Effects of phenobarbital and carbazole on carcinogenesis of the lung, thyroid, kidney, and bladder of rats pretreated with N-bis(2-hydroxypropyl)nitrosamine

Studies were made on potential modifying effects of phenobarbital (PB) and carbazole on tumor development induced by N-bis(2-hydroxypropyl)nitrosamine (DHPN), a wide-spectrum carcinogen in rats. Effects on the lung, thyroid, kidney, bladder and liver were investigated. Male F344 rats were given 0.2% DHPN in their drinking water for 1 week and then 0.05% PB or 0.6% carbazole in their diet for 50 weeks. Control animals were treated with either DHPN or PB or carbazole only. Neither PB nor carbazole affected the incidence or histology of lung tumors. However, PB promoted the development of thyroid tumors and preneoplastic lesions of the liver, while carbazole promoted the induction of renal pelvic tumors.     

Promoting effects of phenobarbital and barbital on development of thyroid tumors in rats treated with N-bis(2-hydroxypropyl)nitrosamine

Phenobarbital (PB) and barbital (BB) promoted the developmentof thyroid tumors in rats treated with a sub-effective doseof N-bis(2-hydroxypropyl)nitrosamine (DHPN) for thyroid tumorigenesis.Rats were given s.c. injections of 70 mg DHPN/100 g body weightonce a week for 4 or 6 weeks with or without diet containing500 p.p.m. PB or BB for the next 12 weeks. The incidences ofthyroid tumors at the end of week 20 of the experiment were66% in rats given DHPN for 4 weeks and then PB, 23% in ratsgiven DHPN for 4 weeks and then BB, 100% in rats given DHPNfor 6 weeks and then PB, 45% in rats given DHPN for 6 weeksand then BB, and 23% in rats given DHPN for 6 weeks. Rats givenonly DHPN for 4 weeks or only PB or BB had no thyroid tumorsafter 20 weeks.     

The Promoting Effects of Food Dyes, Erythrosine (Red 3) and Rose Bengal B (Red 105), on Thyroid Tumors in Partially Thyroidectomized N-Bis(2-hydroxypropyl)- nitrosamine-treated Rats

The effects of erythrosine (Red 3), rose bengal B (Red 105) and thyroidectomy on the development of thyroid tumor were examined in male Wistar rats treated with N-bis(2-hydroxypropyl)nitrosamine (DHPN). Red 3 and Red 105 were used at 4% in the basal diet and were administered for 19 weeks from week 2 to 20. Thyroidectomy was performed by resection of the left lobe at week 4. Single injection of DHPN was performed intraperitoneally at 280 mg per 100 g body weight at the beginning of the experiment. Red 3 and Red 105 significantly promoted the development of thyroid tumors in thyroidectomized rats given DHPN, but had no significant effect in non-thyroidectomized rats. The incidence of thyroid tumors was 91% in rats with partial thyroidectomy, Red 3 and DHPN, 100% in rats with partial thyroidectomy, Red 105 and DHPN, and 64% in rats with partial thyroidectomy and DHPN. Serum TSH was 5.5±3.1 ng/ml in rats with partial thyroidectomy, Red 3 and DHPN, 2.1 ± 2.2 ng/ml in rats with partial thyroidectomy, Red 105 and DHPN, and 1.5±0.5 ng/ml in rats with partial thyroidectomy and DHPN.     

The promoting effects of food dyes, erythrosine (Red 3) and rose bengal B (Red 105), on thyroid tumors in partially thyroidectomized N-bis(2-hydroxypropyl)-nitrosamine-treated rats

The effects of erythrosine (Red 3), rose bengal B (Red 105) and thyroidectomy on the development of thyroid tumor were examined in male Wistar rats treated with N-bis(2-hydroxypropyl)nitrosamine (DHPN). Red 3 and Red 105 were used at 4% in the basal diet and were administered for 19 weeks from week 2 to 20. Thyroidectomy was performed by resection of the left lobe at week 4. Single injection of DHPN was performed intraperitoneally at 280 mg per 100 g body weight at the beginning of the experiment. Red 3 and Red 105 significantly promoted the development of thyroid tumors in thyroidectomized rats given DHPN, but had no significant effect in non-thyroidectomized rats. The incidence of thyroid tumors was 91% in rats with partial thyroidectomy, Red 3 and DHPN, 100% in rats with partial thyroidectomy, Red 105 and DHPN, and 64% in rats with partial thyroidectomy and DHPN. Serum TSH was 5.5 +/- 3.1 ng/ml in rats with partial thyroidectomy, Red 3 and DHPN, 2.1 +/- 2.2 ng/ml in rats with partial thyroidectomy, Red 105 and DHPN, and 1.5 +/- 0.5 ng/ml in rats with partial thyroidectomy and DHPN.     

Effect of varying the duration of exposure to phenobarbital on its enhancement of N-bis(2-hydroxypropyl)nitrosamine-induced thyroid tumorigenesis in male Wistar rats

Male Wistar rats were injected s.c. with a single dose of 280mg N-bis(2-hydroxypropyl)nitrosamine (DHPN) per 100 g body weightand the effect of subsequent exposure to 500 p.p.m. phenobarbitone(PB) for 6, 12 and 19 weeks on development of thyroid tumorswas studied. Exposure to PB for 12 or 19 weeks enhanced thedevelopment of thyroid tumors in the rats. The incidences ofthyroid tumors in DHPN-treated rats at the end of the experimentfor 20 weeks were 87%, 83%, 42% and 37%, respectively, in ratsgiven PB for 19 weeks, 12 weeks, and 6 weeks, and in those givenno PB. The incidence of thyroid cancers was 12% in rats givenDHPN and then PB for 19 weeks. The total numbers of thyroidtumors were 241, 125, 65 and 23, respectively, in DHPN-treatedrats given PB for 19 weeks, 12 weeks, and 6 weeks, and in thosegiven no PB. Thus, the total numbers of thyroid tumors werecorrelated with the period of PB treatment.     

Potassium perchlorate, potassium iodide, and propylthiouracil: promoting effect on the development of thyroid tumors in rats treated with N-bis(2-hydroxypropyl)-nitrosamine

The effect of 1000 ppm potassium perchlorate (KClO4), 1000 ppm potassium iodide (KI) or 1000 ppm propylthiouracil (PTU) in the diet on the development of thyroid tumors was studied histologically and biochemically in Wistar rats given a single ip injection of 280 mg of N-bis(2-hydroxypropyl)nitrosamine (DHPN) per 100 g body weight. Basal diet containing 100 ppm KClO4, 1000 ppm KI or 1000 ppm PTU was given for 19 weeks from week 2 to week 20. The incidence of thyroid adenomas at the end of week 20 of the experiment was 100% (20/20) in rats treated with DHPN followed by KClO4, 85% (17/20) in rats given DHPN followed by KI, 95% (19/20) in rats given DHPN followed by PTU, and 5% (1/20) in rats given DHPN alone. The incidence of thyroid cancers was 100% (20/20) in rats treated with DHPN followed by KClO4, 65% (13/20) in rats treated with DHPN followed by KI and 0% (0/20) in rats treated with DHPN followed by or not followed by PTU. Rats given KClO4, KI or PTU alone and untreated rats had no thyroid tumors. The mean values of TSH in serum were 2.94 +/- 0.79 ng/ml in rats treated with DHPN followed by KClO4, 9.40 +/- 16.0 ng/ml in rats treated with DHPN followed by KI and 60.94 +/- 20.60 ng/ml in rats treated with DHPN followed by PTU. It was confirmed that (1) KClO4, PTU and KI promote the development of thyroid tumor in rats treated with DHPN, (2) the promoting effect of KClO4 or KI is stronger than that of PTU and (3) the value of TSH in serum is not parallel to the promoting effect on the development of thyroid tumor.     

The influence of subsequent dehydroepiandrosterone,diaminopropane, phenobarbital,butylated hydroxyanisole and butylated hydroxytoluene treatment on the development of preneoplastic and neoplastic lesions in the rat initiated with di-hydroxy-di-N-propyl nitrosamine

The comparative modifying potential of dehydroepiandrosterone (DHEA), diaminopropane (DAP), phenobarbital (PB), butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT) on the development of lesions initiated by dihydroxy-di-n-propyl nitrosamine (DHPN) in F344 rats were investigated. DHEA, BHA and BHT were all associated with significant reduction in numbers of glutathione-S-transferase P form (GST-P) positive foci in the liver whereas PB brought about their enhanced development. BHT and PB exerted promoting activity on the incidence of thyroid adenomas while DAP similarly increased lung adenoma formation. The results illustrate the advantages to be gained from two stage experiments using broad spectrum carcinogen initiation for comparative analysis of ‘modifiers’ of the neoplastic process and suggest that studies of enzyme alteration within putative preneoplastic lesions may be directly relevant to elucidation of mechanisms underlying such modification.     

Modification by sodium L-ascorbate, butylated hydroxytoluene, phenobarbital and pepleomycin of lesion development in a wide-spectrum initiation rat model

Rats were treated for 1 week each with 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN), 0.2% N-bis(2-hydroxypropyl)-nitrosamine (DHPN) and 0.2% N-ethyl-N-hydroxyethylnitrosamine (EHEN) in the drinking water, and then administered diet containing 5% sodium L-ascorbate (Na-AsA), 1% butylated hydroxytoluene (BHT) or 0.05% phenobarbital (PB), or weekly intraperitoneal injections of 2 mg of pepleomycin per kg body weight until week 36. Histopathological examination revealed that all exerted significant modulation effects on tumor development in the various target organs. Na-AsA was found to inhibit liver but promote renal pelvis and bladder carcinogenesis. BHT similarly decreased liver and enhanced bladder lesion development. PB, in contrast promoted hepatocarcinogenesis. However both PB and BHT were associated with increased incidences of adenomas and adenocarcinomas of the thyroid. Thus the wide-spectrum initiation model allowed confirmation of site-specific modification potential and in addition demonstrated potentiation of kidney and bladder carcinogenesis promotion by pepleomycin.     

Dose- and Sex-related Carcinogenesis by N-Bis(2-hydroxypropyl)nitrosamine in Wistar Rats

An initiation-promotion medium-term bioassay for detection of chemical carcinogens, developed in the male F344 rat, uses 0.1% N-bis(2-hydroxypropyl)nitrosamine (DHPN) among five genotoxic chemicals for the initiation of carcinogenesis in multiple organs. To establish this bioassay in the Wistar strain, the effects of two dose levels of DHPN were evaluated on the main DHPN rat target organs: lung, thyroid gland, kidneys and liver. Four groups of male and female animals were studied: Control—untreated group; Multi-organ initiated group (also referred to as DMBDD, based on the initials of the five initiators)—treated sequentially with N-diethylnitrosamine (DEN, i.p.), N-methyl-N-nitrosourea (MNU, i.p.), N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN, drinking water), N, ďN'-dimethylhydrazine (DMH, s.c.) and DHPN (drinking water) for 4 weeks; a third group treated with 0.1% DHPN in drinking water for 2 weeks and the last group treated with 0.2% DHPN in drinking water for 4 weeks. The animals were sacrificed after 30 weeks. DHPN at 0.2% induced preneoplasia in the liver and kidneys of rats of both sexes, the number and area of the putative preneoplastic liver glutathione S-transferase-positive hepatocyte foci being significantly increased in these animals. It also induced benign and malignant tumors in female and in male rats. However, there was no relationship between the increased incidence of preneoplastic lesions and tumor development in the 0.2% DHPN-exposed groups of both sexes. DHPN at 0.1% induced only a few preneoplastic lesions in the liver and kidney and no tumors in both male and female rats. A clear dose and sex-related carcinogenic activity of DHPN was registered, although Wistar rats of both sexes showed a relative resistance to the carcinogenic activity of this compound.     

Dose- and sex-related carcinogenesis by N-bis(2-hydroxypropyl)nitrosamine in Wistar rats.

An initiation-promotion medium-term bioassay for detection of chemical carcinogens, developed in the male F344 rat, uses 0.1% N-bis(2-hydroxypropyl)nitrosamine (DHPN) among five genotoxic chemicals for the initiation of carcinogenesis in multiple organs. To establish this bioassay in the Wistar strain, the effects of two dose levels of DHPN were evaluated on the main DHPN rat target organs: lung, thyroid gland, kidneys and liver. Four groups of male and female animals were studied: Control -- untreated group; Multi-organ initiated group (also referred to as DMBDD, based on the initials of the five initiators) -- treated sequentially with N-diethylnitrosamine (DEN, i.p.), N-methyl-N-nitrosourea (MNU, i.p.), N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN, drinking water), N, N'-dimethylhydrazine (DMH, s.c.) and DHPN (drinking water) for 4 weeks; a third group treated with 0.1% DHPN in drinking water for 2 weeks and the last group treated with 0.2% DHPN in drinking water for 4 weeks. The animals were sacrificed after 30 weeks. DHPN at 0. 2% induced preneoplasia in the liver and kidneys of rats of both sexes, the number and area of the putative preneoplastic liver glutathione S-transferase-positive hepatocyte foci being significantly increased in these animals. It also induced benign and malignant tumors in female and in male rats. However, there was no relationship between the increased incidence of preneoplastic lesions and tumor development in the 0.2% DHPN-exposed groups of both sexes. DHPN at 0.1% induced only a few preneoplastic lesions in the liver and kidney and no tumors in both male and female rats. A clear dose and sex-related carcinogenic activity of DHPN was registered, although Wistar rats of both sexes showed a relative resistance to the carcinogenic activity of this compound.     

Organ-specific promoting effect of phenobarbital and saccharin in induction of thyroid, liver, and urinary bladder tumors in rats after initiation with N-nitrosomethylurea

Tumor-promoting effects of phenobarbital (PB) and sodium saccharin (SS) were tested in rats pretreated with N-nitrosomethylurea (NMU) with special reference to the site of their action. Male F344 rats were initially given injections of NMU (20 mg/kg i.p.) twice a week for 4 weeks, then given basal diet containing 0.05% PB or 5% SS for the next 32 weeks, and then killed. Appropriate control studies were also done. Histological examination of whole organs of the rats showed that PB promoted thyroid carcinogenesis whereas SS did not. A significant increase in the incidences of total tumors as well as papillary adenocarcinoma of the thyroid was observed in the group given PB after NMU (p less than 0.001). The incidence of papillary adenoma with or without papillary adenocarcinomas was also high in the NMU-PB-treated group. The organ-specific promoting effect of PB in the induction of preneoplastic lesions, as demonstrated by development of gamma-glutamyl transpeptidase-positive foci in the liver and of SS in papillary or nodular hyperplasia in the urinary bladder, as reported previously, was also confirmed. The incidences of papillomas in the forestomach were similar in groups treated with NMU-PB, NMU-SS, or NMU alone. The results indicate that PB is a tumor promoter in the liver and thyroid and that SS is a tumor promoter in the urinary bladder of rats.     

Enhancement of N-bis(2-hydroxypropyl)nitrosamine-initiated lung tumor development in rats by bleomycin and N-methyl-N-nitrosourethane

Potential modification of N-bis(2-hydroxypropyl)nitrosamine (DHPN)-induced lung carcinogenesis by bleomycin and N-methyl-N-nitrosourethane (MNUT) was investigated in male F344 rats. Rats were given 0.2% DHPN for 1 week followed by a weekly i.p. injection of either bleomycin at 2.0 mg/kg body wt or of MNUT at a dose of 1.0 mg/kg body wt for 35 weeks. Animals given DHPN followed by solvent administration alone, either saline or 0.02% ethanol and animals given bleomycin or MNUT without DHPN pretreatment were served as controls. Bleomycin treatment increased the incidence of cancer, whereas hyperplasia, adenoma and cancer of the lung were all significantly elevated after MNUT administration. MNUT alone induced low incidences of lung tumors. Bleomycin also increased the incidence of papillary or nodular hyperplasia of the urinary bladder while it inhibited the development of thyroid tumors. MNUT, however, did not affect tumor development in other organs.     

Effects of castration before and after treatment with N-bis (2-hydroxypropyl)-nitrosamine (DHPN) on the development of thyroid tumors in rats treated with DHPN followed by phenobarbital

The effect of castration on the development of thyroid tumors was studied histologically and biochemically in Wistar rats given a single ip injection of 210 mg of N-bis (2-hydroxypropyl)-nitrosamine (DHPN) followed by phenobarbital (Pb). Castration was performed one week after, or one week before the injection of DHPN. The injection of DHPN was given at the end of the first week, and the rats were fed 500 ppm Pb in the basal diet for 38 weeks from week 3 to week 40. The incidence of thyroid adenomas and cancers was 20% (4/20) and 10% (2/20) in rats treated with DHPN alone. It was 75% (15/20) and 40% (8/20) in rats treated with DHPN and Pb; 30% (6/20) and 15% (3/20) in rats treated with DHPN and Pb, and castrated after DHPN; 20% (4/20) and 0% in rats treated with DHPN and Pb, and castrated before DHPN and Pb; and 0% and 0% in rats castrated either before or after receiving DHPN. Castration thus inhibited the development of thyroid tumor in rats treated with DHPN. The inhibition of tumor development in rats treated with DHPN and Pb, and castrated before receiving DHPN, was greater than in the rats castrated after receiving DHPN. Castration inhibited the secretion of TSH in rats treated with DHPN and Pb.     

Relationships between serum thyroid stimulating hormone levels and development of thyroid tumors in rats treated with N-bis-(2-hydroxypropyl)nitrosamine

Relationships between serum thyroid stimulating hormone (TSH) levels, carcinogen dose and development of thyroid tumors were studied in Wistar rats of both sexes treated with N-bis-(2-hydroxypropyl)nitrosamine (DHPN). DHPN (210 mg/100 g body wt) was injected i.p. weekly. Wistar rats were used, divided into five groups of males (M1-M5) and five groups of females (F1-F5). M1 and F1 received one injection of DHPN, M2 and F2 two injections of DHPN, M3 and F3 three injections of DHPN, M4 and F4 four injections, and M5 and F5 as control rats received saline vehicle. The resultant incidences of total thyroid tumors were 4% in group M1, 24% in M2, 80% in M3, 76% in M4, 0% in F1, 4% in F2, 20% in F3, 17% in F4 and 0% in M5 and F5. Thus dose dependence for DHPN carcinogenesis was found in both sexes for up to at least three injections of DHPN and in all cases males proved more susceptible than females. Similar results were gained for carcinomas treated separately. A sex difference in DHPN induction of thyroid tumor was thus shown for Wistar rats opposite to that reported to exist in humans. However, no clear relationship between dose of DHPN or incidence of thyroid tumors and serum TSH concentration was evident at the end of the experiment (week 30).     

Promoting effects of 3-amino-1,2,4-triazole on the development of thyroid tumors in rats treated with N-bis(2-hydroxypropyl)nitrosamine

3-Amino-1,2,4-triazole (AT) promoted the development of thyroidtumors in rats treated with a subeffective dose of N-bis(2-hydroxypropyl)nitrosamine(DHPN) for thyroid tumorigenesis. The incidences of thyroidtumors at the end of the 20-week experiment were 91% in ratsinjected s.c. once a week for four weeks with 70 mg DHPN per100 g body weight and then given diet containing 2000 p.p.m.AT for 12 weeks, 100% in rats injected s.c. once a week foreight weeks with 70 mg DHPN per 100 g body weight and then givendiet containing 2000 p.p.m. AT for 12 weeks, and 58% in ratsinjected s.c. once a week for 8 weeks with 70 mg DHPN per 100g body weight. Rats only injected s.c. once a week for fourweeks with DHPN or only given diet containing AT for 12 weekshad no thyroid tumors at the end of the experiment.     

Organ specific modifying potential of ethinyl estradiol on carcinogenesis initiated with different carcinogens

Estrogen has been shown to exert a modifying potential on carcinogenesisin various organs, and in particular the hormone-dependent tissues.The present experiments were carried out to detennine the effectsof post-initiation phase administration of etbinyl estradiol(EE) on tumor development in the liver, kidney, lung, thyroid,bladder and esophagus of male E344 rats. Animals were initiatedby 2 weeks treatment with 0.05% N-bis(2-hydroxypropyl)nitrosamine(DHPN), 0.1% N-ethyl-N-hydroxyethylnitrosamine (EHEN), 0.03%N-nitrosopiperidine (NPD), 0.02% 2-acetyl-aminofluorene (2-AAF)or 0.05% N-butyl-N-(4-hydroxy-butyl)nitrosamine (BBN) in theirdiet or drinking water, and starting 1 week after initiation,they were given diet with or without a 0.001% EE supplementfor 49 weeks, at which point the experiment was terminated.EE significantly increased the development of tumors of theliver (DHPN-, EHEN-, 2-AAF-and NPD-treated groups) and kidneys(EHEN-treated group) but inhibited their development in thelungs (DHPN treated group) and urinary bladder (BBN-treatedgroup). In the liver, EE also increased the development of glutathioneS-transferase P type-positive lesions to various extents dependingon the initiator used. EE administration was associated witha decreased incidence of esophageal hyperplasia in the EHEN-initlatedgroup but an opposite increase in the NPD initiated animals.No effect of EE was evident regarding thyroid lesions.     

Modification by Analgesics of Lesion Development in the Urinary Tract and Various Other Organs of Rats Pretreated with Dihydroxy-di-N-propylnitrosamine and Uracil

Effects of the analgesics phenacetin, acetaminophen and antipyrine on lesion development in the urinary tract and other organs in male F344 rats were investigated. Animals were concurrently administered with 0.1% dihydroxy-di-N-propylnitrosamine (DHPN) in drinking water and 3.0% uracil in the diet for 4 weeks and then, starting 1 week after the cessation of this treatment, received basal diet or diet containing phenacetin, acetaminophen or antipyrine for 35 weeks. The occurrences of renal cell tumors were increased in the groups given phenacetin or antipyrine, as compared with the DHPN+uracil alone controls. Antipyrine, but not the two other compounds, also enhanced development of hyperplastic lesions in the renal pelvis and ureter. In the urinary bladder, phenacetin and antipyrine treatments were both associated with increased incidence of preneoplastic or neoplastic lesions. Furthermore, phenacetin alone, without the initiating agent pretreatments, induced simple hyperplasias of the urinary bladder at high incidence. Antipyrine enhanced induction of hyperplastic lesions in the ureter and was also found to increase the incidences of preneoplastic and neoplastic lesions in the liver. Although decreased incidences of tumor development of lung and thyroid were observed for the group given phenacetin, this might have been linked to the decreased weight gain. The results confirmed that combination treatment with DHPN+uracil is effective for wide-spectrum initiation of carcinogenesis in the urological tract and demonstrated significant modification potential for both phenacetin and antipyrine.     

Tumor promoting activities of ethylphenylacetylurea and diethylacetylurea, the ring hydrolysis products of barbiturate tumor promoters phenobarbital and barbital, in rat liver and kidney initiated by N-nitrosodiethylamine

The ring hydrolysis products of the multi-tissue tumor promotingbarbiturates, phenobarbital (PB) and barbital (BB), were fedto F344/NCr male rats previously given a single initiating injectionof N-nitrosodiethylamine. Ethyiphenyl-acetylurea (EPAU) anddiethylacetylurea (EEAU), derived, respectively, from PB andBB, both promoted development of hepatocellular adenomas, butwere much weaker in this respect than PB. Both acetylureas werealso selective inducers of P-450IIB1-mediated benzyloxyresorufinO-dealkylase activity, but both were much less potent inducersthan PB. Neither EPAU nor EEAU had an effect on tumor developmentin the thyroid, unlike both PB and, as shown previously, BB.EEAU, but not EPAU, strongly promoted development of renal corticalepithelial tumors. The opening of the bar biturate heterocyclicring and the subsequent decarboxylation to yield the dialkylacetylureaanalogs thus resulted in compounds displaying a marked reductionin liver tumor promoting activity. EEAU appears to possess anability to promote renal neoplasms similar to that of its parentcom pound, BB. Ring opening appears to be accompanied by lossof promoting activity for thyroid follicular epithelium.     

Effect of propylthiouracil on the thyroid tumorigenesis induced by N-bis(2-hydroxypropyl)nitrosamine in rats

The effect of 0.15% propylthiouracil (PTU) on thyroid tumorigenesiswas studied in male Wistar rats given a single i.p. injectionof 280 mg of N-bis(-2-hydroxypropyl)nitros-amine (DHNP) per100 g body weight. The mean weights of the thyroid of rats treatedwith DHPN followed by PTU and with PTU alone were significantlyhigher than those of rats treated with DHPN only and controlrats. The incidences of follicular adenoma at the end of week20 of the experiment were 100% (21/21) hi rats treated withDHPN followed by PTU, and 19% (4/21) hi rats given DHPN alone.Papillary adenoma was observed in one rat treated with DHPNfollowed by PTU. The incidence of follicular carcinomas withinvasive growth into the capsule, adipose tissues or blood vesselswas 52% (11/21) in rats given DHPN and then PTU. No papillarycarcinomas or solid tumors were found in any rats. Rats givenPTU alone and untreated rats had no thyroid tumors. The serumconcentration of T₄ in rats treated with PTU alone was significantlylower than that hi the control group. The serum concentrationof T₄ in rats treated with DHPN followed by PTU was slightly,but not significantly, lower than that in control rats. Theserum concentrations of T₃ in rats treated with DHPN foDowedby PTU, DHPN alone and PTU alone were also slightly, but notsignificantly, lower than that in controls.     

Greater inhibitory effects for testosterone than castration in rat thyroid tumorigenesis initiated by N-bis(2-hydroxypropyl)nitrosamine

The effects of testosterone and castration on thyroid tumorigenesis subsequent to initiation by N-bis(2-hydroxypropyl)nitrosamine (DHPN) were investigated in male Wistar rats. Following 2 weekly i.p. injections of DHPN at the dose of 210 mg/100 g body weight, testosterone was administered in the diet at concentrations of 0.15% or 0.03% for 28 weeks. Castration was performed on a separate group of animals 1 week after the final injection of DHPN. The incidence of thyroid adenomas and carcinomas were 69% (9/13) and 15% (2/13), respectively, in rats treated with DHPN alone, 0% (0/15) and 6% (1/15) in rats treated with DHPN and 0.15% testosterone, 13% (2/15) and 13% (2/15) in rats treated with DHPN and 0.03% testosterone and 33% (5/15) and 33% (5/15) in the castrated animals initiated by DHPN. The reduction in adenoma development associated with testosterone treatment was significant at both concentrations. In contrast, only a tendency for decrease of thyroid tumor incidence was observed in rats castrated.