Total Tumor Incidence Research Articles

Dietary deficiency or enrichment of essential fatty acids modulates tumorigenesis in the whole body of cobalt-60-irradiated mice

The effect of dietary polyunsaturated fatty acids (PUFAs) on whole body-induced tumorigenesis was assayed in mice fed on essential fatty acid sufficient (EFAS) or essential fatty acid deficient (EFAD) diets following cobalt-60 irradiation. Four groups of mice were maintained, one on a control stock diet and three on experimental diets: a) without added fat (fat free, FF); b) containing 5% olein (O), rich in n-9; and c) containing 5% corn oil, rich in n-6 EFA (CO). Only mice fed on FF or O diets showed clinical and biochemical signs of EFAD. Total incidence of tumors showed an increase in FF ( P < 0.02) and O ( P < 0.03) mice. Tumors developed mostly in the liver in each of the EFAD groups ( P < 0.001). Slight promoting activity on lung tumorigenesis was recorded in the CO group when this parameter was compared in EFAD and EFA sufficient mice. It may be concluded that, when a tumor initiator injures the body as a whole, EFAD, achieved either through a fat-free or an oleic-supplemented diet, behaves as a general promoting condition for tumorigenesis. The borderline tumorigenic effect of n-6 corn oil on the lungs suggests that this effect, when present, is target specific.

Induction of Insulinomas and Kidney Tumors in SD Male Rats by X-Irradiation of Gastric Region.

X-ray induction of tumors were examined in five-week-old male CD(SD) : Crj rats, treated with two 10 Gy doses to the gastric region with a 3-day interval (total 20 Gy). After irradiation, the rats received a 1% NaCI supplement in the diet and survivors were killed 22 months after the first X-irradiation. The total tumor incidence was 59% (48 of 82 effected rats), the first animal demonstrating a sarcoma at day 273. Islet tumors of the pancreas appeared from the 455 day time point. Pancreatic and kidney tumors developed in 15 rats (18%) each, and apocrine tumors at the irradiated site and sarcomas in 9 rats (11%) and 5 (6%), respectively. Gastric tumors were found in 3 rats (4%). Immunohistochemistry revealed the islet tumor cells to be generally positive for insulin, although some cells contained somatostatin or glucagon, but not gastrin. The present results thus showed that the insulinomas and tumors other than gastric lesions are induced by X-irradiation of the upper peritoneal region.

Non-promoting effects of iron from beef in the rat colon carcinogenesis model

Significant alarm has existed among the general public in the past few years that eating red meat may cause human colon cancer. Iron in beef has been hypothesized as one of the factors in the etiology of this cancer. The present study was designed to test the hypothesis that dietary iron solely from beef would enhance colon tumorigenesis induced in rats. Tumors were induced in Sprague-Dawley rats with 1,2-dimethylhydrazine (20 mg/kg body weight for 10 weeks). Seventy male weanling rats were randomized to two dietary treatment groups with two iron sources (very lean beef vs. iron citrate) as the factor. The rats were allowed free access to the respective diet and deionized water for 27 weeks. At termination of the study, the rats were examined for location, size and type of colon or extracolonic lesions. No significant differences were found in total incidence and number of colon tumors between the beef (51.7%, 0.8 tumors/rat) and casein (62.1%, 0.9 tumors/rat) diets, although the serum iron levels of rats fed the beef diet were higher than for those fed the casein diet. The results demonstrate that, when lean beef is used as an iron source, the risk for colon carcinogenesis is not increased.

Suppressive effects of S-methyl methanethiosulfonate on promotion stage of diethylnitrosamine-initiated and phenobarbital-promoted hepatocarcinogenesis model.

Modifying effects of S‐methyl methanethiosulfonate (MMTS) on diethylnitrosamine (DEN)‐initiated and phenobarbital (PB)‐promoted hepatocarcinogenesis were examined in rats. Five‐week‐old male F344 rats were divided into 8 groups. After a week, groups 1–5 were given DEN (100 mg/kg body weight, i.p.) once a week for 3 weeks, whereas groups 6–8 received vehicle treatment. Group 2 was given 100 ppm MMTS containing diet in the initiation phase. From 4 weeks after the start of experiment, groups 3 and 5 were fed MMTS, and groups 1–3 and 7 received drinking water containing 500 ppm PB. Group 6 was given MMTS diet alone throughout the experiment (24 weeks). The incidences of hepatocellular adenoma and total liver tumors were significantly smaller in group 3 than those of group 1. The average numbers of hepatocellular adenoma, carcinoma and total tumors in group 3 were significantly smaller than in group 1. Glutathione, S‐transferase placental form‐positive foci were also significantly decreased by MMTS treatment in the promotion phase. MMTS treatment in the initiation or promotion phase reduced ornithine decarboxylase activity in the liver of rats given DEN. The antioxidant activity against lipid peroxidation of MMTS was confirmed in tests with rabbit erythrocyte membrane ghosts or rat hepatocytes. These results suggest that MMTS is a promising chemopreventive agent for liver neoplasia when concurrently administered with PB.

Chronic Toxicity and Carcinogenicity Studies of 2-Methylnaphthalene in B6C3F1 Mice

The toxicity and carcinogenic potential of 2-methylnaphthalene (2-MN) were examined in B6C3F1 mice. Groups of 50 male and 50 female mice were given diets containing 0, 0.075, and 0.15% 2-MN for 81 weeks. Both 0.075 and 0.15% 2-MN caused pulmonary alveolar proteinosis at high incidence: 55.1 and 45.8% in females and 42.9 and 46.9% in males, respectively. The incidences of total lung tumors, including bronchiolar/alveolar adenomas and carcinomas, were 20.4 and 12.2% in male mice given 0.075 and 0.15% 2-MN, respectively, the former value being significantly increased compared with the 4.1% in control males. However, in the respective incidences of the adenomas and carcinomas, neither in-tergroup differences nor dose dependencies were observed. The incidences of other tumors did not differ between mice treated with 2-MN and the controls. The results indicated that 2-MN induces pulmonary alveolar proteinosis but does not possess unequivocal carcinogenic potential in B6C3F1 mice.

Strain Differences in Induction and Modification of Stomach Tumor Development in Mice Treated with X-irradiation.

The stomach region of male hypocatalasemic (Cbs), C3H, and BALB mice of both sexes was irradiated once with a dose of 20 Gy of X-ray. After irradiation the Cbs mice were administered with 0.1% hydrogen peroxide (H2O2) solution as their drinking water, or 10% sodium chloride (NaCl) in their diet. The resultant total tumor incidences were 50% to 100% by the end of the experiment after 13 months. More female mice died in the early phase after X-irradiation than males. Well differentiated tumors were observed in the glandular stomachs of 35 to 100% and signet ring cell carcinomas in 0 to 22% of the animals. Squamous cell carcinomas (SCCs) were most frequently encountered in BALB mice of both sexes. The present results indicate that X-ray induction of adenocarcinomas, signet ring cell carcinomas, and SCCs of the glandular stomach in CS mice is not promoted by H2O2 or NaCl.

Inhibitory effects of 6-phenylhexyl isothiocyanate on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone metabolic activation and lung tumorigenesis in rats.

This study examined the effects of 6-phenylhexyl isothiocyanate (PHITC) on lung tumorigenesis in F344 rats induced by the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Two biomarkers of NNK metabolism, 4-hydroxy-1-(3-pyridyl)-1-butanone (HPB)-releasing hemoglobin adducts and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and its glucuronide (NNAL-Gluc) in urine, were also quantified during the course of the tumor induction experiment. Rats were divided into groups as follows: (1) NNK, 2 p.p.m. in drinking water, 60 rats; (2) NNK, 2 p.p.m. in drinking water and PHITC, 1 micromol/g NIH-07 diet, 60 rats; (3) PHITC, 1 micromol/g NIH-07 diet, 20 rats; (4) control, 20 rats. PHITC was added to the diet for 1 week prior to and during 111 weeks of NNK treatment. There were no effects of PHITC on body weight, mortality, blood chemistry or hematology. Seventy percent of the rats treated with NNK had adenoma or adenocarcinoma of the lung. In the rats treated with NNK plus PHITC, the total percent incidence of lung tumors was 26% (P < 0.01 compared with NNK). PHITC had no effect on the total incidence of exocrine pancreatic tumors induced by NNK. The rats treated with PHITC and NNK had significantly lower levels of HPB-releasing hemoglobin adducts throughout the course of the bioassay than did those treated with NNK alone and significantly higher levels of NNAL plus NNAL-Gluc excreted in urine at two time points during the bioassay. These results demonstrate that near lifetime administration of PHITC to rats strongly inhibits the metabolic activation and lung tumorigenicity of NNK.

Study of post-natal effect of chemopreventive agents on ethylnitrosourea-induced transplacental carcinogenesis in rats. III. Inhibitory action of indomethacin, voltaren, theophylline and epsilon-aminocaproic acid.

The influence of the arachidonic acid metabolism inhibitors, indomethacin and voltaren; an inhibitor of phosphodiesterase activity, theophylline and the protease inhibitor epsilonaminocaproic acid (EACA) on N-ethyl-N-nitrosourea (ENU)-induced transplacental carcinogenesis was studied in rats. ENU was given to pregnant rats as a single i.v. exposure at a dose of 75 mg/kg body weight on the 21st day after conception. Indomethacin and voltaren (20 p.p.m. in drinking water), theophylline (0.01% in diet) and EACA (1000 p.p.m. in drinking water) were given to the offspring throughout their post-natal life until all survivors were killed at 12 months. In the ENU-only control groups, 100% of the offspring developed tumors of brain, spinal cord, peripheral nervous system or kidneys, with a total average number of 3.1 tumors per rat. The most marked inhibitory effect was exerted by theophylline, which significantly decreased the incidence and multiplicity of total tumors, and at all main sites selectively (brain, spinal cord, peripheral nerves and kidneys). It also prolonged average survival time of the offspring. Indomethacin and voltaren significantly decreased total tumor incidence and multiplicity and brain tumor incidence and multiplicity. Indomethacin also decreased kidney tumor multiplicity and voltaren diminished spinal cord tumor multiplicity. EACA decreased multiplicities of total, brain, peripheral nerve and kidney tumors, and diminished the incidence of brain tumors. These chemopreventive agents decreased tumor incidences 20-33% and tumor multiplicities 1.4-2.7 times, compared with the ENU-only controls.

Effects of selenium on gallbladder carcinogenesis induced by an intracholecystic 3-methylcholanthrene beeswax pellet in female Syrian golden hamsters.

This study represents the first report of the effects of selenium (Se) on chemically induced gallbladder carcinogenesis in hamsters. A total of 100 female Syrian golden hamsters was randomly assigned to four groups, which groups of 25 hamsters were given ad libitum drinking water containing either 0.0, 0.5, 2.0 or 4.0 ppm Se (as sodium selenite) for 24 weeks. Initiation was performed at week 4 by the insertion of a Beeswax pellet containing 3-methylcholanthrene (3-MC) into the gallbladder. The incidence of total malignant tumors at the end of the study (24 weeks) was 88, 75, 81 and 82% in the 0.0, 0.5, 2.0 and 4.0 ppm Se groups, respectively. All the cases of carcinoma but two were considered to develop through the sequence from dysplasia to carcinoma in situ (CIS) and from CIS to adenocarcinoma of invasive type. The incidence of CIS was significantly lower in hamsters treated without Se than in those treated with Se (P < 0.05). On the other hand, the incidence of invasive adenocarcinoma was significantly higher in the former than in the latter (P < 0.05). These results were summarized that Se might retard the progression of hamster gallbladder carcinogenesis induced by a 3-MC beeswax pellet.

Study of the post-natal effects of chemopreventive agents on ethylnitrosourea-induced transplacental carcinogenesis in rats. II. Influence of low-molecular-weight polypeptide factors from the thymus, pineal gland, bone marrow, anterior hypothalamus, brain cortex and brain white substance.

The influence of the polypeptide factors extracted from thymus, pineal gland, bone marrow, anterior hypothalamus, brain cortex or brain white substance on N-ethyl-N-nitrosourea (ENU)-induced transplacental carcinogenesis was studied in rats. ENU was given to pregnant rats as a single i.v. exposure at a dose of 75 mg/kg body weight on the 21st day of gestation. The polypeptide factors were given to the offspring as a series of s.c. injections, at a dose of 0.5 mg/rat/day, starting at one or 2.5 months of age and continuing throughout the whole of post-natal life. ENU induced tumors of the brain, spinal cord, peripheral nerves and kidneys in 94-98% of the offspring exposed to the carcinogen, with an average number of 2.3-2.6 tumors per rat, and an average survival time of 294 days. Post-natal thymus factor or pineal gland factor administration was followed by an increase in mean lifespan of approximately 2 months and a significant decrease (P < 0.05) in the total tumor number per tumor-bearing rat, as well as the incidence and multiplicity of spinal cord tumors. Pineal gland factor also decreased the incidence of peripheral nerve and kidney tumors and their number per tumor-bearing rat. Brain cortex factor and brain white substance factor treatment was followed by a decrease in total tumor multiplicity of 1.2- to 3.3-fold, and a decrease in incidence of brain tumors of 10 to 33% per rat in comparison to the controls. Brain cortex factor also decreased the total tumor incidence. At the same time, brain white substance factor administration increased the incidence of peripheral nerve tumors and decreased the mean lifespan. Both bone marrow factor and anterior hypothalamus factor did not have any modifying effects on any of the ENU-induced tumors and mean lifespan. Thus, our results show the possibility of attenuation of transplacental ENU-induced carcinogenesis with post-natal administration of some polypeptide substances.

Susceptibility of Fetal, Virgin, Pregnant and Lactating Rats for the Induction of Mammary Tumors by Gamma Rays

Pregnant Wistar-MS rats received a whole-body irradiation of 0-2.6 Gy gamma rays at day 20 of pregnancy. The mother rats were implanted with a diethylstilbestrol (DES) pellet 30 days after weaning, and the female pups delivered by the irradiated mother were treated with DES after maturation. Lactating rats were irradiated with gamma rays 21 days after parturition and then treated with DES. Virgin rats 70 days of age were also irradiated and then administered DES. The rats which received intrauterine irradiation did not develop mammary tumors at doses less than 2.1 Gy and showed a low incidence of tumors at 2.6 Gy. In virgin rats, the maximum tumor incidence was obtained with 1 Gy. The incidence of total mammary tumors in the mother rats and lactating rats increased in a dose-dependent manner with increasing doses of gamma rays up to 2.1 Gy. With 0.1-1 Gy, the incidence of adenocarcinoma in the mother rats was significantly lower than that observed in the lactating rats. However, the incidence in the mother rats irradiated with 1.0-1.5 Gy was significantly higher than that of virgin rats treated with the corresponding gamma-ray doses. These findings suggest that the susceptibility of the mammary glands to radiation depends upon the differentiation at the time of exposure.

Anticarcinogenic effect of beta carotene on the development of renal tumors in rats induced by 3-(αL-arabinopyranosyl-1) methyl-1-nitrosourea (AMNU)

The effect of beta carotene on AMNU-induced carcinogenesis was studied in rats. Administration of beta carotene reliably decreased both the total incidence of tumors and the incidence of renal tumors. The results are an experimental validation of the possibility of using beta carotene to lower the risk of second primary malignancies during the treatment of cancer patients with nitrosoalkylurea drugs.

Tumor induction and prophylaxis following different forms of intestinal urinary diversion in a rat model.

Eighty Wistar rats were randomized into two groups. In group 1 vesicosigmoidostomy with proximal colostomy was performed, in group 2, vesicosigmoidostomy. The total tumor incidence did not significantly (group 1 10/40, 25%; group 2 13/40, 32.5%). The tumor spectrum differed, with more adenocarcinomas in group 2 (11/40, 27.5% vs 4/40, 10%; P = 0.047) and urothelial carcinomas only in group 1 (5/40, 2.5%). One hundred and ten other Wistar rats were randomized into three groups. Animals in group A received vesicoileosigmoidostomy, group B, two-step vesicosigmoidostomy with initial separation of urine and the urocolonic anastomosis, group C, vesicosigmoidostomy. Significantly fewer adenocarcinomas were observed in group A (2/40, 5%) than in group B (16/40, 40%; P < 0.002) and group C (9/30, 30%; P < 0.007). These results indicate a similar cancer risk in all continent forms of urinary diversion, at least via colon. Ileal interposition seems to be an effective carcinoma prophylaxis following ureterosigmoidostomy. The proliferative instability at the urointestinal anastomosis is crucial for the pathogenesis and prophylaxis of this form of carcinogenesis, whereas urine seems to play only a minor role.

Carcinogenesis induced by neonatal exposure to various doses of 5-bromo-2'-deoxyuridine in rats.

Male and female outbred LIO rats were exposed to subcutaneous injections of 3.2 mg 5-bromo-2'-deoxyuridine (BrdUrd), on day 1; days 1 and 3; or days 1, 3, 7, and 21 following birth. The mean life-span decreased by 40.9, 31.2 and 38.9% in males exposed to 1, 2 or 4 injections of BrdUrd, respectively, and by 22.9, 10.5 and 23.4% in females, respectively, compared to the controls. The agent increased the population aging rate of the exposed male and female rats. Total tumor incidences in males exposed to 0, 3.2, 6.4 or 12.8 mg of BrdUrd were 21.1, 27.3, 40.0 and 33%, respectively, and in the females 44.3, 54.5, 48.1 and 56.3%, respectively. Only the largest dose of BrdUrd significantly increased the tumor incidence in the exposed rats as compared to the control ones (P < 0.05). However, tumor latency was shorter in any group of rats exposed to BrdUrd, as compared to the control one. The exposure to 0, 1, 2 or 4 injections of BrdUrd was followed by the development of testicular Leydigomas in 0, 0, 28 and 12% of males, respectively. There was no organ or tissue target for BrdUrd in the females. However, the development of tumours not typical for the rats and the widening of tumor spectrum was observed in the female rats exposed to the agent.

Reduced tumour incidence in mice with inherited seborrhoeic dermatitis.

121 mice homozygous for the gene seb (inherited seborrhoeic dermatitis) and their 142 unaffected heterozygous littermates were kept for their natural lifespan. Heterozygotes showed 84.1% total tumour incidence in males and 95.9% in females. The most common neoplasms were lymphomas, osteomas, lung tumours and neoplasms of the female genital tract. Homozygotes showed a tumour incidence of 36.1% in males and 45.0% in females. The reduction in incidence included all types of neoplasms except epithelial tumours of the skin: skin tumours were detected in 11 homozygous but only in one heterozygous animal. Life expectancy was not affected significantly by genotype. Homozygous mice showed rough and greasy fur and became alopecic with age. Energy intake was increased but growth and depository fat was reduced compared with heterozygous mice. Higher heat loss may incompletely be compensated by higher metabolic rate and thus 'dietary restriction' results in decreased tumour rates. As females show small gonads and a higher increase in food consumption hormonal factors may also be involved.

Head and neck tumors after energetic proton irradiation in rats

This is a two-year progress report on a life span dose-response study of brain tumor risk at moderate to high doses of energetic protons. It was initiated because a joint NASA/USAF life span study of rhesus monkeys that were irradiated with 55-MeV protons (average surface dose, 3.5 Gy) indicated that the incidence of brain tumors per unit surface absorbed dose was over 19 times that of the human tinea capitis patients whose heads were exposed to 100 kv x-rays. Examination of those rats that died in the two-year interval after irradiation of the head revealed a linear dose-response for total head and neck tumor incidence in the dose range of 0–8.5 Gy. The exposed rats had a greater incidence of pituitary chromophobe adenomas, epithelial and mesothelial cell tumors than the unexposed controls but the excessive occurrence of malignant gliomas that was observed in the monkeys was absent in the rats. The estimated dose required to double the number of all types of head and neck tumors was 5.2 Gy. The highest dose, 18 Gy, resulted in high mortality due to obstructive squamous metaplasia at less than 50 weeks, prompting a new study of the relative bological effectiveness of high energy protons in producing this lesion.

Pulmonary toxicity of indium arsenide and arsenic selenide following repeated intratracheal instillations to the lungs of hamsters

AbstractChronic toxicity of indium arsenide (InAs) and arsenic selenide (As2Se3) was studied in male Syrian golden hamsters which received InAs or As2Se3 particles, each containing a total dose of 7.5 mg of arsenic, by intratracheal instillations once a week for 15 weeks. As a control, hamsters were treated with the vehicle, phosphate buffer solution. During their total lifespan, the cumulative body weight gain of the hamsters in the InAs group was suppressed significantly compared with that in the control group, but not in the As2Se3 group when compared with that in the control group. However, the survival rate for the InAs group was significantly higher compared with the control group, but not for the As2Se3 group when compared with the control group. During the animals' total lifespan, one lung adenoma was seen in the 27 hamsters in the InAs group and one lung adenoma in the 23 hamsters in the control group. No tumors of the lung were observed in the As2Se3 group. Malignant tumors outside the lung appeared in four hamsters in the InAs group and in two in the As2Se3 group. No non‐lung malignant tumours were seen in the control group. Total tumor incidence rates were 25.9% (7/27) in the InAs group, 10.3% (3/29) in the As2Se3 group and 8.7% (2/23) in the control group. There were therefore no significant differences in tumor incidence between the InAs or the As2Se3 group, and the control group.Regarding histopathological findings in the lung, incidence rates of proteinosis‐like lesions, pneumonia, metaplastic ossification and emphysema were seen only in the InAs group, and alveolar or bronchiolar cell hyperplasia observed in both the InAs and the As2Se3 groups were at significantly higher rates than those in the control group.From these results, it was concluded that InAs and As2Se3 particles could induce pulmonary toxicity when instilled intratracheally into hamsters. A great deal of attention should be paid to the toxicity of both InAs and As2Se3, even though in this study the adverse health effects of As2Se3 appeared to be less than those of InAs.

Dietary carbohydrates modify azoxymethane-induced intestinal carcinogenesis in rats.

The effect of different dietary carbohydrates (sucrose, cornstarch and high amylose cornstarch) on intestinal carcinogenesis was studied in male Sprague-Dawley rats treated subcutaneously with azoxymethane (AOM) at a weekly dose of 8 mg/kg body wt for 8 wk. The diets, high in fat and low in calcium and fiber, were fed during and after AOM treatment. The number of colonic adenomas per rat in the groups fed either starch was lower (P < 0.05) than the number in the sucrose-fed rats [1.06 +/- 0.38, 0.30 +/- 0.10 and 0.41 +/- 0.22 (mean +/- SEM), in the sucrose-, cornstarch- and high amylose cornstarch-fed groups, respectively]. The incidence of total intestinal tumors (adenomas + adenocarcinomas) was not affected by dietary treatment. However, the incidence of tumors in the small intestine of the rats fed the two cornstarch diets tended to be slightly lower than for rats fed the sucrose diet (P = 0.075). Adenoma dysplasia and adenocarcinoma differentiation were similar among the rats fed the three diets. However, the adenocarcinomas in the rats fed the cornstarch diet were significantly smaller than those in the rats fed sucrose [0.99 +/- 0.14 cm2 (n = 13), 0.56 +/- 0.14 cm2 (n = 13) and 0.55 +/- 0.17 cm2 (n = 9) in rats fed the sucrose, cornstarch and high amylose starch diets, respectively]. Moreover, in the rats fed the cornstarch diet, the adenocarcinomas showed lower invasive potential than those in rats fed the sucrose diet. The results suggest an overall inhibition of AOM-induced carcinogenesis in rats fed the cornstarch diets.

High incidence of malignant lung carcinomas in rats after inhalation of 239PuO2 aerosol.

Female Wistar strain rats were exposed to a single inhalation of a submicron-size aerosol of high-fired 239PuO2 to investigate pulmonary carcinogenesis during lifespan periods. The absorbed lung doses of the exposed animals ranged from 0.6 to 12 Gy and were well correlated with the initial lung deposition (ILD) of 0.1 to 2.3 kBq. Survival and induction of primary lung tumors in 116 exposed rats were compared with those in 56 untreated control rats in respect to lung doses received. Mean survival time was greatly reduced, and the cumulative incidence of total lung tumors was markedly increased to 90-100% in rats that received more than 4 Gy, whereas of the controls only one animal (1.8%) died of primary lung tumors. Primary but benign adenomas were present in exposed animals given 1.0 Gy or less, and the incidence of adenomas was 22-25% at 4-5 Gy, but decreased sharply to 3-5% at 6-8 Gy. In contrast, no malignant carcinomas, including adenocarcinomas, adenosquamous carcinomas and squamous cell carcinomas, developed at a dose of less than 1.0 Gy, whereas they were present in 75% or more of the rats given 4-10 Gy, but only in 55% at 12 Gy. Although there were no clear differences in the dose and time required for induction among the carcinoma types, all tended to develop in earlier periods after inhalation than adenomas. Despite the limited number of exposed animals that received lower doses, results suggest that malignant lung carcinomas are highly and early induced and have a different dose-effect relationship than benign adenomas at doses of more than 1 Gy after inhalation exposure to 239PuO2.

Life span reduction and carcinogenesis in the progeny of rats exposed neonatally to 5-bromo-2′-deoxyuridine

Outbred LIO rats were given subcutaneous injections (3.2 mg) of a synthetic analogue of thymidine, 5-bromo-2'-deoxyuridine (BrdUrd) on days 1, 3, 7 and 21 postnatally. At 3 months, the treated males and females were mated to generate F1 progeny. The mean life span decreased by 31.6% and 9.1% in male rats and by 21.1% and 7.2% in female rats exposed to BrdUrd and in their offspring, respectively. Exposure to BrdUrd increased the aging rate of the rats and of their progeny. Age-related changes in the length of the estrus cycle and in the incidence of persistent estrus and/or anestrus were observed earlier in female rats exposed neonatally to BrdUrd and in their offspring compared to controls; also, developmental stigmas were observed in the offspring of rats exposed neonatally. The incidence of total and malignant tumors was increased in rats that had received BrdUrd as well as their progeny. Our observations on the decrease in mean and maximum life span, the increase in aging rate, the acceleration of age-related changes in female reproductive system function, and the increase in tumor incidence and decrease in tumor latency in rats exposed to BrdUrd in early life suggest that this system could serve as a model of accelerated aging. These effects persist at least to the next generation.