Search PubMed⌕ Search

Biomedical subjects

N A Littlefield

Publications and source records attributed to N A Littlefield.

32 records · Page 2Linked to original sources
PubMed1980

Biologic and morphologic characteristics of hepatocellular lesions in BALB/c female mice fed 2-acetylaminofluorene.

2-Acetylsaminofluorene (2-AAF) induced foci of hepatocellular alterations, hepatocellular adenomas, and hepatocellular carcinomas in BALB/c female mice. The incidence of basophilic cell foci decreased with high dose levels of 2-AAF, and the incidence of hepatocellular adenomas decreased with both high dose levels and length of administration of 2-AAF. The results suggest that the hepatocellular foci of cellular alteration may give rise to the hepatocellular adenomas which in turn may give rise to hepatocellular carcinomas. The study also suggests that both hepatocellular adenomas and carcinomas may develop de novo. Hepatocellular carcinomas rarely metastasized before 18 months, and the less differentiated hepatocellular carcinomas were more likely to metastasize. 2-AAF did not alter the incidence of spontaneous hemangiosarcomas.

2-Acetylaminofluorene↗
PubMed1980

Effects of dose and time in a long-term, low-dose carcinogenic study.

Large numbers of female BALB/c StCrlfC3Hf/Nctr mice were exposed for up to 33 months to low doses of 2-acetylaminofluorene (2-AAF) under controlled conditions. The study design consisted of sacrifice intervals, life span, and discontinued dosing groups. Two separate and distinct endpoints, that is urinary bladder neoplasms and liver neoplasms, resulted in 2 different types of dose response relationships. Although bladder neoplasms exhibited a minimum effect level (or a nonlinear response) for specific conditions, the total results were consistent with a "no threshold concept." The late appearing liver neoplasms displayed a nearly linear type response that extrapolated directly to zero dose. Time of exposure was shown to be an important factor in that, as animals were sacrificed at 18, 24, and 33 months, a positive response was noted at the next lower dose as time was extended. Discontinuing dosing and sacrificing at 18 and 24 months also demonstrated the effects of exposure to the carcinogen 2-AAF. Induction of bladder neoplasms was shown to occur early in the study, but was dependent upon the continuous presence of 2-AAF. The liver neoplasms appeared very late in the study but were shown to be induced at a very early point in the exposures and did not require the continuous presence of the carcinogen in order to develop. A standard 18 month bioassay study, if conducted under the same conditions, would have classified this chemical as a weak acting carcinogen. These studies demonstrate the importance of the time factor in safety evaluation or risk assessment in carcinogenesis.

2-Acetylaminofluorene↗
PubMed1980

Chemical surveillance and quality assurance for preparation of dosed (2-AAF) animal feed (ED01 study).

Protocol development of the ED01 experiment included assurances that only minimal levels of contaminants were present and correct concentrations of 2-AAF were present in animal feed. Laboratory and administrative controls were developed to assure proper feed packaging and delivery, and to conduct a personnel surveillance as well as a chemical surveillance of work environs to ensure safe work areas. Animal feed and ancillary animal supplies were monitored prior to use to provide assurances that acceptable levels of nutrients were present and to prohibit the entrance of unacceptable levels of contaminants such as pesticides and heavy metals.

2-Acetylaminofluorene↗
PubMed1980

Effects of continuous and discontinued exposure to 2-AAF on urinary bladder hyperplasia and neoplasia.

The effect of discontinued feeding of 2-acetylaminofluorine (2-AAF) was compared with the effect of continuous 2-AAF feeding on the urinary bladder of BALB/c female mice. Dietary concentrations of 2-AAF examined in this regard were 60, 75, 100, and 150 ppm. These diets were fed for 9, 12, or 15 months and then replaced with control feed, and the animals were killed at 18 or 24 months. Observations on these animals were contrasted with observations made at the same intervals on animals continuously fed these concentrations of 2-AAF throughout the study. Discontinuing 2-AAF exposure decreased prevalence of bladder tumors below that found in continuously exposed mice and resulted in a decrease in severity and prevalence of hyperplasia. Mild hyperplasia was retained in a portion of each population and the prevalence of this hyperplasia was dependent on both the period of exposure and the dose of 2-AAF. Mild persistent hyperplasia was correlated closely with neoplasia and may be a necessary stage in neoplastic development. Moderate or severe hyperplasia apparently regress when 2-AAF feeding is discontinued and do not appear to be essential steps in the neoplastic process.

2-Acetylaminofluorene↗
PubMed1980

Analysis of life-shortening effects in female BALB/C mice fed 2-acetylaminofluorene.

A total of 4320 female BALB/cStCrlfC3H/Nctr mice were continuously fed 2-acetylaminofluorene (2-AAF) in the diet at various concentrations in order to obtain a quantitative assessment of dose-related life-shortening effects. Statistical procedures which adjust for extraneous deaths were used to analyze the survival data. In addition to the demonstration of a reduced survival time associated with bladder and liver tumors induced by 2-AAF, a further toxic effect was observed at 150 ppm. Since the experiment was replicated six times, variability in the survival times of animals in different replicates was studied. Although all replicates were conducted under specific pathogen free / defined flora (SPF/DF) conditions, a significant change in survival time was demonstrated across replicates.

2-Acetylaminofluorene↗
PubMed1979

Influence of genetic population structure on the results of chronic toxicity studies.

The importance of the genetic makeup of animals used for toxicological testing has been recognized, although there are few data regarding this. In the study discussed here offspring from a BALB/cStCrlfC3Hf/Nctr male and C57BL/6jfC3Hf/Nctr female cross were used to produce a homogeneous (F1) strain, and brother-sister mating of the F1 population was used to produce a heterogeneous (F2) strain of mice, both having essentially the same gene pool but with different distributions. The end points of mortality and body weights were used to demonstrate relative variability about a mean resulting from genetic constitution when the mice were exposed to benzidine dihydrochloride. This life-span study demonstrated that genetic constitution in research animals should be an important consideration in toxicological research. There were significant differences in body weight and mortality between the two populations, with the F2 mice exhibiting wider body weight ranges and greater susceptibility to the test chemical.

Animals↗
PubMed1975

Alkaline phosphatase activity in hyperplastic and neoplastic urinary bladder epithelium of mice fed 2-acetylaminofluorene.

Studies were made on the urinary bladder of 66 BALB/c mice of both sexes; 21 were fed a normal diet and 45, a diet containing 100-500 parts per million (ppm) of 2-acetylaminofluorene (2-AAF). Bladder epithelial hyperplasia was noted in 22 of 24 mice given 2-AAF for 7 months and in 20 of 21 given 2-AAF for 19 months. Transitional cell carcinomas were in 12 of 21 mice given 2-AAF for 19 months and in all except the 9 females given the low dose (100 ppm). Special stains revealed marked alkaline phosphatase activity in the bladder epithelium of untreated controls and slightly to moderately reduced activity in the hyperplastic epithelium, particularly the lower layers, of mice given 2-AAF for 7 months. Activity was markedly reduced and confined largely to the upper layers in mice treated for 19 months. The transitional cell carcinomas showed no activity except focally in a few tumor masses in 11 of 12 mice with tumors. Alkaline phosphatase activity was usually slightly to moderately increased in the sub-epithelial stroma after 7 months' treatment with 2-AAF and markedly increased after 19 months. Loss of alkaline phosphatase activity in the bladder epithelium may be a preneoplastic change.

Alkaline Phosphatase↗
PubMed1966

Fungistatic effects of controlled atmospheres.

The fungistatic effects of controlled atmospheres composed of increased CO(2) and decreased O(2) was studied in a manner such that the condition of stored fruit was not a factor in the growth of the fungi. Varying concentrations of O(2) and CO(2) were used. The fungi used were Botrytis alli, Rhizopus nigricans, and Penicillium expansum. The results showed that controlled atmospheres, within the limits of concentrations usable for fruit storage, are effective fungistatic agents.

Antifungal Agents↗
PubMedDate not supplied

Response to the society of toxicology task force re-examination of the ED01 study.

This communication has re-examined and justified certain of the NCTR's analyses and recommendations from the ED01 Study, which were either misunderstood or misinterpreted by the SOT Task Force. In addition, we have shown that some of the Task Force's own analyses and interpretations are subject to review on scientific grounds. The Task Force's rejection of the linear extrapolation method recommended by the NCTR was stated because of a suspected force-fitting of a linear model to data, an approach that is not part of the NCTR procedure. In suspecting a protective effect of 2-AAF against bladder tumors, the Task Force used an inappropriate model that overpredicted the background bladder tumor rate in control mice. Contrary to the Task Force's belief, a failure to account adequately for time to tumor response was more characteristic of analyses performed by the Task Force rather than those performed by the NCTR. The Task Force's questioning of the multistage model for risk assessment was based on its use of inappropriate, crude tumor data rather than upon NCTR's use of the multistage model with time-adjusted tumor data. The Hartley-Sielken model did not fit the ED01 tumor data as well as the Task Force had presumed. In a risk extrapolation comparison by the Task Force, a coarse time partition of the ED01 data that had been questioned by the Task Force actually produced more stable results than a finer partition proposed by the Task Force. Another problem in the Task Force report concerns the change of protocol. Instead of resulting in a loss of strength as anticipated by the Task Force, the change of protocol during the ED01 Study resulted in an increase in information as alluded to by the Task Force. If the Task Force's proposal for restricting the length of feeding studies had been followed in the ED01 Study, most of the dose related tumor information would not have been obtained. Also, the Task Force's belief that low doses of 2-AAF had some effect on the prevention of early death was not supported by a statistical analysis. In summary, the review conducted by the SOT Task Force contained some misleading representations of the data from the ED01 Study and statements that showed a misunderstanding of NCTR's analyses of the study.

Aging↗
PubMedDate not supplied

Benzidine dihydrochloride: toxicological assessment in mice during chronic exposures.

Although benzidine is recognized as a bladder carcinogen in humans and a liver carcinogen in laboratory animals, its toxicological effects appear to be extended to several other endpoints. This economically important chemical is the base for over 200 dyes and is used extensively in manufacturing. In a chronic lifespan study lasting 33 months, both sexes of F1 hybrid (genetically homogeneous) and monohybrid cross (genetically heterogeneous) mice from BALB/c male and C57BL/6 female crosses were exposed to benzidine dihydrochloride in their drinking water at concentrations of 0, 20, 30, 40, 60, 80, and 120 ppm for the females, and 0, 30, 40, 60, 80, 120, and 160 ppm for males. Animals were removed from the study when they were dead or moribund. In addition to hepatocellular carcinomas, there were several other toxicological end-points identified that appeared to be related to the administration of benzidine. Dose-response trends were noted for pigmentation of the spleen, hepatic cytological alterations, hyperplasia of the bile ducts, megakaryocytosis of the bone marrow, vacuolization of the brain, adenoma of the Harderian gland, atrophy of the ovaries, and angioma of the uterus. Also, dose-related effects were noted with respect to time to lung tumor and time to mortality due to reticulum-cell sarcomas.

Animals↗
PubMedDate not supplied

Damage to DNA by cadmium or nickel in the presence of ascorbate.

The interactive effects of the anti-oxidant ascorbate (Asc) and the metals cadmium (Cd, as CdCl2) or nickel (Ni, as NiCl2) on the in vitro formation of breaks in double-stranded deoxyribonucleic acid (d/s DNA) were determined. Concentrations of 50 microM Cd or 200 microM Ni were dosed for 4 hours in factorial combinations with 500 microM Asc in RPMI 1640 medium (7 percent bovine serum) in which AHH-1 TK+/- cells (a spontaneously transformed human B lymphoblastoid cell line by Gentest Corp.) were replicating. In combination with Asc, Cd caused significant d/s DNA breaks (p < 0.01, n = 5), while Cd in the absence of Asc produced only a slight (but not significantly different) amount of d/s DNA damage when compared to the cells with no Cd added. The Asc alone was not damaging. The Cd caused damage to the d/s DNA only when Asc was present. The percent of d/s DNA remaining following the respective treatments was: +Cd+Asc, 13 +/- 3; +Cd-Asc, 46 +/- 8; -Cd+Asc, 54 +/- 5; -Cd-Asc, 55 +/- 7. Conversely, the presence of Ni resulted in increased amounts (percent) of d/s DNA compared to control values: +Ni+Asc, 63 +/- 5; +Ni-Asc, 58 +/- 5; -Ni+Asc, 52 +/- 1; -Ni-Asc, 51 +/- 4, (p < 0.05, n = 3). The contrasting results between Cd and Ni in the presence of Asc may reside in the point of action; while Cd acts directly on DNA, Ni is reported to act on heterochromatin. Although Asc is a recognized anti-oxidant, its presence in the media mixture potentiated d/s DNA damage from the Cd. This may be caused by a Fenton-type reaction in which an antioxidant in the presence of metal generates hydroxyl radicals and consequently d/s DNA breaks. Oxidative reactions between metals, oxygen, and antioxidants such as Asc may represent an important mechanism of cell death, toxicity, and transformation.

Ascorbic Acid↗
PubMedDate not supplied

Actions and interactions of nickel and magnesium on the transformation response of transformed cells in culture.

Nickel (Ni) and magnesium (Mg) exert separate and interacting effects on cells: Ni is toxic while Mg enhances the transformation response of transformed cells and protects from heavy metal-induced toxicity. Transformed rat liver epithelial cells were used in the soft agar (SA) assay to measure the effect of Ni and/or Mg on the expression of anchorage independence. Cells were exposed to +/- Ni and +/- Mg in a single passage of growth medium (GM) prior to assay in SA. The cells were then treated with +/- Ni and +/- Mg in the SA resulting in a 4 x 4 treatment matrix yielding 16 Ni/Mg combinations. Nickel was expected to decrease the transformation frequency (TF) and did so in 6 of the 16 cases. Magnesium was expected to enhance the TF independently of Ni; Mg increased TF values in 7 of 16 cases. The Ni-Mg interaction occurred in 11 of 16 cases. In general, Mg and Ni effects were observed more in GM than is SA. It is not evident from this study why the Ni, Mg, and Ni-Mg effects are not observed universally, but it is evident that metal-metal interactions are not simply defined or analyzed in biological systems. A refined factorial design may be useful in further separating such interactions. From the point of view of the implementation of the SA assay, in which test substances are typically dose previous to the implementation of putting the exposed cells in SA, it is clear that assay results can be markedly altered by the presence of the test compound in the soft agar.

Animals↗