Biomedical subjects

N A Littlefield

Publications and source records attributed to N A Littlefield.

At least 19 recordsLinked to original sources

PubMed1994

Protective effect of magnesium on DNA strand breaks induced by nickel or cadmium.

Magnesium, an essential metal that is important in the normal functioning of DNA, has been shown to interact with some of the toxic heavy metals in respect to biochemical and molecular mechanisms and in altering the tumorigenic process. This study examined the influence of magnesium in combination with nickel and cadmium in respect to damage of the DNA molecule. The purpose of this study was to evaluate the influence of magnesium on the amelioration of the toxic metals nickel and cadmium in respect to sustaining DNA damage. Two types of lymphocytes were used, i.e., primary Fischer 344 rat splenocytes and AHH-1 TK+/-, a human B-lymphoblastoid cell line that has been spontaneously transformed. These cells were grown in either a magnesium-free or magnesium-supplemented RPMI 1640 medium that was specifically formulated for this study. A 2 x 2 factorial design was employed with magnesium and either nickel or cadmium serving as the two factors. The experimental groups were as follows: +Mg+Ni, +Mg-Ni, -Mg+Ni, -Mg-Ni, with cadmium alternating for the nickel in the subsequent studies. The nickel or cadmium was added at a concentration of 50 mumol/L. The presence of double-stranded DNA was determined in each of the respective treatment groups with the two types of cell lines. Based on the results of this study, nickel is not directly toxic to DNA, whereas cadmium produces damage directly on the DNA molecule.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1991

Effect of magnesium on the growth and cell cycle of transformed and non-transformed epithelial rat liver cells in vitro.

The effects of magnesium (Mg) restriction on cell growth and the cell cycle were determined in transformed (TRL-8) and non-transformed (TRL-12-15) epithelial-like rat liver cells. Cells were cultured in RPMI 1640 medium in which the Mg concentration was reduced to 0.5, 0.1, and 0 x the concentration in the regular RPMI 1640 media (100mg/l). Cell growth in the transformed cells was not influenced by the Mg restriction as greatly as in the non-transformed cell line. Transit through the cell cycle also exhibited an independence of the Mg in the medium in the transformed cells. When transformed cells were grown for two generations in Mg-limited medium, the growth rate slowed to a rate similar to that demonstrated by the non-transformed cells. Analysis by flow cytometry showed that transit through the cell cycle was minimally slowed in Mg deficient transformed cells; however, transit through the G1 and S phases in the non-transformed cells was slowed. The TRL-8 cells in Mg-limited medium resulted in fewer nuclei in G1 with subsequent increases in the percentages of S-phase nuclei. The TRL 12-15 cells reacted oppositely with the number of G1 nuclei increased and the number of S-phase nuclei decreased. In respect to growth, these results show that epithelial cells respond in a similar manner to Mg-limitation as do fibroblast cells. The transformed cells exhibited a level of independence from Mg in respect to growth, reproduction, and cell-cycle kinetics.

Animals↗

PubMed1991

Hydroxylation and deglycosylation of 2'-deoxyguanosine in the presence of magnesium and nickel.

Nickel (Ni), a carcinogenic and genotoxic metal, has been shown to enhance deglycosylation and hydroxylation of 2'-deoxyguanosine (dG) that has been caused by ascorbic acid and H2O2. There is evidence that Mg is a competitive antagonist of the toxicological effects of Ni. A factorial design was used to examine the interactive influence of Mg and Ni on the deglycosylation and hydroxylation of dG under a range of pH conditions in which ascorbate (Ascb) and H2O2 were added. Formation of guanine (Gu) (deglycosylation) and 8-hydroxy-2'-deoxyguanosine (8-OH-dG) (hydroxylation) appeared in large amounts in samples in which both H2O2 and Ascb were present. The largest amounts of Gu appeared where both Ni or magnesium (Mg) were present. When Mg alone was present, the amounts of Gu was intermediate between these two. Slightly less 8-OH-dG was formed where only Mg was present. The reaction mixtures were more sensitive to the pH than to the respective presence or absence of metals. At slightly acid or neutral pH (6.2-7.0) large amounts of both Gu and 8-OH-dG were formed. Gu formation decreased dramatically between pH 7.0 and 7.2. There was no 8-OH-dG formed at pH 7.8 and only small amounts at pH 7.6. The formation of 8-OH-dG was generally less where Mg was present. When Ni was absent, 8-OH-dG formation was greater in the pH 6.8 mixtures. The formation of Gu and 8-OH-dG from 2'-deoxyguanosine are directly a function of pH. Slight changes in pH greatly effected the formation of these biomarkers of oxidatively damaged DNA. Additional research is needed to determine if this is a cause or effect, i.e. does pH enhance toxicity conditions, thus permitting formation of 8-OH-dG, or does pH permit the reaction to proceed.

Ascorbic Acid↗

PubMed1990

Chronic toxicity/carcinogenicity studies of sulphamethazine in Fischer 344/N rats: two-generation exposure.

Fischer 344 rats were given 10, 40, 600, 1200 or 2400 ppm sulphamethazine (SMZ) in the diet to determine the toxicity and potential carcinogenicity of SMZ. There were 225 rats of each sex in the control groups and 135 of each sex in each dose group. Animals were killed after 3, 12, 18 or 24 months of continuous dosing. Body weights, feed consumption, clinical observations, organ weights and histopathology data were collected. A slight decrease in body-weight gain was observed in the high-dose groups compared with the controls. No difference in feed consumption was found between the control and dosed rats. Mortality was inversely related to SMZ dose, especially in females, that is mortality was highest in the controls and decreased as the dose of SMZ increased. A statistically significant dose-related increase in the incidence of follicular cell adenocarcinomas of the thyroid gland was observed in the animals killed after 24 months. The incidences of non-neoplastic lesions of the thyroid gland in treated animals were significantly higher among treated animals than among controls; these lesions included follicular cell hyperplasia, follicular cell focal cellular change and multilocular cysts. The incidences of retinal atrophy, atrophy of the acinar pancreas (males), and dilatation of the uterine lumen also increased with increasing SMZ dose.

Adenocarcinoma↗

PubMed1989

Chronic toxicity/carcinogenicity studies of sulphamethazine in B6C3F1 mice.

A chronic feeding study was carried out in B6C3F1 mice with sulphamethazine (SMZ). The test substance was administered in the diet at dose levels of 0 (control), 300, 600, 1200, 2400 and 4800 ppm for 24 months. Mice were killed after 12, 18 and 24 months of continuous dosing. Body weights and food consumption were measured weekly, and mortality was recorded daily. All animals received a complete necropsy and histopathological examination, the results of which were analysed statistically. A slight decrease in body-weight gain was noted for mice of all dose groups with females showing the greater effect. Food consumption based on g food/g average body weight was relatively constant among the controls and various dose groups. The mortality rate for males and females of the control groups (8 and 8%, respectively) was higher than that for males and females of some of the higher dose groups. Neoplastic lesions associated with the ingestion of SMZ in the diet included follicular cell adenomas of the thyroid gland. At the 24-month necropsy, the incidence of this lesion for males and females of the 4800-ppm dose groups was 33 and 26%, respectively. Non-neoplastic dose-related lesions observed in both males and females included follicular cell hyperplasia (diffuse and focal) of the thyroid gland, haematopoietic cell proliferation of the spleen and pigmentation of the spleen. In females, pigmentation of the lymph nodes and hyperplasia of the mammary gland were also noted.

Adenoma↗

PubMed1989

Chronic toxicity/carcinogenicity studies of gentian violet in Fischer 344 rats: two-generation exposure.

A chronic feeding study was carried out in the F1a generation of dosed Fischer 344 rats of both sexes with gentian violet (GV). The test substance was administered in the diet to 570 male and 570 female rats at dose levels of 0 (control), 100, 300 and 600 ppm for 24 months. Rats were killed and necropsied after 12, 18 and 24 months of continuous dosing. Measurements of body weights, food consumption (and dose rate) and mortality and the results of histopathological examination were analysed statistically. Male and female rats fed 600 ppm GV for 24 months showed a decrease in body weights. Average food consumption based on g food/kg average body weight was essentially equal in all groups. Mortality at the end of the study (24 months) was approximately 33% in the controls for both males and females and approximately 66% in females of the high-dose group and 48 and 39% in males of the mid- and high-dose groups, respectively. All dose-related neoplastic pathology was noted at the final necropsy. Following 24 months of dosing, there was a significant difference from the controls in the incidence of follicular cell adenocarcinoma of the thyroid gland for both males (600 ppm GV) and females (300 and 600 ppm GV). Although the incidences were very low, statistical analysis showed a significant difference from the controls for hepatocellular adenomas in the mid-dose group of the females and the mid- and high-dose groups of the males. A dose-time-related incidence of mononuclear cell leukaemia was also noted in the females. There was high background incidence of the leukaemia. Several non-neoplastic dose-related lesions were observed in both males and females, principally in the 18- and 24-month necropsies. Almost all of these lesions were focal changes in the liver, many of which were probably related to the mononuclear cell leukaemia.

Animals↗

PubMed1987

Influence of oral administration of sulfamethazine on thyroid hormone levels in Fischer 344 rats.

Fischer 344 rats (810 of each sex) were divided into treatment groups and fed diets containing 0, 10, 40, 600, 1200, or 2400 ppm sulfamethazine. Serum samples were analyzed for levels of thyroid-stimulating hormone (TSH), total thyroxine (T4), total triiodothyronine (T3), and T3 uptake after 12, 18, or 24 mo of continuous dosing. There were no statistically significant differences in T3 levels or percent T3 uptake for either sex after any of the exposure periods. The serum T4 levels were lower (p less than 0.05) for females dosed at 1200 and 2400 ppm for 18 mo and for males dosed at 600, 1200, or 2400 ppm sulfamethazine for 24 mo than for those dosed at levels of 40 ppm or less. Serum TSH levels showed a general increasing trend (but not statistically significant) among animals receiving 600 ppm or more sulfamethazine. There was a significant dose-related reduction in (T3 + T4)/TSH ratio for both sexes (p less than 0.05) after 18 and 24 mo of exposure at dose levels of 600 ppm or more. A lack of response at 12 mo may have been due to the shorter treatment time. At each sacrifice period both sexes of rats fed sulfamethazine at 1200 and 2400 ppm had significantly heavier (p less than 0.05) thyroid weights than animals fed control diet. The heavier thyroid weights in the dosed animals may have resulted from increased TSH levels. The cause of reduction in serum T4 was not clearly evident. Therefore, the thyroid hormone to pituitary feedback mechanism apparently compensated for sulfamethazine effects in most animals. This would suggest that the thyroid gland was not irreversibly affected.

Administration, Oral↗

PubMed1985

Chronic toxicity and carcinogenicity studies of gentian violet in mice.

Gentian violet is a dye belonging to a chemical class known as the di- and triaminophenylmethanes. Although it has been used for many years for the control of fungal and intestinal parasites, for various uses in veterinary medicine, and as an additive to the feed of chickens to inhibit propagation of mold and fungus, very few long-term toxicity data are available. A life span dosing study of gentian violet in the diet of 720 males and 720 females of B6C3F1 mice (C57BL/6 X C3H) at dose levels of 0, 100, 300, and 600 ppm was done to determine its toxicity and carcinogenicity. Sacrifices were conducted after 12, 18, and 24 months of continuous dosing. There was no effect on food consumption or body weight gain; however, a dose effect was noted for mortality rates. Mortality (adjusted for sacrifices) in the controls of both sexes was less than 15% at 24 months, but was approximately 64% in the females and 23% in the males given the high dose. Females appeared to be more susceptible than males. A positive dose response for hepatocellular carcinoma was noted in males at 24 months and in females at 18 and 24 months. Statistical tests for dose-related trends with respect to mortality due to liver neoplasms, prevalence of liver neoplasms, and time to onset of liver neoplasms showed positive trends in both males and females. Other dose-related toxicological responses, particularly in the female mice, included erythropoiesis in the spleen, atrophy of the ovaries, adenoma of the Harderian gland, and the presence of type A reticulum cell sarcomas in the urinary bladder, uterus, ovaries, and vagina. The estimation of risk of 10(-6) over background for malignant liver neoplasms using linear extrapolations showed a lower bound on the virtually safe dose (VSD) to be 2 ppb for the female mice and 1 ppb for the male mice. For benign and malignant liver tumors together, the lower bound on the VSD was essentially the same as for malignant liver neoplasm alone. Under the conditions of the experiment described above, gentian violet appears to be a carcinogen in mice at several different organ sites.

Animals↗

PubMed1985

Carcinogenesis of 4-aminobiphenyl in BALB/cStCrlfC3Hf/Nctr mice.

Male and female (840 each) BALB/cStCrlfC3Hf/Nctr mice were given 0, 7, 14, 28, 55, 110 and 220, and 0, 7, 19, 38, 75, 150 and 300 ppm, respectively, of 4-aminobiphenyl in their drinking water. Necropsies on killed animals were performed at 13, 26, 39, 52 and 96 weeks on dose. Dose-related neoplasms were angiosarcomas, bladder urothelial carcinomas and hepatocellular neoplasms. The non-neoplastic dose-related lesions were left atrial thrombosis, bladder urothelial hyperplasia, splenic hemosiderosis and splenic erythropoiesis. The incidences of bladder carcinoma and atrial thrombosis were higher in the males and the incidences of hepatocellular neoplasms and angiosarcomas were higher in the females.

Aminobiphenyl Compounds↗

PubMed1985

Influence of genetic composition of test-animal populations on chronic toxicity studies used for risk estimation.

A lifespan exposure of mice to benzidine dihydrochloride was conducted for 33 m using both sexes of two populations of mice with the same gene pool. One population was the genetically homogeneous F1 hybrid produced by crossing BALB/cStCrlC3Hf/Nctr males with C57BL/6jfC3Hf/Nctr females. The second population consisted of genetically heterogenous monohybrid cross (MC) offspring produced by mating the F1 hybrids inter se. Data comparisons were made to determine if gene distribution among members of a population affects the response to a toxic insult. Endpoints tested consisted of mortality, liver tumor incidence and time of tumor onset, mortality from reticulum-cell sarcoma, and body weights. In most instances it was noted that among animals not dosed (controls), the F1 population had lower background incidence of lesions and lived longer than the MC population. However, among the dosed animals, the F1 mice were generally more susceptible to the toxic agent and developed higher incidences of the chemically induced lesions than did the MC population. The F1 hybrid population gave a more conservative estimate of risk than did the MC population. The calculation of the liver tumor risk for these two populations showed that lifespan exposure to benzidine would be predicted to result in a larger number (higher risk) when using the F1 data. A 4.5-fold difference in the toxic response was observed between the F1 females and the MC males. This emphasizes the importance of gene distribution in risk estimation studies.

Animals↗

PubMed1985

Influence of total dose and dose rate in carcinogenicity studies.

One element of the ED01 Study contained a group of animals that were dosed with 2-acetylaminofluorene for 9, 12, 15, 18, or 24 mo and then sacrificed at 18 or 24 mo. This provided data to compare the relative effects on carcinogenicity of dose rate versus total dose. The prevalence of liver and bladder tumors were used as the comparison. Animals receiving similar total doses but over a different length of time (different dose rates) were compared at the 18- and 24-mo sacrifices. When the total doses were similar, the higher dose rates for shorter time periods induced a higher prevalence of tumors. Results were more consistent for bladder tumors than for liver tumors, although the same trends were noted for both endpoints. Those groups dosed at higher rates but for fewer months had a generally higher prevalence than those receiving similar total doses but at lower rates for more months. This data from the ED01 Study illustrates the importance of experimental design, dosing regime, length of study time, and age of the animals at time of dosing in respect of calculation of risk.

2-Acetylaminofluorene↗

PubMed1984

Benzidine dihydrochloride: risk assessment.

Benzidine, recognized as a bladder carcinogen in man and as a liver carcinogen in experimental animals, is the chemical basis of as many as 200 commercial dyes. Physiological processes can metabolize these dyes to release benzidine, thereby creating a potential exposure hazard. To assess this hazard, both sexes of F1 hybrid (genetically homogeneous) and monohybrid (genetically heterogeneous) mice from a BALB/c male and C57BL/6 female cross were exposed for their respective lifespans to benzidine dihydrochloride in their drinking water at concentrations of 0, 30, 40, 60, 80, 120, and 160 ppm for males, and 0, 20, 30, 40, 60, 80, and 120 ppm for females. Animals were removed from the study when they were dead or moribund. This study was terminated after 33 months of exposure. Using the endpoint of hepatocellular adenomas and carcinomas, the Armitage Doll multistage model was used to describe the tumor rates in the experimental dose range and to obtain the upper confidence level on tumor rates. Linear interpolation was used between zero dose and the upper confidence level of the lowest experimental dosage for predicting potential low dose tumor rates. Dose-response effects on body weight, survival, and liver neoplasms were noted in both stocks. For each of the endpoints, the females were more susceptible than males and the F1 (homogeneous) stock was more susceptible than the monohybrid cross (heterogeneous). The calculated virtually "safe" dose predicted to produce less than one per million F1 female mice with a liver tumor is 0.045 ppb. One part per billion of benzidine dihydrochloride in the drinking water of these mice is estimated to produce liver tumors in less than 2.23 mice per 100,000 population.

Animals↗

PubMed1984

Morphological effects of subchronic oral sulfamethazine administration on Fischer 344 rats and B6C3F1 mice.

One hundred and forty-four Fischer 344 rats and 144 B6C3F1 mice (72/sex/species) were fed either a control diet or a diet containing 300, 600, 1200, 2400 or 3600 ppm sulfamethazine for 90 days. They were then necropsied and tissue specimens were evaluated for pathological changes by light and transmission electron microscopy. No gross or light microscopic lesions related to sulfamethazine administration were evident in the mice. Thyroid gland enlargement was evident at necropsy in one half of the rats (12 of 24) which received the 3600 ppm level of sulfamethazine and in 1 of 24 rats fed the 2400 ppm level. By light microscopy, thyroid gland hyperplasia was evident in rats which received all 5 dose levels of the compound, but this change was more pronounced and more frequent in those animals administered the higher concentrations. This thyroid hyperplasia was observed in rats of both sexes, but with greater incidence in males than in females, among the groups receiving the lower concentrations of compound. Ultrastructural changes included markedly dilated rough endoplasmic reticulum, altered microvilli, and diminished colloid droplets involving the thyroid follicular cells and compartmentalization of colloid within the follicular lumina.

Administration, Oral↗

PubMed1984

Effect of subchronic oral sulfamethazine administration on Fischer 344 rats and B6C3F1 mice.

One hundred and forty four Fischer 344 rats and 144 B6C3F1 mice of both sexes were fed either a control diet or a diet containing 300, 600, 1200, 2400 or 3600 ppm sulfamethazine for 90 days. They were then necropsied and tissue specimens were evaluated for pathological changes by light and transmission electron microscopy. No gross or light microscopic lesions related to sulfamethazine administration were evident in the mice. Thyroid gland enlargement was evident at necropsy in one half of the rats (12 of 24) which received the 3600 ppm dosage level of sulfamethazine and in 1 of 24 rats fed the 2400 ppm level. By light microscopy, thyroid gland hyperplasia was evident in rats which received all five dosage levels of the compound, but the change was more pronounced and of a greater incidence in those administered the higher concentrations. This effect was observed in rats of both sexes but its incidence was greater in males than in females among the groups receiving the lower concentrations of compound. Ultrastructural changes included markedly dilated rough endoplasmic reticulium, altered microvilli and diminished colloid droplets involving the thyroid follicular cells and compartmentalization of colloid within the follicular lumina.

Administration, Oral↗

PubMed1981

Incidence of pulmonary metastases for various neoplasms in BALB/cStCrlfC3H/Nctr female fed N-2-fluorenylacetamide.

Incidence of pulmonary metastases for a variety of neoplasms was studied in many inbred BALB/cStCrlfC3H/Nctr female mice fed 2-fluorenylacetamide. Bladder carcinomas and hepatocellular carcinomas appeared to be the only neoplasms that were dose related. Hepatocellular carcinomas metastasized to the lungs at an incidence of 4.8%, and bladder carcinomas metastasized at an incidence of 0.28%. Osteogenic sarcomas metastasized to the lungs at an incidence of 46.2%; renal adenocarcinomas, at 20%; fibrosarcomas, at 16.7%; mammary adenocarcinomas, at 9.8%; and myoepitheliomas, at 10.5%. Other malignant neoplasms, including leiomyosarcomas, granulosa cells tumors, adrenocortical carcinomas, angiosarcomas, squamous cell carcinomas, and harderian gland tumors, metastasized at an incidence of less than 5%.

2-Acetylaminofluorene↗

PubMed1980

Commercial laboratory animal diets: toxicant and nutrient variability.

A commercial rodent feed was analyzed for a series of nutrients and potential contaminants during a 5-yr period. Annual average Cu and vitamin A concentrations were generally at least 12% lower than the approximate concentrations listed by the manufacturer, whereas Ca, protein, and vitamin B1 were within +/- 5% and fat and Zn within +/- 8% of the manufacturer's specifications. Frequently, Se was found at concentrations at which it has been shown to interact with the process of chemical carcinogenesis. DDT, dieldrin, Cd, and Pb were occasionally close to concentrations known to have biological effects.

Animal Feed↗

PubMed1980

Barrier animal facility operations for a large-scale chronic study (ED01 study).

The physical facilities of the specific pathogen free/defined flora barrier animal rooms and their support operations are described as used in the conduct of a large-scale, long-term, low-dose carcinogenicity study. Specifically described are the floor plan of the facility, the mechanical operations, air flow, temperature and humidity controls, personnel screening and requirements, cleaning operations, and traffic flow patterns of personnel, equipment, and animals.

Animals↗

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↗