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R L Kodell

Publications and source records attributed to R L Kodell.

At least 73 records · Page 4Linked to original sources
PubMed1984

Association between cage shelf level and spontaneous and induced neoplasms in mice.

Data from a chronic feeding study with 2-acetylaminofluorene [(2-AAF) CAS: 53-96-3; N-fluoren-2-yl-acetamide] done on 20,880 female BALB/c mice were analyzed for associations between cage shelf level and occurrence of induced and spontaneous neoplasms. Each cage was maintained on a rack at a given shelf level throughout the experiment, allowing analysis of data by shelf level. Differences in the crude incidence of 2-AAF-induced liver and bladder neoplasms appeared to be shelf related, but these differences were small and disappeared when shelf-level analyses of time-to-tumor onset distributions were performed. There was evidence for a shelf-level influence on 5 of the 6 major spontaneous neoplasms noted. Time to onset of uterine polyps and reticulum cell sarcomas was significantly delayed on the top shelf of five of six animal rooms. Also, there was a significant delay in onset of lymphomas, adrenocortical adenomas, and lung alveolar cell tumors on the top shelf when data were combined from all six animal rooms, but these delays on the top shelf were significant in no more than two of six animal rooms when rooms were analyzed separately. There was no indication of any shelf-level influence on the development of harderian gland adenomas. In conclusion, shelf level is an environmental factor that should be considered in the design and analysis of carcinogenesis studies.

2-Acetylaminofluorene↗
PubMed1983

Dominant lethal test response with IMS and TEM using different combinations of male and female stocks of mice.

We conducted dominant lethal studies with chemical mutagens IMS and TEM to investigate the influence which different treated male stocks might have upon individual female response. In both studies, treated males from a CD-1 random bred stock and each of two F1 hybrid stocks (C57BL/6N X C3H; C57BL/6J X BALB/c) were mated to untreated females from the two F1 hybrid stocks. We found that variation in response due to the treatment effect was modulated by the specific male stock/female stock combination involved. The male-dependent variation observed prevented any meaningful evaluation of relative female stock sensitivity but it was obvious that factors other than differences in repair capacity of female germ cells contributed to the response differences observed.

Animals↗
PubMed1983

Primary harderian gland neoplasms in mice.

Five hundred and seventy-four spontaneous harderian gland neoplasms were observed in 3,123 male and 9,024 female untreated experimental mice of various ages and of 6 inbred strains and substrains and 3 hybrid stocks. Adenomas occurred in 86 males and 458 females, and adenocarcinomas were present in 3 males and 27 females. The highest tumor incidence occurred in mice after 24 months of age; no tumors were observed in any mice prior to 6 months of age. With the exception of 1 age group, both sexes of the BALB/c mice had the highest incidence, and also this strain accounted for 463 of the neoplasms. The adenomas were classified into one of four different histologic types: papillary, cystic papillary, acinar, and cystic. The papillary type was the most frequently observed in both sexes. The cystic papillary type was the second most frequently observed and was the type most frequently associated with gross lesions. This type may represent a developmental variant of the papillary type. The incidence of the acinar type was similar in both sexes. The cystic type had the lowest incidence. All except 3 adenocarcinomas appeared to evolve from adenomas, with evolvement occurring primarily in the acinar type. Five of the adenocarcinomas either metastasized to the lung or invaded periorbital tissues. The remaining 25 were confined to the harderian gland.

Adenocarcinoma↗
PubMed1983

Relationship of mouse body weight and food consumption/wastage to cage shelf level.

The relationships between the shelf level at which mice were housed and body weight and food consumption/wastage were examined by analyzing data obtained from the first 9 months of a carcinogenic dose-response study carried out in 24,192 female BALB/c mice using 2-acetylaminofluorene (2-AAF) as the carcinogen. Each cage, containing four mice, was maintained on a rack at a given shelf level throughout the course of the experiment to allow analysis of data by shelf level. The amount of food removed from each feeder and the body weight of each mouse was measured weekly. Average body weight gain during the first 12 weeks was lowest on the top shelf, highest on the next two shelves, and progressively lower as the shelf approached the lowest level on the rack. Body weights attained by week 36 of the experiment generally reflected this same pattern. Weekly food consumption/wastage, as measured by disappearance of food from the feeder, generally showed the converse shelf-level pattern as that shown by body weight gain. Removal of food from feeders was greatest on the top shelf, lowest on the next shelf, and progressively increased with each succeedingly lower shelf. Although it is not clear whether the food removal pattern was related more to food consumption or food wastage, the observation was reproducible.

2-Acetylaminofluorene↗
PubMed1982

Induction of mutations and sister-chromatid exchanges in Chinese hamster ovary cells by ethylating agents.

Chinese hamster ovary (CHO) cells were exposed to [3H]ethyl nitrosourea (ENU) or [3H]ethyl methanesulfonate (EMS) and the following DNA ethylation products were quantitated: 3- and 7-ethyladenine, O2-ethylcytosine, 3-, 7- and O6-ethylguanine, O2- and O4-ethyldeoxythymidine and the representative ethylated phosphodiester, deoxythymidylyl (3'-5')ethyl-deoxythymidine. When mutations at the hypoxanthine-guanine phosphoribosyl transferase (HGPRT) locus induced by these same treatments were compared with the observed ethylation products, mutations were found to correlate best with 3- and O6-ethylguanine. EMS induced approximately twice as many sister-chromatid exchanges (SCEs) as ENU at doses yielding equal mutation frequencies. When SCEs were indirectly compared with DNA ethylation products, 3-ethyladenine and ethylated phosphodiesters related best to SCE formation. Because mutation and SCE induction appear, at least in part, to be related to different DNA adducts, SCE induction by simple ethylating agents may not be a quantitative indicator of potentially mutagenic DNA damage.

Animals↗
PubMed1982

Accelerated appearance of chemically induced mammary carcinomas in obese yellow (Avy/A) (BALB/c X VY) F1 hybrid mice.

Latent periods and cumulative incidence of mammary carcinomas (MT) up to 50 wk after initial gavage with 7.12-dimethylbenz[a]anthracene (DMBA) were determined in virgin yellow (Avy/A) and agouti (A/a) (BALB/cStCrlfC3Hf/Nctr X VY/WffC3Hf/Nctr-Avy) F1 hybrid female mice. When subcutaneous masses reached 5-10 mm in diameter, the mice were killed and necropsied, and the tissues examined histologically. No MT were found in control mice. Cumulative MT incidence in the 1.5-mg DMBA group (A) was 43% (41/95) among yellow mice, and 33% (32/96) among agoutis. In the 6.0-mg DMBA group (B), corresponding MT incidences were 86% (83/96) and 71% (67/95). In group A, the first percentile of MT detection was 13.0 wk after initial carcinogen treatment in yellow mice; it was 18.0 wk in agoutis. Corresponding latent periods for the 20th percentile were 34.3 and 47.0 wk. In group B, latencies for the first percentile were 8.3 and 9.0 wk. Corresponding latencies for the 20th percentile were 15.3 and 16.0 wk. Within genotypes and dose groups, rates of weight gain of mice that developed MT and those that did not were similar. We conclude that MT induced by low doses of DMBA arise more rapidly in yellow mice than in nonyellow littermates. The absence of spontaneous MTs, acceleration of chemically induced MT formation at a low dose level that does not induce general toxicity, and availability of genetically identical (except for one gene) normal control animals make this experimental system suitable for development of an assay to efficiently test the carcinogenic potential of low dose levels of chemical substances.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1982

Influence of cause-of-death assignment on time-to-tumor analyses in animal carcinogenesis studies.

The importance of cause-of-death determination in an animal carcinogenesis study with respect to estimation of time-to-tumor distributions of internally occurring (occult) tumors is discussed. A nontechnical description of time-to-tumor estimation is presented. The information obtained from time-to-tumor estimation when cause-of-death designation was used is illustrated for liver tumors in female mice of the inbred strain BALB/cStCrlfC3Hf/Nctr from the ED01 study with N-2-fluorenylacetamide done at the National Center for Toxicological Research. A time-to-tumor analysis of reticulum cell sarcoma data from the same study has provided insight into some difficulties involved in routine case-by-case determination of cause of death. A more flexible system for assigning of cause of death to dead animals and cause of morbidity to moribund animals is described as a way to improve cause-of-death assignment.

2-Acetylaminofluorene↗
PubMed1982

Nonparametric joint estimators for disease resistance and survival functions in survival/sacrifice experiments.

The nonparametric estimators proposed in this paper simultaneously estimate the disease resistance function, S(t), for the distribution of time to occurrence of disease, and the survival function, P(t), for the distribution of time to death caused by the disease. The estimators are applicable to animal survival data when the disease of interest is irreversible and the cause of death of each animal can be determined. Diseases need not be classified as universally lethal or universally nonlethal, and time to occurrence of the disease of interest need not be observable directly. It is shown that the proposed estimators are maximum likelihood estimators under the condition that S(t)/P(t) is monotonically decreasing. Application of the derived estimators is illustrated with experimental survival/sacrifice data, and results of a simulation study of the estimators' performance are reported.

Animals↗
PubMed1982

Influence of cage shelf level on retinal atrophy in mice.

The correlation between cage shelf level and retinal atrophy was examined by analyzing data obtained from a chronic study carried out in 24,192 female BALB/c mice. Each cage of animals was maintained on a cage rack at a given shelf level throughout the course of the experiment, thus allowing analysis of data by shelf level. Retinal atrophy was first observed in a mouse killed at 12 months but subsequently was observed only at and after 16 months. This lesion was confined largely to animals on the top shelf. At 24 months, 19.7% of the mice on the top shelf had retinal atrophy while 0.2% of animals on all other shelves had the lesion. By 33 months, retinal atrophy was present in 30.2% of the mice on the top shelf, 12.0% on the next shelf, and 0.7% on the lower shelves. Differences in retinal morphology were probably caused by differences in lighting intensity. It was concluded that cage shelf level should be considered as an important factor in any chronic studies with mice.

Animals↗
PubMed1980

The heritable translocation assay: its relationship to assessment of genetic risk for future generations.

The Heritable Translocation Assay (HTA) is an in vivo mammalian mutation test which measures specific clastogenic damage. It can be subjected to rigorous statistical scrutiny and detects a type of heritable genetic damage that is known to contribute to the human disease burden. Because of these factors the HTA is one of the major tests of the battery used in regulatory evaluation of potential environmental mutagens. Although tests for detecting inherited translocations have been developed and improved over the past 40 years, further emphasis on several statistical considerations affecting the precision and reliability of HTA animal model data applied to regulatory hazard evaluation and risk assessment seems warranted. In this paper we have presented a brief history and the basic methodology for the HTA. Statistical concepts related to the design and implementation of HTA studies, such as the incorporation of false classification error probabilities in determination of required sample size and use of the single sample binomial versus Fisher's exact test for analysis of data, hory and the basic methodology for the HTA. Statistical concepts related to the design and implementation of HTA studies, such as the incorporation of false classification error probabilities in determination of required sample size and use of the single sample binomial versus Fisher's exact test for analysis of data, hory and the basic methodology for the HTA. Statistical concepts related to the design and implementation of HTA studies, such as the incorporation of false classification error probabilities in determination of required sample size and use of the single sample binomial versus Fisher's exact test for analysis of data, have been examined in detail. We have also suggested a simplified method of extrapolating HTA animal data to man similar to that used with carcinogenesis data and propose other developmental needs and perspectives for application of this assay to regulatory assessment of environmental mutagens.

Animals↗
PubMed1980

The effects of ascorbic acid on the induction of urothelial lesions in mice by 2-acetylaminofluorene.

288 BALB/c male mice were allocated to: Group 1-control; Group 2-500 ppm of 2-acetylaminofluorene (2-AAF) in the food, with control water; Group 4-500 ppm of 2-AAF in the food and 250 mg/100 ml of vitamin C in the water; and Group 3-control food and 250 mg% of vitamin C in the water. Major histopathologic changes at the end of 28 days included both inflammation of the lamina propria and hyperplasia of the transitional epithelium of the urinary bladder in mice receiving 2-AAF. The most severe lesions were seen in the mice administered the combination of 2-AAF and vitamin C. It was postulated that either decreased water consumption and concentration of the urine and/or reduction in urinary pH may have contributed to the severity of the lesions.

2-Acetylaminofluorene↗
PubMed1980

Linear interpolation algorithm for low dose risk assessment of toxic substances.

In order to detect potential toxic effects of substances, relatively high doses generally are administered to relatively small numbers of laboratory animals. It is impossible to estimate low levels of disease incidence with precision at low environmental dose levels even with large numbers of laboratory animals. However, upper limits on risk can be obtained for convex dose response curves by linear interpolation between the lowest experimental dose level and zero. A simple mathematical algorithm is provided for low dose risk assessment from dose response data and the performance of this procedure is evaluated for a variety of toxicological data, including but not limited to carcinogenesis. The low dose confidence limits resulting from linear interpolation are similar to those obtained from the Armitage-Doll multistage model.

2-Acetylaminofluorene↗
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

Dose and time responses models for the incidence of bladder and liver neoplasms in mice fed 2-acetylaminofluorene continuously.

The incidence of bladder and liver neoplasms developed in mice continuously fed 2-acetylaminofluorene (2-AAF) in a multidisciplined study conducted at the National Center for Toxicological Research (NCTR) is represented using a probit model. The estimated incidences are made from time intervals using both sacrificed and dead and moribund mice. A probit log dose model is fit for each type of neoplasm at each time interval where the incidence permits. A probit log time model is fit for each of the neoplastic types for each dose level where the incidence permits. Finally, the response of liver neoplasms to 2-AAF is represented in the dose time plane using a probit plane model. 2-AAF appears to be an early acting bladder carcinogen and a late acting liver carcinogen. The bladders seem to be much more uniform in their response to the carcinogen than the livers and the uniformity of neither response appears to be age dependent. Although the time to appearence of both liver and bladder neoplasms is dose related, the increment in incidence of liver neoplasms with respect to time is not dose related while that of the bladder neoplasms is dose related. The data for bladder neoplasms do not contradict the "no threshold" theory of carcinogenesis while the liver data strongly support it.

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↗