive. Of the 39 with conclusive data, only 20 also have definitive carcinogenesis classifications. 15 of the 19 carcinogens were positive. Four of the carcinogens were negative and 1 noncarcinogen was positive, for an overall agreement of 75%. Of 44 compounds tested for nondisjunction, 15 were positive, 13 were negative, 16 were inconclusive. Of the 28 compounds with conclusive data, only 9 have definitive carcinogenesis classifications (all positive). Five of these were deemed negative and agreement was only 44%. It should be noted that these data do not fairly represent these short-term tests as conducted with current protocols. A more equitable comparison could be achieved with planned experiments that include the sex-linked recessive lethal (SLRL) test in the comparison.

Aneuploidy↗
PubMed1998

Site-specific data confirm arsenic exposure predicted by the U.S. Environmental Protection Agency.

The EPA uses an exposure assessment model to estimate daily intake to chemicals of potential concern. At the Anaconda Superfund site in Montana, the EPA exposure assessment model was used to predict total and speciated urinary arsenic concentrations. Predicted concentrations were then compared to concentrations measured in children living near the site. When site-specific information on concentrations of arsenic in soil, interior dust, and diet, site-specific ingestion rates, and arsenic absorption rates were used, measured and predicted urinary arsenic concentrations were in reasonable agreement. The central tendency exposure assessment model successfully described the measured urinary arsenic concentration for the majority of children at the site. The reasonable maximum exposure assessment model successfully identified the uppermost exposed population. While the agreement between measured and predicted urinary arsenic is good, it is not exact. The variables that were identified which influenced agreement included soil and dust sample collection methodology, daily urinary volume, soil ingestion rate, and the ability to define the exposure unit. The concentration of arsenic in food affected agreement between measured and predicted total urinary arsenic, but was not considered when comparing measured and predicted speciated urinary arsenic. Speciated urinary arsenic is the recommended biomarker for recent inorganic arsenic exposure. By using site-specific data in the exposure assessment model, predicted risks from exposure to arsenic were less than predicted risks would have been if the EPA's default values had been used in the exposure assessment model. This difference resulted in reduced magnitude and cost of remediation while still protecting human health.

Algorithms↗
PubMed1982

Tradescantia cytogenetic tests (root-tip mitosis, pollen mitosis, pollen mother-cell meiosis). A report of the U.S. Environmental Protection Agency Gene-Tox Program.

3 kinds of cytogenetic tests for screening of environmental mutagens were established for Tradescantia, namely, root-tip mitosis, pollen mitosis, and pollen mother-cell meiosis [commonly referred to as the Tradescantia-micronucleus (Trad-MCN) test]. All these tests are technically simple, inexpensive, and can yield reliable results in a relatively short time (36-72 h). The root-tip mitosis test is suitable only for liquid agents, while pollen mitosis is suitable for both liquid and gaseous agents. Pollen tube mitotic chromosomes are extremely sensitive to mutagens; therefore, they are good materials for detecting very low concentrations of mutagens. Both root-tip mitosis and pollen mitosis tests use chromosome and/or chromatid aberrations as end points for scoring. The Trad-MCN test is suitable for both liquid and gaseous agents. In addition, it is especially suitable for in situ monitoring of water and air pollutants. Of the 12 chemicals tested, 5-fluorouracil and 1,2-dibromoethane indicate that they are very potent mutagens based on the effective dosage used to produce a positive response. Sulfur dioxide, ethyl methanesulfonate, sodium azide, Phosdrin, and Bladex rank next in potency.

Meiosis↗
PubMed1982

Soybean (Glycine max [L.] merrill) as a short-term assay for study of environmental mutagens. A report of the U.S. Environmental Protection Agency Gene-Tox Program.

The soybean (Glycine max [L.] Merrill) spot test is suggested as a preliminary screening test for environmental mutagens. This system makes use of various types of spots that originate from the treatment of seeds or seedlings with mutagens. The homozygous dominant y11y11 dark green leaves may show light green and very dark green spots; the heterozygous y11y11 light green leaves may show dark green, yellow or twin spots; and the homozygous recessive y11y11 yellow leaves show light green receptors. The interpretation is that twin spots on the y11y11 leaves originate from somatic crossing-over, and the singles originate primarily from losses or gains of the segments or chromosome carrying the gene y11 or y11. The yellow plants (y11y11) can produce light green sectors if y11 mutates to y11. Studies carried out with a host of chemical and physical agents lend support to the idea that the soybean system can distinguish between several genetic mechanisms underlying the formation of spots. Spots are detected against their native genetic and phenotype background, thus minimizing the effects due to physiological changes. The system is rapid (4-5 weeks per chemical), inexpensive, and involves an eukaryotic organism. It has the advantage of being adaptable for liquid solutions of chemicals, solid wastes, emulsions of chemicals (e.g., in lanolin), and gaseous products.

Crossing Over, Genetic↗
PubMed1982

Vicia cytogenetic tests for environmental mutagens. A report of the U.S. Environmental Protection Agency Gene-Tox Program.

Vicia root-tip mitotic and pollen mother-cell meiotic tests are two major kinds of cytogenetic tests for environmental mutagens. According to the present review, 81 of 85 earlier studies used mitotic tests to determine the frequencies of chromosome or chromatid aberrations and/or sister-chromatid exchange from root-tip meristematic cells; only 4 used meiotic tests to determine the frequencies of chromosome aberration from pollen mother cells. Treatment of root-tip meristem can be done by allowing the newly germinated roots to absorb the chemical mutagens from a water solution. Pollen mother cells can be treated by spraying the solution or pipetting the liquid over the flower buds. After an appropriate recovery time, the samples are fixed and stained, and the slides are prepared for metaphase or anaphase figures for scoring aberration frequencies. Slides for meiotic tests are prepared for metaphase I and/or Anaphase I stages for scoring chromosome aberration frequencies. Results of both cytogenetic tests should be expressed in terms of number of breaks per cell or per 100 cells. Test results of 76 chemicals from 32 classes in this review indicate that the Vicia root-tip mitotic test is reliable, efficient, and relatively inexpensive. These results also reveal that antibiotics are most frequently studied, followed by alkyl sulfones, pyrimidine, and purine derivatives. Of all the agents studied through root-tip mitotic tests, about 90% gave positive responses; antibiotics (phleomycin and bleomycin) had very high mutagenicity (less than 1 ppm gave positive response).

Chromosome Aberrations↗
PubMed1986

The Salmonella typhimurium/mammalian microsomal assay. A report of the U.S. Environmental Protection Agency Gene-Tox Program.

The Salmonella assay has been in use for almost 15 years and can be defined as a routine test for mutagenicity and for predicting potential carcinogenicity. It detects the majority of animal carcinogens and consequently plays an important role in safety assessment. The test is also routinely used as the frontline screen for environmental samples (complex mixtures) isolated from air, water and food. This role will continue to remain an area of growth as or because sample volumes associated with these testing areas are generally very limited and more extensive testing is generally impossible. While this test, like all others, has some limitations, it is recommended that it be regularly included in all genetic testing batteries.

Animals↗
PubMed2005

Influence of geographic location in modeling blood pesticide levels in a community surrounding a U.S. Environmental protection agency superfund site.

In this study we evaluated residential location as a potential determinant for exposure to organochlorine compounds. We investigated the geographic distribution characteristics of organochlorine levels in approximately 1,374 blood samples collected in 1974 from residents of a community with a potential organochlorine source. Street addresses of Washington County, Maryland, residents were obtained and geocoded in a geographic information system. We used multivariate linear regression models to characterize the blood organochlorine levels of these residents that had been analyzed as part of previous studies using both environmental- and individual-level covariates. This was done to evaluate if the geographic distribution of blood levels in participants was related to the environmental source in the community. Model inference was based on generalized least squares to account for residual spatial variation. A significant inverse relationship was found between blood dieldrin levels and residential distance from the potential source. For every mile of distance from the source, blood dieldrin levels decreased 1.6 ng/g in study participants (p-value = 0.042), adjusting for age, sex, education level, smoking status, and drinking water source. 1,1-Dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE) levels in the blood did not change significantly based on residential distance from the source, taking the same covariates into account. However, these results are limited by the inability to account for several potential confounders. This study demonstrates that spatially distributed covariates may play an important role in individual exposure patterns. Spatial information may enable researchers to detect a potential exposure pattern that may not be revealed with only nonspatial variables.

Environmental Monitoring↗
PubMed1983

An evaluation of human sperm as indicators of chemically induced alterations of spermatogenic function. A report of the U.S. Environmental Protection Agency Gene-Tox Program.

To evaluate the utility of sperm tests as indicators of chemical effects on human spermatogenesis, the literature on 4 sperm tests used to assess chemically induced testicular dysfunction was reviewed. The tests surveyed included sperm count, motility, morphology (seminal cytology), and double Y-body (a fluorescence-based test thought to detect Y-chromosomal nondisjunction). There were 132 papers that provided sufficient data for evaluation. These reports encompassed 89 different chemical exposures: 53 were to single agents; 14 to complex mixtures; and 22 to combinations of 2 or more identified agents. Approximately 85% of the exposures were to experimental or therapeutic drugs, 10% were to occupational or environmental agents, and 5% were to drugs for personal use. The most common sperm parameter studied was sperm count (for 87 of the 89 exposures reviewed). Sperm motility was evaluated for 59 exposures, morphology for 44, and double Y-bodies for only 4. The 89 exposures reviewed were grouped into 4 classes: those which adversely effected spermatogenesis, as measured by one or more of the sperm tests (52); those suggestive of improving semen quality (11); those showing inconclusive evidence of adverse effects from exposure (14); and those showing no significant changes (12). Since the reviewed reports had a large variety of study designs, and since every attempt was made to include all reports with interpretable data, these classifications were based on reviewing committee decisions rather than on uniform statistical criteria. This review gives strong evidence that human sperm tests can be used to identify chemicals that affect sperm production, but because of our limited understanding of underlying mechanisms, the extent to which they can detect mutagens, carcinogens or agents that affect fertility remains uncertain. For the very few agents studied with both human and mouse sperm tests, similar test-responses were seen; thus sperm tests in mice and other laboratory mammals may have a potential role in hazard identification. An overall comparison of the 4 human sperm tests suggests that no one test is biologically more responsive than another; all of them may thus be needed when testing for chemically induced changes from agents of unknown activity. This review also gives evidence that sperm tests can be used to assess the extent and the potential reversibility of induced spermatogenic damage. The reviewing committee recommends further studies to determine (a) the dose-response characteristics of the human sperm tests, (b) details of the reversibility of induced changes with time after exposure, (c) the relative responses in the 4 sperm tests in exposed individuals, (d) the mechanism of action, (e) the biological and genetic implications of chemically induced effects, and (f) the comparison of responses among different species for risk assessment. The reviewing committee outlines specific considerations for planning new sperm studies on chemically exposed men.

Animals↗