Biomedical subjects

S Tamano

Publications and source records attributed to S Tamano.

At least 19 recordsLinked to original sources

PubMed1998

Carcinogenicity of antioxidants BHA, caffeic acid, sesamol, 4-methoxyphenol and catechol at low doses, either alone or in combination, and modulation of their effects in a rat medium-term multi-organ carcinogenesis model.

The carcinogenicity of low dietary levels of the antioxidants butylated hydroxyanisole (BHA), caffeic acid, sesamol, 4-methoxyphenol (4-MP) and catechol, known to target the forestomach or glandular stomach, were examined alone or in combination in a 2-year long-term experiment and their modifying effects assessed in a medium-term multiorgan model. In the carcinogenicity study, groups of 30-31 male F344 rats were treated with 0.4% BHA, 0.4% caffeic acid, 0.4% sesamol, 0.4% 4-MP and 0.16% catechol either alone or in combination for up to 104 weeks and then killed. In the medium-term multi-organ model, groups of 10 to 15 male F344 rats were given diethylnitrosamine (DEN), N-methylnitrosourea (MNU), 1,2-dimethylhydrazine (DMH), N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) and 2,2'-dihydroxy-di-n-propylnitrosamine (DHPN) for a total multiple initiation period of 4 weeks (DMBDD treatment). BHA, caffeic acid, sesamol and 4-MP, each at doses of 0.4% or 0.08%, and catechol at doses of 0.16% or 0.032% were administered in the diet either alone or in combination after completion of the initiation regimen. All surviving animals were killed at the end of week 28, and major organs were examined histopathologically. In the carcinogenicity study, slightly increased incidences of forestomach papillomas were found in the sesamol- (15.8%), caffeic acid- (14.8%), catechol- (3%) and 4-MP- (11.5%) treated groups as compared with basal diet (0%), and a significant increase was observed with the five antioxidants in combination (42.9%, P < 0.001). In a medium-term multiorgan carcinogenesis model, incidences of forestomach papillomas and/or carcinomas were increased in each high dose group, but additive or synergistic effects were not found in the combination group. In the low dose case, the incidence of forestomach papillomas was significantly increased only in the combination group. With regard to other organs, the incidence of colon tumors was significantly decreased only in the high dose combination group. The results indicate that even at low dose levels phenolic compounds can exert additive/synergistic effect on carcinogenesis.

Animals↗

PubMed1997

Carcinogenicity of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in the rat.

A total of 10 highly-mutagenic heterocyclic amines have been identified to be carcinogenic in rodents. Among these, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), generally the most abundant with normal cooking procedures, induces mammary and colon carcinomas in rats in a clear dose-dependent manner. In a two-generation exposure (transplacental and trans-breast milk) experiment using Sprague-Dawley rats, an increased risk of mammary adenocarcinoma development was found in the second generation. Excretion of PhIP into the milk and transfer of PhIP to fetuses and neonates with resultant hepatic PhIP-DNA adduct formation were also confirmed. On the other hand, PhIP mammary carcinogenesis was significantly inhibited by coadministration of chlorophyllin or a synthetic antioxidant, 1-O-hexyl-2,3,5-trimethylhydroquinone, in long-term experiments using female F344 rats. The available findings strongly suggest that this food-derived carcinogen might be of importance as an environmental factor in the production of human cancers and that its carcinogenicity could be largely avoided by reducing intake of such compounds or by adoption of appropriate chemopreventive measures.

Adenocarcinoma↗

PubMed1997

The prostate: a target for carcinogenicity of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) derived from cooked foods.

Prostate tissues obtained from rats given a food-derived carcinogen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), at a dose of 400 ppm in the diet for 52 weeks were histopathologically evaluated and found to contain prostate carcinomas limited to the ventral lobe in 18 of 27 cases. Atypical hyperplasias were also detected in the ventral and anterior prostate as well as the seminal vesicles. 32P-Postlabeling analysis of DNA demonstrated that PhIP-DNA adducts are produced in all lobes of the prostate of rats receiving PhIP. The findings indicate that PhIP is carcinogenic to rat prostate in addition to the previously demonstrated targeting of the colon and mammary glands, providing evidence of a possible role of PhIP in human prostate carcinogenesis and highlighting the potential importance of PhIP for man.

Animals↗

PubMed1997

Decrease of prostaglandin E2 and 5-bromo-2'-deoxyuridine labeling but not prostate tumor development by indomethacin treatment of rats given 3,2'-dimethyl-4-aminobiphenyl and testosterone propionate.

The modifying effects of indomethacin (IM) on rat prostate carcinogenesis induced by 3,2'-dimethyl-4-aminobiphenyl (DMAB) were investigated. F344 rats were given 50 mg/kg body weight of DMAB at 2-week intervals for 20 weeks and then received IM at a dose of 20 ppm in the drinking water for 37 weeks. Separate groups additionally received testosterone propionate (TP) in Silastic tubes throughout the experiment. DMAB alone induced carcinomas in situ in the ventral lobe and in combination with TP caused invasive carcinomas of the dorso-lateral and anterior lobes and seminal vesicles. No clear suppression by IM of development of in situ carcinomas or invasive carcinomas was observed. In a short-term satellite experiment, it was revealed that prostaglandin E2 (PGE2) levels in the dorso-lateral prostate and seminal vesicles, but not the ventral prostate, were significantly reduced by IM and that TP itself also suppressed PGE2 levels. The 5-bromo-2'-deoxyuridine labeling index in the ventral prostate was significantly decreased by IM administration. These results indicate that while IM can efficiently suppress tissue PGE2 levels, it does not inhibit tumor development in the prostate or seminal vesicles of rats in the present model.

Aminobiphenyl Compounds↗

PubMed1996

Dose-related increases in quantitative values for altered hepatocytic foci and cytochrome P-450 levels in the livers of rats exposed to phenobarbital in a medium-term bioassay.

The dose-response relationship between liver tumor promoting activity and cytochrome P-450 (CYP) induction by phenobarbital sodium (PB) was investigated using the liver medium-term bioassay system of Ito. Two weeks after a single dose of N-nitrosodiethylamine (DEN) (200 mg/kg body weight, i.p.), rats were given PB at dietary levels of 500, 250, 125, 60, 30, 15 and 8 parts per million (ppm) for 6 weeks. All rats were subjected to partial hepatectomy at week 3, and were killed at week 8. Quantitative values for glutathione S-transferase placental form positive hepatocytic (GST-P+) foci were increased in the high dose groups dose-dependently. In contrast, the values in the low dose groups were rather lower than that of the control. CYP2B1, 2C6 and 3A2 were predominantly immunostainable in hepatocytes around the central vein. While Western blotting revealed CYP2B1 and 2C6 proteins to be increased with strict dose-dependence, CYP3A2 was only elevated at high doses. Thus, a good correlation between increase of GST-P+ foci and CYP3A2 induction was observed, as well as with CYP2B1 and 2C6 in high dose groups.

Animals↗

PubMed1996

Lack of tumor promoting effects of KCB-1, a recombinant human basic fibroblast growth factor, on two-stage skin carcinogenesis in female CD-1 (ICR) mice.

Skin tumor promoting and co-promoting potentials of KCB-1, a recombinant human basic fibroblast growth factor, were investigated in a two-stage skin carcinogenesis model using female ICR mice. Animals were allocated to either normal (non-injured) or injured skin groups, and given a single topical application of dimethylbenz[alpha]anthracene (DMBA) at 100 micrograms/mouse to fur-clipped back skin. One week after the DMBA initiation step, mice were injected with KCB-1 (0.4, 4.0 and 40 micrograms/mouse, s.c.) and/or 12-O-tetradecanoylphorbol-13-acetate (TPA) at 4.0 micrograms/mouse twice a week until the termination at week 20. The treatment with KCB-1 was not associated with any increases of papillomas and hyperplasias in either the normal or the wounded skin cases. High incidences and multiplicities of skin papillomas and hyperplasias developed in TPA-treated groups. The positive control TPA promotion was not influenced by the KCB-1 treatment in the present initiation/promotion protocol. Thus, KCB-1 exerted no tumor promoting effects on mouse skin two-stage carcinogenesis, and also no amplification activity for the established skin tumor promoter TPA.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1996

Subchronic toxicity study of L-isoleucine in F344 rats.

A subchronic toxicity study with L-isoleucine was conducted using F344 rats. Groups of 10 rats of each sex were given diet containing 0, 1.25, 2.5, 5.0, or 8.0% L-isoleucine for 13 wk. No treatment-related effects were observed in terms of body weight change, food consumption or hematology. In both sexes given 8.0% L-isoleucine, increased or a tendency for increased urine volume and relative kidney weights were observed. Furthermore, the high-dose L-isoleucine treatment brought about an elevation of urinary pH and variations in serum electrolytes. However, histopathological alterations related to these changes were not observed in any organs of either sex. In conclusion, the present study demonstrated that L-isoleucine possessed minimal toxicity at dietary levels of 5.0% and 8.0%, while it did not exert any adverse affects at a dietary level of 2.5% or less.

Animals↗

PubMed1996

Inhibitory effects of phenolic compounds on development of naturally occurring preneoplastic hepatocytic foci in long-term feeding studies using male F344 rats.

Five phenolic compounds, namely caffeic acid, sesamol, hydroquinone, catechol, and 4-methoxyphenol, were fed to groups of 30 male F344 rats at dietary levels of 2, 2, 0.3, 0.8, and 2%, respectively, for 2 years. Retardation of body weight and elevated relative liver weights were noted for all groups. Formalin-fixed and paraffin-embedded liver tissues from rats killed terminally were cut and stained for glutathione S-transferase placental form (GST-P) and tumor growth factor alpha (TGF alpha) immunohistochemically. Numbers and areas of GST-P-positive (GST-P+) foci per unit area of liver section were measured, and the respective treated/control proportional values were calculated to be 58 and 57% for caffeic acid. 58 and 54% for sesamol, 71 and 71% for hydroquinone. 58 and 133% for catechol, and 49 and 39% for 4-methoxyphenol. These data were comparable with results obtained with medium-term liver bioassays (Ito test). However, no intergroup differences were detected with regard to quantitative findings for TGF alpha foci, which were relatively rare. Long-term inhibitory effects of phenolic compounds on liver carcinogenesis, predicted from the Ito test, were thus confirmed in the present feeding studies using quantitative analysis of immunohistochemically demonstrable GST-P+ foci as end point marker lesions.

Animals↗

PubMed1996

Non-carcinogenicity of 2,2'--(4-aminophenyl)imino-bisethanol sulfate in a long-term feeding study in Fischer 344 rats.

2,2'-[(4-aminophenyl)imino]bisethanol sulfate (4APE) was administered at dietary levels of 0 (control), 300, 1000 and 3000 ppm to groups of 50 male and 50 female Fischer 344/DuCrj rats for 104 wk. As slight body weight retardation was observed in the male 3000 ppm group in the preliminary 13-wk feeding study, this dose was selected for the highest exposure level. Mean body weights of both sexes in the 3000 ppm group were lower than those of the controls from wk 2 to termination. However, there were no treatment-related clinical signs or adverse effects on survival rate, food consumption or haematology data. Very slight but statistically significant increases in relative thyroid weights were found in males of the 3000 ppm group, but there was no significant treatment-related increase in the incidence of any non-neoplastic or neoplastic lesions. Thus, under the experimental conditions used, 4APE was not carcinogenic in Fischer 344 rats of either sex.

Animals↗

PubMed1996

Lack of carcinogenicity of tamarind seed polysaccharide in B6C3F1 mice.

The carcinogenic potential of tamarind seed polysaccharide was examined in both sexes of B6C3F1 mice. Groups of 50 male and 50 female animals were given diets containing 0, 1.25 and 5% of tamarind seed polysaccharide for 78 wk. Body weight retardation was exhibited by the females in the 1.25 and 5% groups from 34 wk to termination. However, there were no treatment-related clinical signs or adverse effects on survival rate, food and water consumption, haematology findings or organ weights. Detailed histopathological examination also revealed no treatment-related increase in the incidence of any non-neoplastic or neoplastic lesions. These results demonstrated that tamarind seed polysaccharide is not carcinogenic in B6C3F1 mice of either sex.

Animals↗

PubMed1996

Histogenesis and the role of p53 and K-ras mutations in hepatocarcinogenesis by glyceryl trinitrate (nitroglycerin) in male F344 rats.

Glyceryl trinitrate (GTN) was previously reported to induce hepatocellular carcinoma (HCC) in rats after prolonged feeding. The present experiments were undertaken to evaluate the histogenesis and molecular biology of these tumors and the possible role of nitric oxide (NO), a GTN metabolite, in their development. Male F344 rats received a single i.g. intubation of GTN (1.2 g/kg) at 6 weeks of age and/or a diet containing 1% GTN from 8 weeks of age until necropsy, i.e. for up to 78 weeks. Some animals were subjected to 2/3 partial hepatectomy (PH) at 9 weeks of age. Five sequential sacrifices (14, 32, 52, 78 and 84 weeks of age) were performed. No liver tumors developed in control rats or in rats that received GTN only by a single i.g. intubation, even when intubation was followed by PH. Preneoplastic foci, mainly of clear cell and mixed cell type (identified as positive for glutathione S-transferase placental form) were found from 14 weeks of age in rats receiving GTN in the diet. Focal eosinophilic areas (atypical foci) composed of atypical hepatocytes that often extended into the veins were observed beginning at 52 weeks of age. Some mixed hepatocholangiocellular adenomas and carcinomas arose in eosinophilic lesions. HCCs were seen beginning at 78 weeks of age, but only in rats receiving dietary GTN. Incidence of HCC in the latter animals was 50-75%. Most HCCs were well differentiated. The carcinogenic effect of GTN given in the diet was not affected by prior intubation of a large single dose followed by PH. No p53 mutations were found in 18 tumors but K-ras point mutations, all within codon 12, were found in 8/18 tumors, mostly those with cholangiocellular elements. These were first or second position G-->T transversions or second position G-->A transitions. While these mutation types have also been commonly seen in bacteria after NO-related DNA damage, the fact that tumors arose only on prolonged feeding of this potently bioactive agent at massive doses seems consistent with a more complex mechanism involving multiple (i.e. genetic and/or epigenetic) factors in carcinogenesis by GTN.

Animals↗

PubMed1996

High incidence and histogenesis of seminal vesicle adenocarcinoma and lower incidence of prostate carcinomas in the Lobund-Wistar prostate cancer rat model using N-nitrosomethylurea and testosterone.

The origin of chemically induced male accessory sex gland tumors was studied in Lobund-Wistar rats. Rats were treated at the age of 3 months with a single intravenous injection of 30 mg N-nitrosomethylurea (NMU)/kg body weight and given subcutaneous silastic implants filled with 40 mg testosterone propionate. Previous reports described a high incidence of prostate carcinomas in these rats with this treatment protocol. Additional animal groups included untreated controls, rats that received only an injection of 30 mg NMU/kg, and rats that were subjected to ablation of the seminal vesicle lobes prior to the treatment with NMU and testosterone. Three to 14 rats per group were sacrificed 4 to 10 months after NMU treatment and all remaining rats after 12 months. Twenty-four additional rats died or became moribund during the study. All rats were necropsied and the dorsolateral and ventral prostate and seminal vesicles with coagulating gland (anterior prostate) were examined histologically according to a standardized protocol. Lesions detected included atypical hyperplasia in all glands (resembling prostate intraepithelial neoplasia of human beings), adenomas in seminal vesicles only, and early carcinomas and adenocarcinomas in seminal vesicles and coagulating gland. Early carcinomas of the seminal vesicle, microscopically small and with invasion of the lamina propria and/or tunica muscularis, were detected as rapidly as 4 months after treatment. The vast majority (> 95%) of the grossly visible nodules/masses originated from the seminal vesicles. Testosterone treatment enhanced occurrence and increased the incidence of all lesions, particularly of seminal vesicle adenocarcinomas, from 30% (7/23) to 64% (21/33). Coagulating gland tumors were found in 21% (7/33) of the rats. Ablation of the seminal vesicle lobes reduced the incidence of seminal vesicle adenocarcinomas to 11% (3/29), and these tumors arose from tissues remaining within the parenchyma of the seminal vesicle/prostate complex after ablation. Thus, NMU-induced and testosterone-promoted male sex gland tumors of the Lobund-Wistar rat arise almost exclusively in the seminal vesicles and coagulating gland (anterior prostate), are highly invasive in seminal vesicles before attaining a grossly visible size, and progress rapidly within 4 months, spreading to adjacent tissues and other organs.

Adenocarcinoma↗

PubMed1995

Validation of silver-stained nucleolar organizer regions for evaluation of invasive character of urinary bladder carcinoma in rats and mice.

A series of 8 rat and 16 mouse invasive bladder carcinomas were investigated for the presence of silver-stained nucleolar organizer regions (AgNORs) to clarify whether this parameter is applicable to the estimation of their invasive character. With regard to number of AgNORs per cell, neither rat nor mouse carcinomas showed any difference between invasive and noninvasive sites within the same tumor. However, the frequency of cancer cells bearing bizarre dots, irregular in size and shape, was significantly higher at sites of actual invasion. Quantitative data generated using an image analyzer revealed significantly lower values for NOR roundness and significantly larger NOR size in invasive sites than in noninvasive sites in all groups. Double staining for the proliferation marker proliferating cell nuclear antigen (PCNA) and AgNORs was performed on eight rat carcinomas and a close correlation between the two was confirmed. Thus the number of AgNORs in PCNA-positive cells was significantly greater than in PCNA-negative cells. Furthermore, a particularly strong correlation was observed for incidences of PCNA-positive cells and bizarre dots (P < 0.01). The quantitative data also demonstrated significant differences in size and shape of dots. It is concluded that AgNORs have diagnostic value for the invasive character of bladder carcinomas.

Animals↗

PubMed1995

Lack of carcinogenicity of pesticide mixtures administered in the diet at acceptable daily intake (ADI) dose levels in rats.

Carcinogenic effects of pesticide mixtures were examined with our medium-term carcinogenesis protocols using male F344 rats. In the 8-week liver model, combined dietary administration of 20 pesticides (19 organophosphorus compounds and 1 organochlorine), each at acceptable daily intake (ADI) levels, did not enhance rat liver preneoplastic lesion development initiated by diethylnitrosamine. In contrast, a mixture of 100 times ADI significantly increased the number and area of liver lesions. In the second experiment using a multi-organ carcinogenicity protocol of 28 weeks, mixtures of 40 pesticides (high volume compounds) and 20 pesticides (suspected carcinogens) added to the diet at their respective ADI levels did not enhance carcinogenesis in any organ initiated by 5 different known carcinogens in combination. These results provide support for the safety factor (usually 100) approach presently used for the quantitative hazard evaluation of pesticides.

Animals↗

PubMed1995

Site-specific effects of testosterone propionate on the prostate of rat pretreated with 3,2'-dimethyl-4-aminobiphenyl: dose-dependent induction of invasive carcinomas.

It has been shown that testosterone propionate (TP) strongly promotes induction of invasive carcinomas in previously initiated accessory sex organs. In this study, in order to clarify the dose-dependence of this promotion, TP was given at 3 different levels (high, medium or low doses) using different sizes (2, 1 and 0.5 cm long) of Silastic tube for 40 weeks after administration of 3,2'-dimethyl-4-aminobiphenyl to male F344 rats. The data showed development of invasive carcinomas in the dorso-lateral and anterior prostate and in the seminal vesicle to be dose-dependent with the high dose of TP being most effective for tumor induction. Average levels of serum testosterone were approximately 800, 600, 300 and 150 ng/dl in rats given the high to low doses and in control rats, respectively. Development of neoplastic lesions in the ventral prostate demonstrated an inverse dependence on the dose of TP. These findings, together with previous data, suggest that the tumor-promoting potential of TP on rat prostate is unlikely to be simply due to its androgenic action and other factors should also be considered.

Aminobiphenyl Compounds↗

PubMed1995

Increased susceptibility to N-nitrosomethylurea gastric carcinogenesis in transforming growth factor alpha transgenic mice with gastric hyperplasia.

Glandular stomach carcinogenesis after N-nitrosomethylurea (NMU) treatment was examined in transgenic mice bearing a human transforming growth factor alpha (TGF-alpha) cDNA driven by the mouse metallothionein-I promoter (mouse line MT100) in the inbred mouse line FVB/N. Untreated MT100 mice exhibit a severe age-related gastric fundic hyperplasia. Both sexes of MT100 mice were given 10 weekly intragastric intubations of 0.5 mg NMU per mouse from 6 weeks of age and/or zinc chloride in drinking water to stimulate transgene expression from 5.5 weeks of age to the experiment termination. Animals were killed sequentially at 10, 19 and 29 experimental weeks. Several histochemical markers (AB-PAS, TGF-alpha, pepsinogen isozyme 1, proliferating cell nuclear antigen) were used. Abnormal histochemical patterns were found in untreated MT100 and NMU-treated MT100 mice for all 4 markers of differentiation and carcinogenesis. Precancerous lesions including atypical and/or adenomatous hyperplasia were found in the fundic region of 16/22 male and 8/22 female MT100 mice but not in 27 male and 24 female FVB/N mice treated with NMU. One of 22 MT100 males had fundic carcinoma. FVB/N mice treated with NMU had neither precancerous lesions nor carcinomas in the fundus. Well differentiated adenocarcinomas in the pyloric region were induced at incidences of 2/22 male and 1/22 female MT100 mice treated with NMU and 4/27 male and 4/24 female FVB/N mice treated with NMU. Both strains also had a high incidence (55 to 92%) of squamous cell carcinomas of the forestomach. In conclusion, TGF-alpha induced a hyperplastic lesion in the gastric fundus that appeared to predispose the MT100 mice to carcinogenesis by NMU.

Adenocarcinoma↗

PubMed1995

Carcinogenicity of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in rats: dose-response studies.

The carcinogenic potential of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), identified as the most abundant mutagenic heterocyclic amine in cooked meat and fish, was investigated in dose-response studies. Six-week-old F344 rats of both sexes were administered PhIP in the diet at concentrations of 0, 25, 100, or 400 ppm for up to 104 weeks. Animals receiving the highest dose were killed at week 52 due to marked retardation in body weight gain. PhIP was demonstrably carcinogenic for the colon in males and for the mammary glands in females, in a clear dose-dependent manner for both cases. Mammary carcinogenicity of PhIP was also confirmed in female SD rats with a clear dose-response relationship. In rat two-stage carcinogenicity models, PhIP exerted tumor-promoting activity in the small intestine as well as in the large intestine, but no promoting effects were apparent in the liver, although DNA adducts were formed dose dependently. The virtually safe dose (VSD) at the 10(-6) risk level calculated from the long-term carcinogenicity test was 0.023-0.52 ppm in the diet. This range of values is very close to or lower than human intake in daily life. Since PhIP is a most abundant heterocyclic amine and its carcinogenic organotropism overlaps with the types of neoplasias most commonly observed in western countries, the compound is likely to be extremely important with respect to human cancer development.

Adenocarcinoma↗

PubMed1994

Synergistic enhancement of small and large intestinal carcinogenesis by combined treatment of rats with five heterocyclic amines in a medium-term multi-organ bioassay.

The carcinogenic potential of five heterocyclic amines in combination was analyzed using a medium-term multi-organ bioassay. Male F344 rats were initially treated with five known carcinogens (diethylnitrosamine, N-methyl-N-nitrosourea, N-butyl-N-(4-hydroxybutyl)-nitrosamine, 1,2-dimethylhydrazine and 2,2'-dihydroxy-di-n-propylnitrosamine) over a 4 week period to induce preneoplastic changes in a variety of organs (wide spectrum initiation) and then given the five heterocyclic amines, all having the intestines as a target of their carcinogenicity, individually or in combination in the diet for a further 24 weeks. In the small and large intestines, simultaneous administration of five heterocyclic amines at doses 1/5 or 1/25 of those used in reported carcinogenicity studies resulted in higher incidences and multiplicities of adenocarcinomas than expected from the five individual effects, although the differences were not statistically significant. A synergistic effect based on the additive model was most evident (P < 0.141) with multiplicity data for carcinoma in the small intestine at the 1/25 dose. A similar trend was observed for Zymbal gland (P < 0.077), but not other carcinoma induction. Thus the results suggested that synergism depends on the carcinogenic organotropism of individual agents as well as the doses applied in combination.

1,2-Dimethylhydrazine↗