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E Zeiger

Publications and source records attributed to E Zeiger.

At least 37 records · Page 2Linked to original sources
PubMed1998

Validating new toxicology tests for regulatory acceptance

Before a new or revised toxicology test is considered acceptable for safety evaluation of new substances, the test users and the industrial and regulatory decision makers must feel comfortable with it, and the decisions it supports. Comfort with, and the acceptance of, a new test comes after knowing that it has been validated for its proposed use. The validation process is designed to determine the operational characteristics of a test, that is, its reliability and relevance, in addition to its strengths and limitations. The reliability of a test is measured by its reproducibility. Its relevance is judged by its mechanistic relationship to the health effects of concern, and its ability to predict or identify those effects. The U.S. government has recently formed the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) to work with federal agencies and test developers to coordinate the evaluation and adoption of new test methods. The ICCVAM will provide guidance to agencies and other stakeholders on criteria and processes for development, validation, and acceptance of tests; coordinate technical reviews of proposed new tests of interagency interest; facilitate information sharing among agencies; and serve as an interagency resource and communications link with parties outside of the federal government on matters of test method validation. Copyright 1998 Academic Press.

Journal Article↗
PubMed1998

Identification of rodent carcinogens and noncarcinogens using genetic toxicity tests: premises, promises, and performance.

The basic premises that guide genetic toxicity testing for identifying carcinogens and to support administrative and regulatory decisions are: the Salmonella mutagenicity test is a necessary component of testing schemes; a chromosome aberration test is needed in addition to a gene mutation test; a mammalian cell mutagenicity test is needed in addition to the Salmonella test; in vivo tests are needed to confirm the results of in vitro tests; and test batteries are more predictive than the individual tests of the battery. Results from the Salmonella mutagenicity, in vitro chromosome aberration, mutations in mouse lymphoma cells, rodent bone marrow micronucleus, and rodent carcinogenicity tests, performed by the U.S. National Toxicology Program, were used to evaluate these premises. A positive Salmonella test was most predictive of carcinogenicity. However, the data do not support using the other tests in addition to Salmonella for predicting carcinogenicity. The genetic toxicity tests did not complement each other, and batteries or combinations of the tests were no more predictive of carcinogenicity than Salmonella alone. If a chemical is mutagenic in Salmonella it should be considered a potential rodent carcinogen, unless ancillary information suggests otherwise. Positive responses in the other in vitro or in vivo tests do not increase the probability that the chemical is a carcinogen, and negative responses in the other tests do not diminish the implications of the positive Salmonella response.

Animals↗
PubMed1998

The effectiveness of Salmonella strains TA100, TA102 and TA104 for detecting mutagenicity of some aldehydes and peroxides.

Several aldehydes and peroxides were tested for mutagenicity using Salmonella typhimurium tester strains TA97a, TA100, TA102 and TA104, in the presence and absence of Aroclor-induced liver S9 mix from F344 rats and B6C3F1 mice, in either preincubation or vapour phase protocols. Some chemicals were tested in additional Salmonella strains. Benzaldehyde, butyraldehyde, benzoyl peroxide, 4-chlorobenzaldehyde, isobutyraldehyde, propionaldehyde and veratraldehyde were non-mutagenic. Acetaldehyde and dicumyl peroxide gave inconsistent results and furfural gave equivocal responses in TA100 and TA104. Cumene hydroperoxide, formaldehyde and glutaraldehyde were mutagenic in TA100, TA102 and TA104. trans-Cinnamaldehyde exhibited a weak mutagenic response in TA100 with mouse liver S9 only. 2,4,5-Trimethoxybenzaldehyde was mutagenic only in strain TA1538 with rat liver S9. With the exception of butanone peroxide, which was mutagenic only in TA104, all chemicals mutagenic in strains TA102 and/or TA104 were also mutagenic in TA100. The data do not, therefore, support the preferential use of strains TA102 and TA104 for screening aldehydes and peroxides for mutagenicity. For a number of these chemicals the advantages of using TA102 or TA104 was in the increased responses compared with those obtained with TA100. Two of the four peroxides were mutagenic and one of these was mutagenic only with TA104. This suggests that strains TA102 and TA104 be used if peroxides are not mutagenic in TA100 or TA97.

Aldehydes↗
PubMed1998

Validating new toxicology tests for regulatory acceptance.

Before a new or revised toxicology test is considered acceptable for safety evaluation of new substances, the test users and the industrial and regulatory decision makers must feel comfortable with it, and the decisions it supports. Comfort with, and the acceptance of, a new test comes after knowing that it has been validated for its proposed use. The validation process is designed to determine the operational characteristics of a test, that is, its reliability and relevance, in addition to its strengths and limitations. The reliability of a test is measured by its reproducibility. Its relevance is judged by its mechanistic relationship to the health effects of concern, and its ability to predict or identify those effects. The U.S. government has recently formed the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) to work with federal agencies and test developers to coordinate the evaluation and adoption of new test methods. The ICCVAM will provide guidance to agencies and other stakeholders on criteria and processes for development, validation, and acceptance of tests; coordinate technical reviews of proposed new tests of interagency interest; facilitate information sharing among agencies; and serve as an interagency resource and communications link with parties outside of the federal government on matters of test method validation.

Animals↗
PubMed1997

Genetic toxicity studies of 1,2,3,4-tetrahydro-9-acridinamine (tacrine).

The mutagenicity and clastogenicity of 1,2,3,4-tetrahydro-9-acridinamine (tacrine) were studied in vitro using the Salmonella mutagenicity test and the induction of chromosome aberrations in Chinese hamster ovary (CHO) cells, and in the mouse bone marrow micronucleus test in vivo. This chemical is currently being used to treat dementia arising from Alzheimer's Disease. Tacrine was mutagenic in Salmonella but did not produce chromosome damage in CHO cells or in mouse bone marrow cells. A clear mutagenic response was seen in strain TA97 with rat and hamster liver S9; inconsistent results were obtained without S9. No mutagenicity was seen in strains TA98 and TA100 without S9, and inconsistent results were seen with S9. There was no induction of chromosome aberrations in cultured CHO cells with or without S9. Oral administration to mice of tacrine daily for three days did not result in the induction of micronuclei in their bone marrow cells. The mutagenic response in Salmonella, and the structure of the molecule, suggests that tacrine may be carcinogenic when tested in rodents. This information must be considered when preparing benefit-risk determinations for medical uses of this substance.

Animals↗
PubMed1997

Formation of 8-hydroxy-2'-deoxyguanosine following treatment of 2'-deoxyguanosine or DNA by hydrogen peroxide or glutathione.

We have demonstrated that free radicals generated by hydrogen peroxide (H2O2), in the presence of divalent iron (Fe2+) and a chelator (EDTA), oxidize 2'-deoxyguanosine (dG) to 8-hydroxy-2'-deoxyguanosine (8-OHdG). The 8-OHdG formed by this reaction was isolated and quantitated using reverse-phase HPLC with UV and electrochemical detection. A 1-h incubation of dG with H2O2 caused a 50% increase in 8-OHdG over background, which increased to 100% after 2 h. However, when an H2O2-generating system [glutathione (GSH), Fe2+, EDTA] was used, there was no increase in 8-OHdG yield after the 1-h incubation, but up to a 50% increase over background was observed with GSH after 2-h incubation. Attempts to detect increased levels of 8-OHdG after H2O2- or GSH-treatment of purified calf thymus or rat DNA, or purified Salmonella typhimurium DNA were not successful. This may have been because the treatment procedures used generated 8-OHdG in the control samples at sufficiently high levels to mask any H2O2-induced responses that may have been present. This artifactual production of 8-OHdG has presented a problem in all in vitro studies to date. In contrast, treatment of Salmonella cells (strain TA104) with increasing concentrations of H2O2, caused a doubling in the 8-OHdG yield. GSH-treatment of strain TA104 cells under the same conditions did not result in an increase of 8-OHdG. The study presented here shows that the ubiquitous molecule H2O2 can play a major role in DNA oxidation, mutation, and damage.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1997

Predicting rodent carcinogenicity from mutagenic potency measured in the Ames Salmonella assay.

Many in vitro tests have been developed to identify chemicals that can damage cellular DNA or cause mutations, and secondarily to identify potential carcinogens. The test receiving by far the most use and attention has been the Salmonella (SAL) mutagenesis test developed by Ames and colleagues [(1973): Proc Natl Acad Sci USA 70:2281-2285; (1975): Mutat Res 31:347-364], because of its initial promise of high qualitative (YES/NO) predictivity for cancer in rodents and, by extension, in humans. In addition to the initial reports of high qualitative predictivity, there was also an early report by Meselson and Russell [in Hiatt HH et al (1977): "Origins of Human Cancer, Book C: Human Risk Assessment," pp 1473-1481] of a quantitative relationship between mutagenic potency measured in SAL and carcinogenic potency measured in rodents, for a small number of chemicals. However, other reports using larger numbers of chemicals have found only very weak correlations. The primary purpose of this study was to determine whether mutagenic potency, as measured in a number of different ways, could be used to improve predictivity of carcinogenicity, either qualitatively or quantitatively. To this end, eight measures of SAL mutagenic potency were used. This study firmly establishes that the predictive relationship between mutagenic potency in SAL and rodent carcinogenicity is, at best, weak. When predicting qualitative carcinogenicity, only qualitative mutagenicity is useful; none of the quantitative measures of potency considered improves the carcinogenicity prediction. In fact, when qualitative mutagenicity is forced out of the model, the quantitative measures are still not predictive of carcinogenicity. When predicting quantitative carcinogenicity, several possible methods were considered for summarizing potency over all experiments; however, in all cases, the relationship between mutagenic potency predictors and quantitative carcinogenicity is very weak.

Animals↗
PubMed1997

Human monitoring.

Explore the source record for details and available documents.

Environmental Monitoring↗
PubMed1997

Multilaboratory comparison of in vitro tests for chromosome aberrations in CHO and CHL cells tested under the same protocols.

Different test results have been reported for the same chemicals in two in vitro chromosome aberration test systems, CHL cells tested by a Japanese protocol and CHO cells tested by the US National Toxicology Program [Sofuni et al., Mutat Res 241:173-213,1990]. Here, laboratories in Japan, the US and the UK tested 9 such chemicals in CHL and CHO cells using the same protocols and found all 9 positive in both cell types; differences in earlier conclusions with these chemicals were due mainly to test protocol, not to different sensitivities of the cells. The most important protocol difference is sampling time. Chemicals that were negative in the NTP series using a sampling time of 10 to 13 hours often produced positive results when retested here with a 20- to 24-hour sampling time. While positive results were obtained in both cell types, CHL cells sometimes had higher aberration levels and survived at higher doses than CHO cells would tolerate. This may reflect some intrinsic difference in sensitivity but may also be affected by factors such as cell cycle length and culture media (e.g., oxygen scavenging capacity). The collaboration reported here also contributed to a better understanding of scoring aberrations, especially "gaps"; there was good agreement on what types of aberrations should be included in the totals when scoring criteria were clearly defined, for example, many changes classified as "gaps" by the Japanese system were classified as "breaks" in the scoring systems used in the United States and the United Kingdom, and were appropriately included in total aberration counts.

Animals↗
PubMed1996

Close correspondence between the action spectra for the blue light responses of the guard cell and coleoptile chloroplasts, and the spectra for blue light-dependent stomatal opening and coleoptile phototropism.

Fluorescence spectroscopy was used to characterize blue light responses from chloroplasts of adaxial guard cells from Pima cotton (Gossypium barbadense) and coleoptile tips from corn (Zea mays). The chloroplast response to blue light was quantified by measurements of the blue light-induced enhancement of a red light-stimulated quenching of chlorophyll a fluorescence. In adaxial (upper) guard cells, low fluence rates of blue light applied under saturating fluence rates of red light enhanced the red light-stimulated fluorescence quenching by up to 50%. In contrast, added blue light did not alter the red light-stimulated quenching from abaxial (lower) guard cells. This response pattern paralleled the blue light sensitivity of stomatal opening in the two leaf surfaces. An action spectrum for the blue light-induced enhancement of the red light-stimulated quenching showed a major peak at 450 nm and two minor peaks at 420 and 470 nm. This spectrum matched closely an action spectrum for blue light-stimulated stomatal opening. Coleoptile chloroplasts also showed an enhancement by blue light of red light-stimulated quenching. The action spectrum of this response, showing a major peak at 450 nm, a minor peak at 470 nm, and a shoulder at 430 nm, closely matched an action spectrum for blue light-stimulated coleoptile phototropism. Both action spectra match the absorption spectrum of zeaxanthin, a chloroplastic carotenoid recently implicated in blue light photoreception of both guard cells and coleoptiles. The remarkable similarity between the action spectra for the blue light responses of guard cells and coleoptile chloroplasts and the spectra for blue light-stimulated stomatal opening and phototropism, coupled to the recently reported evidence on a role of zeaxanthin in blue light photoreception, indicates that the guard cell and coleoptile chloroplasts specialize in sensory transduction.

Journal Article↗
PubMed1996

Prediction of Salmonella mutagenicity.

The ability of a number of prediction systems was examined to determine how well they could predict Salmonella mutagenicity. The prediction systems included two computer-based systems (CASE and TOPKAT), the measurement of a physiochemical parameter (ke) and the use of structural alerts by an expert chemist. The computer-based systems operators and the chemist were supplied with the structures of 100 chemicals that had been tested for mutagenicity in the Salmonella test; the actual chemicals were needed for the physiochemical measurement. None of the participants was provided with the chemical names or Salmonella test results prior to submitting their predictions. The three systems that predicted the mutagenicity from the structure of the chemicals produced equivalent results (71-76% concordance with the Salmonella results); the physiochemical system produced a lower (60-61%) concordance.

Databases, Factual↗
PubMed1996

Stomata from growth-chamber-grown Vicia faba have an enhanced sensitivity to CO2.

Abaxial stomata from Vicia faba leaves grown in a growth chamber under constant light, temperature and humidity showed an elaborate pattern of aperture changes over the course of a light cycle. These aperture changes were tightly correlated with changes in chamber CO2 concentration (r2=0.83). Changes in chamber [CO2] resulted, in turn, from substantial daily fluctuations in ambient [CO2], typical of the Los Angeles environment, with a constant offset caused by photosynthesis and respiration of the plants within the chamber. The dominant role of the stomatal response to CO2 in the control of aperture was confirmed by manipulation of chamber [CO2]. Fast (15 min) increases and decreases in [CO2] caused rapid decreases and increases in aperture, while constant [CO2] resulted in constant aperture. In contrast, aperture changes in comparable plants grown under greenhouse conditions were tightly correlated with changes in incident solar radiation (r2=0.80), and poorly correlated with changes in [CO2] (r2=0.09). Greenhouse-grown plants transferred to growth chamber conditions showed no apparent response to CO2. These data indicate that growth-chamber-grown V. faba leaves provide an experimental system optimally suited for the study of the stomatal response to CO2, and suggest that acclimation to environmental conditions alters the sensitivity of stomata to CO2.

Acclimatization↗
PubMed1994

Genetic variability for stomatal conductance in Pima cotton and its relation to improvements of heat adaptation.

Responses of stomata to environment have been intensively studied, but little is known of genetic effects on stomatal conductance or their consequences. In Pima cotton (Gossypium barbadense L.), a crop that is bred for irrigated production in very hot environments, stomatal conductance varies genetically over a wide range and has increased with each release of new higher-yielding cultivars. A cross between heat-adapted (high-yielding) and unadapted genotypes produced F2 progeny cosegregating for stomatal conductance and leaf temperature. Within segregating populations in the field, conductance was negatively correlated with foliar temperature because of evaporative cooling. Plants were selected from the F2 generation specifically and solely for differing stomatal conductance. Among F3 and F4 populations derived from these selections, conductance and leaf cooling were significantly correlated with fruiting prolificacy during the hottest period of the year and with yield. Conductance was not associated with other factors that might have affected yield potential (single-leaf photosynthetic rate, leaf water potential). As breeders have increased the yield of this crop, genetic variability for conductance has allowed inadvertent selection for "heat avoidance" (evaporative cooling) in a hot environment.

Journal Article↗
PubMed1994

The effects of antioxidants and enzymes involved in glutathione metabolism on mutagenesis by glutathione and L-cysteine.

The effects of small molecular weight antioxidants and antioxidant enzymes on the mutagenicities of glutathione (GSH) and L-cysteine were studied in Salmonella typhimurium strain TA102. GSH and cysteine mutagenesis were inhibited by antioxidants and radical scavengers such as alpha-tocopherol, Trolox C, butylated hydroxyanisole (BHA), and retinyl acetate. Superoxide dismutase (SOD) had no effect, but catalase and horseradish peroxidase (HRP) inhibited mutagenesis. The heat-denatured enzymes had no effect on mutagenesis. Cysteine mutagenesis was enhanced by native and by heat-denatured rat-kidney post-mitochondrial supernatant, and by ferric ions. H2O2 and the H2O2-generating system of glucose-glucose oxidase (GOX) were mutagenic in TA102. Synergistic increases in mutagenesis were obtained in systems containing combinations of GSH or cysteine, with either H2O2 or the H2O2-generating system of glucose-GOX. GSH peroxidase (GPX) had no effect on mutagenesis of GSH or of H2O2, whereas the synergistic increase in mutagenesis by a combination of GSH and H2O2 was effectively inhibited by GPX. The results suggest strongly that, at least in biochemically-defined systems, GSH and cysteine mutagenesis are oxidative in nature, and involve reactive forms of oxygen and/or other radicals.

Animals↗