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J Ashby

Publications and source records attributed to J Ashby.

At least 217 records · Page 12Linked to original sources
PubMed1991

Activity of aniline in the mouse bone marrow micronucleus assay.

Aniline gave a positive response in the mouse bone marrow micronucleus assay 24 h after the second of two intraperitoneal injections of 80% of the median lethal dose (MLD). Negative results were observed at lower dose levels and at earlier and later sampling times. The significance of this unique activity profile is discussed within the context of the non-carcinogenicity of aniline to the mouse.

Aniline Compounds↗
PubMed1991

Micronucleus morphology as a means to distinguish aneugens and clastogens in the mouse bone marrow micronucleus assay.

Detailed dose-response data for two reference aneugens, vincristine and nocodazole, have been derived for the mouse bone marrow micronucleus assay. Positive data have also been described for six other micronucleus-inducing agents: cyclophosphamide; aniline; urethane; 1,2-dimethylhydrazine; 7,12-dimethylbenzanthracene and procarbazine. Micronuclei (MN) were classified according to the morphological criteria listed by Yamamoto and Kikuchi, i.e. normal, double, multiple, ring, crescent and large. Aniline and control slides exhibited low incidences of aberrant MN (less than 3%). The remaining seven chemicals gave incidences of aberrant MN that varied from 3 to 25%. Only the aneugens vincristine and nocodazole, and the possible aneugen urethane, gave both crescent shaped and large MN (greater than 0.25 cell diameter). It is therefore concluded that only these last two classes of aberrant MN can be taken as indicative of aneugenic activity. Vincristine and nocodazole gave the highest incidences of aberrant MN and these were shown to be strongly dose-related in the case of vincristine.

Aneuploidy↗
PubMed1991

Lymphocyte transformation and thiuram sensitization.

The use of a lymphocyte transformation test (LTT) to confirm allergic contact dermatitis from thiurams has been investigated. The responses of peripheral blood mononuclear cells (PBMC) from thiuram-sensitive and non-sensitive individuals following culture with dimethylcarbamoyl-protein (human serum albumin; HSA) and dimethylthiocarbamoyl-HSA conjugates has been compared. Only PBMC from those patients who were patch-test-positive with thiuram-mix and sensitized to tetramethylthiuram monosulphide (TMTM) or TMTM and tetramethylthiuram disulphide (TMTD) exhibited significant proliferative responses to these conjugates. Thiuram-patch-test-negative patients and control donors with no history of allergic contact dermatitis failed to mount a significant response to any concentration of either conjugate. Two of the thiuram-sensitive patients were also nickel-patch-test-positive, and PBMC isolated from these donors, but not from nickel-patch-test-negative patients, proved positive in a nickel LTT. The data reveal that relevant hapten-protein conjugates are capable of provoking specific human lymphocyte proliferative responses in vitro, and that, using this technique, the LTT can, in principle, be used for the investigation and/or diagnosis of skin sensitization to lipophilic contact allergens.

Cell Division↗
PubMed1991

Arsenite as the probable active species in the human carcinogenicity of arsenic: mouse micronucleus assays on Na and K arsenite, orpiment, and Fowler's solution.

Sodium arsenite, potassium arsenite, and Fowler's solution (arsenic trioxide dissolved in potassium bicarbonate) are equally active in the mouse bone marrow micronucleus assay (approximately 10 mg/kg by IP injection). The natural ore orpiment (principally As2S3) was inactive despite blood levels of arsenic of 300 to 900 ng/mL in treated mice at 24 hr. Sodium arsenite was active in three strains of mice. It is suggested that the human lung cancer observed among arsenic ore smelters and the skin cancer among people exposed therapeutically to Fowler's solution, have, as their common origin, the genotoxic arsenite ion AsO2-. The difficulty experienced when attempting to demonstrate rodent carcinogenicity for derivatives of arsenic suggests that the bone marrow micronucleus assay may act as a useful assay for potentially carcinogenic arsenic derivatives.

Animals↗
PubMed1991

Aspects of database construction and interrogation of relevance to the accurate prediction of rodent carcinogenicity and mutagenicity.

Attempts to reconcile qualitative carcinogenicity databases with qualitative mutagenicity database continue to indicate that there is no useful relationship between mutagenicity/genotoxicity and rodent carcinogenicity. It is suggested that recognition of two classes of carcinogen, genotoxic and nongenotoxic, is the first step in finding meaningful correlations between the above parameters. This then leads to purposeful intervention into the databases, including rejecting low quality data, abandoning some assays from the database, and clustering certain end points as repetitive rather that independent of each other. Seeking specific correlations within a focused database may yield knowledge from the current wealth of information. The effort required to build databases, particularly quantitative ones, has so far prevented the equally arduous task of their correct interrogation. Preliminary indications are the mutagenicity is closely correlated with genotoxic carcinogenesis and completely independent of nongenotoxic carcinogenesis.

Animals↗
PubMed1990

Assay-specific genotoxicity of N-nitrosodibenzylamine to the rat liver in vivo.

N-Nitrosodibenzylamine (NDBzA) is mutagenic to Salmonella typhimurium and induces DNA strand breaks in isolated rat hepatocytes, yet it is reported to be non-carcinogenic to the rat. Here we report that it is inactive in both the rat and mouse bone marrow micronucleus assays and in a rat liver autoradiographic assay for unscheduled DNA synthesis. It is, however, clearly active as a micronucleus-inducing agent and mitogen in the rat liver and is capable of inducing single-strand breaks in the DNA of rat liver. The origin and implications of this curious conflict of in vivo genotoxicity data are discussed. Irrespective of that discussion, it is concluded that NDBzA is genotoxic to the rat liver in vivo.

Animals↗
PubMed1990

Studies on the genotoxicity of beryllium sulphate in vitro and in vivo.

There is limited evidence that beryllium is a lung carcinogen to man, and several compounds of beryllium are carcinogenic to the lungs of the rat, rabbit and monkey. One such compound is beryllium sulphate (BeSO4.4H2O). This soluble salt has been evaluated in a range of genotoxicity tests. It was non-mutagenic to Salmonella typhimurium (strains TA1535, 1537, 1538, 98 and 100) when evaluated in the plate-incorporation assay at dose levels up to 5 mg/plate (+/- induced rat-liver S9 mix). It was also non-clastogenic to Chinese hamster lung (CHL) cells cultured in vitro. When dosed to male CBA mice via oral gavage at dose levels of 80% and 50% of the medium lethal dose (2.3 and 1.4 g/kg, respectively) it failed to increase the incidence of micronucleated polychromatic erythrocytes in the bone marrow (sampled at 24, 48 and 72 h post-dosing). However, a marked depression of erythropoiesis was evident 24 h after dosing suggestive of beryllium-mediated bone-marrow toxicity. When tested in the strain A mouse lung tumour bioassay, BeSO4 induced a significant increase in the number of tumour-bearing animals but not in the number of lung tumours per animal. These findings are discussed within the contexts of other genotoxicity data published for BeSO4, and of current strategies for the detection of possible human carcinogens.

Adenoma↗
PubMed1990

Methyl vinyl sulphone: a new class of Michael-type genotoxin.

Methyl vinyl sulphone (MVS) is a labile, Michael-reactive chemical, similar in structure to acrylamide (AA). Given that acrylamide is a reference mammalian mutagen and a rodent carcinogen, studies were undertaken to evaluate the potential genotoxicity of MVS. In common with AA, MVS was non-mutagenic to Salmonella but active as an aneugen to cultured mammalian cells. It is concluded that vinyl sulphones should be regarded as representative of a new class of genotoxic chemical whose mode of action is probably primarily dependent upon Michael reactivity to proteins.

Acrylamide↗
PubMed1990

Activity of urethane and N,N-dimethylurethane in the mouse bone-marrow micronucleus assay: equivalence of oral and intraperitoneal routes of exposure.

Urethane is shown to be active in the mouse bone-marrow micronucleus assay when administered as a single dose by either gavage or intraperitoneal injection. The magnitude of the response using the two routes was not statistically significantly different. N,N-Dimethylurethane (DMU) is shown to be mutagenic to Salmonella and active in the bone-marrow micronucleus assay by both routes of administration. The activity of DMU in the bone marrow precludes elimination of ethanol, yielding cyanate ion, as an explanation for the micronucleus-inducing activity of urethane.

Administration, Oral↗
PubMed1990

Correlations between bioassay dose-level, mutagenicity to Salmonella, chemical structure and sites of carcinogenesis among 226 chemicals evaluated for carcinogenicity by the U.S. NTP.

Bioassay dose-level data for 226 chemicals unequivocally defined as carcinogens or non-carcinogens in mice and/or rats by the U.S. NTP have been standardized to gavage equivalent dose-levels according to a modification of the methods of Gold et al. Correlations by bioassay dose-level with chemical structure, mutagenicity to Salmonella, sites of carcinogenesis and extent of trans-species activity have been studied. The data obtained add further weight to the proposition that two classes of rodent carcinogen are present in the NTP database--genotoxic carcinogens that occur predominantly in the dose range 20-800 mg/kg and putative non-genotoxic carcinogens that are equally distributed over the dose range less than 20- greater than 3000 mg/kg. The latter carcinogens are characterized by the lack of structural alerts to DNA reactivity, the absence of mutagenicity to Salmonella, an inability to induce tumours in 8 reference tissues and a strong tendency to be tissue and species-specific in their activity. Where comparisons can be made, the present findings for the NTP carcinogens and non-carcinogens are consistent with the recent observations by Gold et al. for a larger group of carcinogens.

Animals↗
PubMed1990

1-Chloromethylpyrene: a reference skin sensitizer and genotoxin.

1-Chloromethylpyrene (1-CMP) has been evaluated as a model mutagen and toxin related to the ultimate electrophiles derived from benzo[a]pyrene and 1-nitropyrene. It was mutagenic to Salmonella (greater than 100 pg/plate) and exceptionally reactive to DNA when assessed by the 32P-postlabelling technique. 1-CMP was inactive in a mouse bone micronucleus assay when administered by gavage, probably due to hydrolysis, whose kinetics have been studied (t1/2 approximately 23 min at 37 degrees C). However, as expected, it was a potent skin toxin as determined by its activity as a mitogen to mouse skin and its contact allergenicity, as determined using the local lymph node proliferative assay. It is concluded that 1-CMP will probably be a potent human skin carcinogen and contact allergen.

Animals↗
PubMed1990

A scheme for classifying carcinogens.

We present a scheme for classifying chemical carcinogens according to the weight of the evidence that each substance poses a human cancer hazard. The approach represents a logical extension of and builds upon those previously developed by the International Agency for Research on Cancer, the U.S. Environmental Protection Agency, and the so-called Tripartite Group of industrial scientists. It takes into account new scientific knowledge about chemical carcinogenesis and animal models. Eight categories are presented: known human carcinogen (Category 1), carcinogenic activity in animals, probable human carcinogen (Category 2), possible human carcinogen (Category 3), equivocal evidence for carcinogenic activity (Category 4), evidence inadequate for classification (Category 5), carcinogenic activity in animals; probably not a human cancer hazard (Category 6), carcinogenic activity in animals; considered not a human cancer hazard (Category 7), evidence of noncarcinogenicity (Category 8). Evidence useful for categorization includes human studies, animal bioassays, corroborative evidence from bioassays, and mechanistic studies relevant to determining the predictivity of animal responses for human hazard. Weighing this evidence to derive a conclusion about classification is a process that requires expert judgment; it cannot now be reduced to a simple set of decision rules. However, we identify the kinds of information that can be useful in this process, and indicate how each might most appropriately be used.

Animals↗
PubMed1990

Prediction of the outcome of rodent carcinogenicity bioassays currently being conducted on 44 chemicals by the National Toxicology Program.

This paper was written to enable evaluation of the concept that knowledge about chemical structure combined with limited short-term genotoxicity and toxicity test results can be used to predict potential carcinogens. Previous attempts have been potentially biased by prior knowledge about the tumorigenicity of chemicals in animals or humans, but the 44 chemicals that are currently being bioassayed for carcinogenicity by the National Toxicology Program provide an opportunity prospectively to evaluate factors that may be predictive of chemical carcinogenicity. Predictions of rodent carcinogenicity for these 44 agents are presented as an example of what we believe is the best available approach at this time. This publication will also enable others to make their own predictions (using whatever methods they believe to have high predictive value) before the results of the animal assays are known.

Animals↗