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This writing details the natural occurrence, synthetic production and use of the carcinogenic hydrazines and related chemicals. Twenty-three such chemicals were found in nature in mushrooms, tobacco, bay leaves, antibiotics, soil and other sources. The synthetically-produced hydrazines and related chemicals include 61 compounds which were or are in use as pharmaceutical drugs, agricultural substances, industrial chemicals and fuels for military and space vehicles and rockets. Because there is an overlap between the naturally-occurring and synthetically-produced compounds, their total number is 76. Altogether, 98 hydrazines and related chemicals were studied for carcinogenic action thus far, of which 84 were found to be carcinogenic and the remaining 14 were inactive. This means that the human population is exposed in various degrees to a substantial number of these agents. Therefore, the hydrazine class, unlike the polycyclic aromatic hydrocarbons, N-nitroso compounds, and aromatic amines, poses a greater environmental risk to the human population. In view of these considerations, it appears reasonable to proceed with additional experimentation in this field of interest.

The antineoplastic activities of hydrazines and hydrazine-containing natural products are summarized and reviewed. Many of these, including the base compound hydrazine, some of its 79 analogues and 2 hydrazine-containing cultivated mushrooms, exhibited antineoplastic actions in animals and some of them in humans. In addition, a substantial number of hydrazine analogues were further derivatized (altogether 331 derivatives were prepared) and studied to a limited extent for cancer chemotherapeutic activity in animals. Subsequently, only one hydrazine, N-isopropyl-alpha-(2-methylhydrazino)-p-toluamide HCl (procarbazine, natulan) was used extensively in human medicine. Because this drug is a highly carcinogenic substance in animals and since a substantial amount of evidence points to the possibility that it is co-carcinogenic or carcinogenic itself in humans, its use has largely been abandoned. Because well over 80% of the studied hydrazine class of compounds are carcinogenic, therefore, it may not be rewarding to search among them for cancer cure.

A comparative assessment is performed on one of the false morel mushrooms, Gyromitra esculenta, including the amounts of some hydrazines present in this fungus, the cancer-inducing doses of these chemicals or the mushroom used in animal experiments, the total amounts of the hydrazines or mushroom needed to induce neoplasms in mice and the estimated total amounts of hydrazines or mushroom needed to induce cancer in humans. When one compares the estimated amounts of hydrazines required to induce cancer with the amount of raw Gyromitra esculenta needed to yield a similar effect, it becomes clear that to date 37 percent of the carcinogenic ingredients of this fungus have been identified.

This assessment focuses on the concentrations of some chemicals present in the Agaricus bisporus mushroom, the cancer-inducing doses of these chemicals or mushroom used in the animal experiments, the total amounts of these chemicals or mushroom needed to induce cancer in these mice, and the estimated total amounts of these chemicals or mushroom needed to induce cancer in humans. By adding the estimated amounts of chemicals needed to induce cancer and by comparing it with the amount of raw mushroom needed to induce the same effect, it becomes obvious that we have accounted for less than 2% of the carcinogenic components of the Agaricus bisporus mushroom. Since some unavailable data handicapped this assessment, it should be regarded as tentative and subject to further adjustment.

The review summarizes the results of 30 hydrazines, which were studied in humans and in six animal species for teratogenic activities. Of these, 23 chemicals were found to induce physical defects in the developing embryos of animals. Six hydrazines failed to induce teratogenic abnormalities in animals under the experimental conditions. Three hydrazine analogues, some of which were given in combination with other drugs to pregnant women, gave ambiguous results concerning teratogenic effects. Some of these investigations were aimed at revealing the teratogenic mode of action of hydrazines. The mechanistic aspect focused on the dose requirements of chemicals and the time period in the development of the fetus susceptible to malformation and chemoprevention. Of interest is the base compound hydrazine, which was found to be teratogenic in five animal species. In general, the hydrazines were found to be powerful teratogens, which coincided in most cases with their known carcinogenic activities.

The carcinogenic, mutagenic and teratogenic activity of 11 hydrazine analogues and diazonium ions are described. These chemicals are ingredients of 22 mushroom species. Of these, one is cultivated, while the remaining 21 are wild fungi. To date, many of these mushrooms are considered to be edible. The appropriate chemistry and biochemistry investigations of the mushroom chemicals are summarized briefly. Human consumption estimates also are provided in as much as possible.

The reaction of 2'-deoxyguanosine (1), substituted hydrazines (Hy) and oxygen, in the presence of Cu(II) as catalyst, yields 8-hydroxy-2'-deoxyguanosine (2). The rate of formation of 2 was found to be dependent upon the oxidation potential of the Hy and on structural factors of the Hy. The conversion of 1 to 2 under these conditions suggested that a Haber-Weiss/Fenton type of process was involved with Hy acting as reductant. However, the dependence of the rate of the conversion of 1 to 2 upon the structure of Hy suggested that the Hy substrates studied may be more directly involved in the process than that of a reducing agent. Additional studies of this reaction system, including the oxygen consumption, radical trapping studies and direct ESR measurements suggest that the conversion of 1 to 2, under the conditions used, involves the intermediacy of complex composed of the metal catalyst, 1, Hy and oxygen. The rate data for the conversion of 1 to 2 appear to be correlated with the carcinogenicity of Hy and therefore 2 may be an important DNA adduct in the carcinogenesis of hydrazines.

Lifetime administration of 0.03125% 1,1-di-n-butylhydrazine in drinking water to Swiss mice, from 6 weeks of age, induced tumors of the lungs, forestomach and liver. The tumor incidences in these tissues in untreated controls were 25, 2 and 0.5%, whereas in the treated groups the corresponding tumor incidences increased to 68, 39 and 5%, respectively. Histopathologically these lesions were classified as adenomas and adenocarcinomas of the lungs, squamous cell papillomas and carcinomas of the forestomach, and benign hepatomas and liver cell carcinomas. The work is part of a structure activity inquiry and its specific aim is to disclose whether the dialkyl derivatives of hydrazine are more active carcinogens than the monoalkyl analogues.

N-ethyl-N-formylhydrazine (EFH) was administered as a 0.02% solution in drinking water continuously for life to randomly bred Swiss mice, from 6 weeks of age. The treatment induced tumors of the lungs, blood vessels, liver, gall bladder and preputial glands. The tumor incidences in treated females for these five tissues were 98, 94, 0, 2 and 0%, whereas in the treated males they were 78, 64, 26, 8 and 10%, respectively. Histopathologically the lesions were adenomas and adenocarcinomas of the lungs, angiomas and angiosarcomas of blood vessels, benign hepatomas, liver cell carcinomas, adenomas and adenocarcinomas of the gall bladder, and squamous cell papillomas and carcinomas of preputial glands. The study is part of a structure activity relationship inquiry and proves the carcinogenicity of EFH, a structural homologue of N-methyl-N-formylhydrazine, an ingredient of the edible false morel mushroom.

Light microscopic autoradiographic studies were made on the distribution of 14C-1,2-dimethylhydrazine dihydrochloride in Swiss mice and on the effect of 1,2-dimethylhydrazine dihydrochloride on DNA synthesis, using the 3H-thymidine incorporation technique. In the first study, 14C-1,2-dimethylhydrazine dihydrochloride was administered subcutaneously or orally. Large amount of silver grains were found in hepatocytes and substantially lower amount of silver grains observed in the endothelial cells and epithelial cells of colon. In the second study, repeated injections or oral administrations of 1,2-dimethylhydrazine dihydrochloride were given to mice which subsequently received 3H-thymidine treatment. A somewhat higher amount of thymidine incorporation in DNA was noted in the epithelial cells of the colon of subcutaneously and orally treated mice at two occasions and a substantially higher amount in the endothelial cells of blood vessels in liver of mice treated by both routes than in the corresponding controls. In three instances, however, the amount of incorporation decreased; in the hepatocytes and endothelium at 1 week and 24 hr, respectively, after oral treatment, and in the epithelium of the colon at 3 months, after subcutaneous administration. In the mice treated with 1,2-dimethylhydrazine dihydrochloride, a significantly high amount of 3H-thymidine incorporation was observed in the endothelial cells of blood vessel in liver from which tumors later arose, and somewhat high in the hepatocytes in which tumor did not develop. In the epithelial cells of colon, no apparent relationship can be seen between these events. No association was seen in the distribution of 14C-1,2-dimethylhydrazine dihydrochloride and tumor development in various cells.

Five substituted hydrazines that induce large bowel and other types of cancer in laboratory animals are described. Two of these compounds, which originate in nature, are 1,1-dimethylhydrazine, a tobacco ingredient, and methylhydrazine, formed from a chemical present in the edible wild mushroom Gyromitra esculenta. The human population is therefore exposed to them considerably. In addition, both compounds are manufactured and used in rocket fuel. The other three chemicals, 1,2-dimethylhydrazine dihydrochloride,1-methyl-2-butylhydrazine dihydrochloride and trimethylhydrazine hydrochloride, are manufactured synthetically only and apparently are not found in substantial quantities in the environment.

The toxic properties of sixty carcinogenic hydrazines are reviewed and presented. Many of these chemicals are synthesized by man and used in industry, agriculture and medicine, while others occur in nature as ingredients of fungi and plants. The human population is, therefore, exposed to them to a considerable degree. These compounds, in addition to being carcinogens, have toxic effects in the gastrointestinal tract, respiratory, nervous, lymphoreticular, hematopoietic, cardiovascular, genitourinary, integumentary, musculoskeletal systems, etc., of 15 animal species and man. Because they caused toxic damage in practically every organ and tissue, earlier claims concerning their tissue specificity are discounted. Their hazardous properties deserve careful attention.

Continuous administration of 0.04% N-n-butyl-N-formylhydrazine (BFH) in drinking water to 6-week-old randomly bred Swiss mice for life produced tumors of the lungs, preputial and clitoral glands. The tumor incidences in these three tissues of the treated animals were 87, 66, and 10%, whereas in the untreated controls they were 25, 0, and 0%, respectively. Histopathologically, the tumors were classified as adenomas and adenocarcinomas of the lungs, squamous cell papillomas and carcinomas, angio-, fibro-, and myxo- sarcomas of preputial glands and squamous cell papillomas and carcinomas of clitoral glands. N-n-Butyl-N-formylhydrazine is a structural homologue of the carcinogenic N-methyl-N-formylhydrazine and N-ethyl-N-formylhydrazine. These studies are integral parts of structure activity relationship inquiries.

Administration of 0.125% formylhydrazine in drinking water to 6-week-old randomly bred Swiss albino mice for life, induced lung tumours. Compared to untreated controls, the lung-tumour incidence rose from 15 to 94% in the females and from 22 to 100% in the males. The treatment had no detectable tumorigenic effect in other organs.

Continuous administration of 0.0625% 1,2-diallylhydrazine dihydrochloride in drinking water for life to 6-week-old randomly bred to Swiss mice induced lung tumors. In comparison with the untreated controls, the lung tumor incidence rose from 25 to 80% in the females and from 26 to 80% in the males. The treatment had no apparent effect on the development of other tumor types. Histopathologically, the lesions were classified as adenomas and adenocarcinomas of the lungs. The work is a continuation of our structure activity inquiry concerning the relative carcinogenic potencies of the dialkyl versus the monoalkyl series of hydrazine analogues.

Gyromitrin, acetaldehyde N-methyl-N-formylhydrazone, is a toxin present in edible wild mushroom Gyromitra esculenta. At 37 degrees under different acidic conditions (pH 1 to 3), mimicking the milieu of human stomach, gyromitrin is converted to methylhydrazine, a known tumor inducer in mice and hamsters, through an intermediate, N-methyl-N-formylhydrazine. In addition, methylhydrazine is formed in the mouse stomach after p.o. administration of gyromitrin. These findings imply that consumption of G. esculenta could present a carcinogenic, as well as an acutely toxic, health hazard.

Toxicity investigations were conducted with 4 chemicals: hydrazine, 1,2-dimethylhydrazine di HCl, phenylhydrazine HCl and Beta-N-(gamma-L(+)-glutamyl)-4-hydroxymethylphenylhydrazine in Swiss mice. Hydrazine and phenylhydrazine HCl were administered daily in drinking water, the former at 0.01% and the latter at 0.001% concentrations. The 1,2-dimethylhydrazine di HCl and Beta-N-(gamma-L(+)-glutamyl)-4-hydroxymethylphenylhydrazine were given as a single subcutaneous injection at 45 mug and 100 mug/gr. body weight basis, respectively. The findings clearly showed that all four chemicals exerted a stronger toxic effect in male than in female mice. It is, therefore, recommended in similar situations to use different doses of chemicals for each sex in the long-term tumorigenesis studies.

Tetramethylhydrazine hydrochloride (TEMH) was administered in drinking water as a 0.125% solution to randomly bred Swiss mice for life beginning at 6 weeks of age. As a result of treatment, the incidence of blood vessel tumors rose from 5 to 96% in females and from 6 to 88% in males, while that of lung tumors increased from 21 to 36% in females and from 23 to 28% in males, as compared with untreated controls. The increased incidence of blood vessel tumors, but not of lung neoplasms, was statistically significant. Histopathologically, the tumors exhibited the characteristics of angiomas and angiosarcomas of blood vessels and adenomas of the lung. The investigation proved for the first time the tumorigenicity of TEMH. The possible role of increased methyl substitution on hydrazine in tumorigenesis was also discussed, as well as hydrazine derivatives as a tumor-producing class.

Separate solutions of 0.015% benzylhydrazine dihydrochloride and 0.01% phenylhydrazine hydrochloride were given continuously in the drinking water of 6- and 5-week-old randomly bred Swiss mice for the remainder of their life. The consumption of benzylhydrazine dihydrochloride significantly increased the lung tumor incidence from 21 to 42% in the females, while in phenylhydrazine hydrochloride-treated mice, the incidence of blood vessel tumors rose significanly from 5 to 22% in females and from 6 to 20% in males, as compared with the controls. Histopathologically, the tumors were classified as adenomas and adenocarcinomas of lungs and angiomas and angiosarcomas of blood vessels. The study thus proves for the first time the tumorigenicity of benzylhydrazine dihydrochloride. It also confirms the tumor inducing ability of phenylhydrazine hydrochloride, which is used in medicine for treatment of polycythemia vera.

Nicotinic acid hydrazide was administered as a 0.125% solution in drinking water continuously for life from 6 weeks of age to randomly bred Swiss albino mice. As a result of treatment, the lung tumor incidence rose from 25 to 76% in females and from 26 to 42% in males. The treatment had no statistically significant effect on the development of other types of tumors. Histopathologically the tumors were classified as adenomas and adenocarcinomas of the lungs. The study thus demonstrates the tumorigenicity of this compound which is a structural homologue of the tuberculostatic and carcinogenic isonicotinic acid hydrazide.

Single subcutaneous injections of each of five substituted hydrazines were given alone and jointly with pyridoxine hydrochloride (PH) to Swiss mice. The convulsive, toxic, and lethal effects of four compounds--methylhydrazine (MH), ethylhydrazine hydrochloride (EH), n-butylhydrazine hydrochloride (BH), and beta-N-[gamma-L(+)-glutamyl]-4-hydroxymethylphenylhydrazine--were successfully prevented by administering PH before and/or after injection. The toxic symptoms caused by N-methyl-N-formylhydrazine (MFH) were, however, only slightly inhibited by this vitamin.

Single or ten weekly subcutaneous injection(s) of 1, 2-dimethylhydrazine dihydrochloride were administered separately to Swiss mice. The repeated application gave rise mainly to high incidences of tumors in the large intestine. These neoplasms occurred most frequently in the colorectal area and in cecum adjacent to ileum. Light microscopically, these lesions were classified as polypoid adenomas and adenocarcinomas. Most of the adenocarcinomas were highly invasive, although they metastasized rarely. The fine structure of the malignant cells exhibited features typical of columnar absorptive cells. A distinctive alteration was the disorderly arrangement and abnormal size and shape of the microvilli. In addition, the cells exhibited numerous free ribosomes, little RER, priminent Golgi bodies, and uniformly dispersed nuclear chromatin. Morphologically, the intestinal tumors were similar to those found in man. In addition, the repeated administration of 1, 2-DMH also induced significant incidences of neoplasms in blood vessels, lungs, anus, and kidneys while the single application produced tumors in blood vessels and liver. The main hypotheses attempting to explain the selective induction of large intestinal neoplasms are discussed.

Twenty actual new cancer-causing hydrazines, hydrazides, and hydrazones of synthetic or natural origin are described. These compounds induce tumors in various target tissues in mice, hamsters and rats. To nine of these compounds the human population is exposed in the form of drugs, agricultural herbicides, and naturally occurring ingredients of edible mushrooms. Yet, with one exception, none of the hydrazines described here were investigated for cancer-inducing abilities in man. The human population should be warned against the use of this hazardous class of chemicals, the total number of which is now 40.

The various synthetic substituted hydrazines, which cause tumors in animals, are briefly enumerated. To date, 19 of them have proved to be tumorigenic in animals. A number of these chemicals are found today in the environment, in industry, in agriculture, and in medicine, and the human population is exposed to a certain degree to some of them. Hydrazine also occurs in nature in tobacco and tobacco smoke. The three other naturally occurring hydrazine compounds are N-methyl-N-formylhydrazine, which occurs in the wild edible mushroom, Gyromitra esculenta, and beta-N-[gamma-L(+)-glutamyl]-4-hydroxymethylphenylhydrazine and 4-hydroxymethylphenylhydrazine, which are found in the commonly eaten cultivated mushroom, Agaricus bisporus. Tumorigenesis studies with the naturally occurring hydrazines are in progress.

Selected hydrazines and related compounds were examined for their mutagenic activity in S. typhimurium strains TA1535 and TA1537. These in vitro assays were conducted with and without metabolic activation by Aroclor-induced rat-liver enzymes. Relatively high levels of mutagenicity were observed with phenylhydrazine X HCl, methylhydrazine, N'-acetyl-4-(hydroxymethyl)phenylhydrazine, and 4-(hydroxymethyl)benzenediazonium tetrafluoroborate, the stabilized salt of a carcinogenic metabolite of agaritine; only low levels of mutagenicity were observed with other compounds, although most are strong carcinogens. Several of the compounds were highly toxic to the bacteria, and detection of mutagenicity was enhanced by calculating the increase in mutagenic activity on the basis of the surviving fractions of bacteria.

A 0.05% solution of trimethylhydrazine hydrochloride (TMH) administered for a lifetime in drinking water to outbred Swiss albino mice, beginning at 6 weeks of age, induced tumors of blood vessels, lungs, and kidneys. The tumor incidences in these tissues in untreated controls were 5,22 and 0%, whereas in the treated groups the corresponding tumor incidences increased to 85, 44, and 6%, respectively. Histopathologically, tumors were classified as angiosarcomas of blood vessels and adenomas of the lungs and kidneys. The study thus demonstrated the tumorigenicity of TMH. Contrary to expectation, the chemical structure modification apparently failed to alter qualitatively the tumorigenic response.

beta-Phenylisopropylhydrazine hydrochloride and thiocarbamylhydrazine were separately administered as 0.0312 and 0.0156% solutions in drinking water for life to randomly bred Swiss mice. The consumption of the chemicals resulted in no detectable tumorigenic effects in the treated animals, and it is therefore concluded that these compounds are apparently noncarcinogenic under the present experimental conditions.

1,2-Diformylhydrazine was administered in drinking water as a 2% solution to randomly bred Swiss albino mice for life from 6 weeks of age. As a result of treatment, the lung tumor incidence rose from 15 to 96% in females and from 22 to 82% in males. The treatment had no statistically significant effect on the development of other types of tumors. Histopathologically, the neoplasms exhibited the characteristic appearance of adenomas and adenocarcinomas of the lungs. The work is part of a series of studies aimed at revealing the relative carcinogenic potency of mono- and dialkyl-hydrazines and also their possible environmental significance as cancer causative agents.

Single sc injections of N-methyl-N-formylhydrazine were given to randomly bred Swiss mice. The females received 180 micrograms per gram of body weight, while two groups of males were treated with either 120 or 100 micrograms per gram of body weight. The treatment resulted in induction of tumors of lungs with an incidence of 40% in the females. In males treated with the higher and lower doses, the incidences of preputial gland tumors were 12 and 12%, respectively. Histopathologically, the tumors were classified as adenomas and adenocarcinomas of lungs, squamous cell papillomas, and carcinomas of preputial glands. N-Methyl-N-formylhydrazine is a constituent of the edible wild false morel mushroom Gyromitra esculenta, to which the human population is exposed in measurable quantities, sometimes at a single meal.

Continuous administration of 0.04% N-n-propyl-N-formylhydrazine (PFH) for life in drinking water to 6-week-old randomly bred Swiss mice induced tumours of the lungs, preputial glands, liver and gallbladder. The tumour incidences in these 4 tissues were 91, 22, 8 and 6%, whereas in the untreated controls they were 25, 0, 0.5 and 0.5%, respectively. The higher dose of 0.08% PFH, given under identical conditions, induced only tumours of the lungs, liver and gall bladder in low incidences, since the compound was too toxic for the mice. Histopathologically, the tumours were classified as adenomas and adenocarcinomas of the lungs, squamous-cell papillomas, and carcinomas and fibrosarcoma of preputial glands, benign hepatomas and liver-cell carcinoma, as well as adenomas and adenocarcinoma of the gall bladder. The investigation is part of our structure/activity relationship inquiry aimed at revealing the mechanism of action of the N-alkyl-N-formylhydrazine series of chemicals.

1,1-Diallylhydrazine was administered as a 0.03125% solution in drinking water for life to Swiss mice, from 6 weeks of age. Compared to untreated controls, in treated animals the lung tumor incidence rose from 25 to 76% in females and from 26 to 76% in males, whereas the incidence of forestomach tumors increased from 4 to 14% in females and from 0 to 34% in males. Histopathologically, the tumors were classified as adenomas and adenocarcinomas of the lungs and squamous cell papillomas and carcinomas of the forestomach. This work is part of our structure activity inquiry and demonstrates the relative carcinogenic potency of another disubstituted allylhydrazine.

Administration of 0.001% 1,2-dimethylhydrazine dihydrochloride, symmetrical, in the drinking water of 7-week-old randomly bred Swiss mice for the remainder of their lifetime induced blood vessel tumors and enhanced the incidence of lung neoplasms. Ninety-eight percent of the females and 92% of the males developed vascular lesions, whereas among the controls the incidence was 3% in the females and 1% in the males. In addition, the incidence of lung tumors rose from 12 to 44% in the females and from 10 to 24% in the males, as compared with the controls. The occurrence of the vascular tumors in order of decreasing frequency was as follows: muscle, pararenal, fat, liver, parametrial, paraepididymal tissues, etc. Gross, light and electron microscopic examinations of vascular lesions revealed the characteristic appearance of angiosarcomas. The type and extent of macroscopic and histologic involvements of the various tissues by the tumors are presented. The ultrastructural descriptions of hemorrhagic areas, vascular spaces, neoplastic endothelial cells, their cytoplasms and organelles are illustrated in detail.In conclusion, whereas hydrazine enhanced the development of lung tumors, when the dimethyl group was attached to it at symmetrical positions, it evoked vascular tumors. Thus, the present study provides evidence for the possible relationship between chemical structure and tumor induction at specific organ sites.