Biomedical subjects
Publications and source records attributed to D L Greenman.
The most frequently observed neoplasm in 2376 nontreated control female BALB/cSTCrlfC3H/Nctr mice examined at intervals up to 1001 days was reticulum cell sarcoma. It was also the primary cause of morbidity and death. Other frequently observed neoplasms were uterine polyps, alveolar cell neoplasms, Harderian gland neoplasms and lymphomas. Neoplasms, which had a low incidence, generally occurred in the older animals.
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.
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.
A recently-developed statistical technique is employed to estimate parameters of the distributions of time to appearance of tumors and time to death from tumors after their appearance using both interval sacrifice and survival information. Estimates are obtained for three types of tumors at each of eight dose levels of 2-AAF, namely, 0, 30, 35, 60, 75, 100 and 150 ppm, which were administered to a total of 20880 female BALB/cStCrlfC3Hf/Nctr mice. For bladder neoplasms, the estimated median times to tumor ranged from 19.8 months at 150ppm to 1876.6 months at 0 ppm, while for liver neoplasms the extremes were 25.2 months at 150 ppm and 37.7 months at 0 ppm. Reticulum cell sarcomas occurred on the average at 24.7 months in all dose groups except 150 ppm, where the average time to appearance was 22.9 months. Although a pronounced dose-response for time-to-tumor was expressed for both bladder and liver neoplasms, the time required for death from either neoplasm following its appearance was not dose-related. The estimated median times to death after appearance of tumors were as follows: bladder neoplasm, 6.8 months; liver neoplasm, 5.7 months; reticulum cell sarcoma, 3.0 months.
Selected oviductal lesions associated with the continuous feeding of diethylstilbestrol (DES) were examined ultrastructurally Virgin female mice were fed diets containing 0, 320 and 640 ppb DES from 4 weeks of age. All animals reported on in this study were removed from the study and sacrificed for histopathological and electron microscopy examination when moribund and ranged from 622 to 762 days on the experiment. One oviductal change consisted of markedly vacuolated ciliated epithelial cells located primarily in the fimbria. Electron microscopy revealed that the large vacuoles were present throughout the cytoplasm of affected cells. These vacuoles were not lipid and appeared to be fluid-filled. No significant alterations in number or structure of cilia were observed. Since this alteration was seen in both DES and control animals, it may be age-related. A second kind of oviductal lesion consisted by enlarged secretory cells located predominantly in the isthmus. The cytoplasm of these cells consisted of extremely enlarged, dilated rough endoplasmic cisternae forming a subnuclear mass. Numerous primary and secondary lysosomes were seen in the apical cytoplasm between the cell membrane and nucleus. No evidence of a Golgi complex was seen. These alterations were seen only in DES-exposed animals and seem to indicate continued protein synthesis by the secretory cells but a deficiency in the packaging of this protein into secretory granules.
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By using cell-free preparations of uteri obtained from immature BALB/c mice, it was demonstrated that zearalenone and zearalanol, Fusarium mycotoxins, inhibited [3H]estradiol-17 beta binding to specific sites in cytosol. Significant inhibition was noted from zearalenone at 4 x 10(-6) M and from zearalanol at 4 x 10(-7) M. Unlabeled mycotoxins (5 x 10(-6) M) incubated with intact uteri caused translocation of specific estrogen binding sites into nuclei that were exchangeable with [3H]estradiol-17 beta. Zearalanol was more effective in this regard than zearalenone. Ability of the mycotoxins to compete with estradiol-17 beta for the cytosol receptor and to cause translocation of the receptor to the nucleus in general is correlated with their biological activity. These data suggest that the uterotrophic effects of Fusarium mycotoxins are mediated through their association with estrogen receptors in the uterus.
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BALB/c StCrlfC3Hf/Nctr, C57BL/6/, C57BL/6 X BALB/c F1 hybrid (B6CF1), and monohybrid-cross offspring from the breeding of B6CF1 mice were examined with respect to uterine, vaginal, and thymus responses to diethylstilbestrol (DES). About 400 mice of each genetic population were used. Weanling mice were fed DES at dietary concentrations of 2.5 to 1,000 ppb (microgram/kg feed) for 6 days and were killed by cervical dislocation about 20 hr after removal of the feed. C57BL/6, B6CF1, and the monohybrid-cross offspring did not differ in the uterine-weight response to DES, but the slope of the dose-response line was shallower for the BALB/c than for the other strains. Dietary DES concentrations of 250 ppb or more inhibited the uterotrophic response in all populations. Vaginal cornification occurred at lower concentrations of DES in the C57BL/6 strain than in the B6CF1 animals. BALB/c and monohybrid-cross offspring were indistinguishable from each other in their vaginal response to Des and were less sensitive to DES than the other mouse populations. The use of ethanol or corn oil as the solvent for mixing DES into the diet had no apparent effect on the uterine weight or vaginal response in any of the mice. DES depressed thymus weight in a dose-related fashion at dietary concentrations of 100 ppb and above in all genetic populations.
The influence of cytidine dosage on uptake and distribution of [3H]cytidine by the uterus of the adult ovariectomized control rat was examined 20 min after injecting the nucleoside. Intracellular accumulation of free cytidine was observed only at a dosage of 4.2 mumol/100g. At lower dosages, the nucleoside was phosphorylated as rapidly as it entered uterine cells, thereby preventing its accumulation within cells. [3H]Cytidine (4.2 mumol/100 g) was used in time-course studies in ovariectomized control and estradiol-treated rats. From this study the following differences between uteri of control and estradiol-treated animals were noted: 1) both nucleotides and RNA were five to six times more highly labeled in treated than control animals after a five minute labeling period, 2) this difference between control and treated animals was reduced to twofold when the labeling period was extended to 20 min, 3) free nucleoside had begun to accumulate intracellularly in treated animals, but had not equilibrated with uterine extracellular space in controls 5 min after [3H]cytidine injection, and 4) at 20 min, the free nucleoside of the uterus was labeled about equally in control and treated rats. It is concluded that estradiol causes a rapid equilibration of circulating cytidine with the uterus and that increases in labeling of RNA and precursor nucleotides 2 h after hormone treatment are largely a consequence of this rapid equilibration.
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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.