Carcinogenicity of captan.

Two studies on the carcinogenicity of the fungicide captan in animals were reviewed. The results and conclusions, which were based on my examination of the histological sections, showed that captan is highly carcinogenic in rats and mice. Neoplasms at all sites, as well as malignant neoplasms, were increased in both low and high dose captan-treated male and female rats. Benign and malignant neoplasms of the endocrine organs were increased in low and high dose male and female rats ingesting captan. Neoplasms of the adrenal and pituitary glands were increased. Increased incidences of benign and malignant neoplasms, and of malignant neoplasms only, were observed in the reproductive system of female rats ingesting captan. The incidence of these neoplasms was markedly increased in the mammary gland and ovary. Female rats given captan were more susceptible to the development of hepatic neoplasms than were male rats. Captan induced neoplasms of the duodenum in male and female mice. There also were toxic changes in rats. Captan-treated male rats were more susceptible to the induction of chronic renal disease than were female rats. Male rats also had a high incidence of particularly severe testicular atrophy as a result of the ingestion of captan. Such lesions interfere with the health of the rats and with the development of neoplasms.

Neoplasms of the skin and other organs observed in Swiss mice treated with nitrosoalkylureas.

A number of nitrosoalkylureas, nitrosoalkylcarbamates, and chlorinated nitrosotrialkylureas were painted twice a week on the skin of female Swiss mice at a concentration of 40 mM. Of the 29 compounds, 16 induced skin tumors in 4 or more of 20 mice; 9 compounds produced tumors in 10 or more mice. Most of the skin tumors were squamous cell or basal cell carcinomas, and some sarcomas. These carcinomas and sarcomas of the skin were large, invasive, and in several animals there were multiple large metastases to the lungs and lymph nodes. Treatment with several of the compounds was associated with poor survival. The median survival in many other groups was reduced considerably below the 2-year survival of acetone-treated controls. Many of the treatments led to development of tumors of internal organs, including mammary carcinomas, adenocarcinomas and squamous cell carcinomas of the lung, and tumors of the stomach. The stomach tumors might have arisen through exposure to the compound licked from the skin. It appears that several of the compounds were absorbed through the skin of the mice and exerted their effect systemically.

Chronic carcinogenesis studies of acrolein and related compounds.

Acrolein and two of its more stable derivatives, the oxime and the diethylacetal, and the related allyl alcohol were given in drinking water to groups of 20 male and 20 female F344 rats at doses close to the maximum that could be tolerated by the animals, for most of their lifetime. Acetaldoxime served as a control for the hydroxylamine derivative of acrolein. Most of the tumors were common in untreated rats of this strain. Only adenomas of the adrenal cortex in females were more numerous than in untreated controls. Acrolein itself was too toxic to hamsters to conduct a carcinogenesis study. Acrolein oxime, acrolein diethylacetal and allyl alcohol were all quite toxic to hamsters, but 2 mg per week by gavage was tolerated by groups of 20 male Syrian hamsters. There was a small number of tumors of the pancreatic ducts and of the forestomach in the treated hamsters, but the incidence was not statistically significant.

Pathologic effects of chronic administration of hydrochlorothiazide, with and without sodium nitrite, to F344 rats.

The diuretic drug hydrochlorothiazide was administered to 24 male and 24 female F344 rats as a mixture of 0.1% in powdered food. A parallel group of the same size was given 0.1% hydrochlorothiazide plus 0.2% sodium nitrite in the food. A third group received 0.2% sodium nitrite in the food and there was a similar group of untreated controls. The treatments were well tolerated and there was no significant life shortening. A majority of the rats given hydrochlorothiazide, with or without nitrite, developed chronic progressive nephropathy, which was more severe in males than in females. Associated with this were diffuse parathyroid hyperplasia in both groups receiving the drug, also more severe in males than in females, and parallel increases in lesions of the blood vessels (mural thrombosis of the heart and polyarteritis). The few adenomas of the parathyroid and tubular cell adenomas of the kidney in rats ingesting hydrochlorothiazide were not statistically significant.

Carcinogenicity of heptachlor and heptachlor epoxide.

Heptachlor and its metabolite heptachlor epoxide are unequivocally carcinogenic in rats and mice. The chemicals induced carcinomas of the liver, which were highly significant. There were neoplasms at other sites in rats. Neoplasms at all sites, as well as malignant tumors, were increased in heptachlor-treated male rats. There were similar increases in benign and malignant neoplasms of endocrine organs, particularly in female rats. Neoplasms of the thyroid and pituitary were increased in male rats and neoplasms of the reproductive system, including the ovary and uterus, in female rats given heptachlor. Mice also developed hepatic vein thrombosis and thrombosis of the atria of the heart. Nephritis, myocarditis, encephalitis, hepatitis, polyarteritis and atrophy of the testes were observed in rats.

Ultrastructure of liver tumors induced in F344 rats by methapyrilene.

Liver tumors induced in F344 rats by methapyrilene were studied by electron microscopy. The tumor cells constituting hepatocellular carcinomas showed a pronounced increase in the number of mitochondria and conformational changes of these organelles while the content of lipid, glycogen and smooth endoplasmic reticulum was greatly reduced. The cholangiocarcinomas consisted of bile duct epithelia at varying stages of squamous metaplasia.

Carcinogenicity and toxicity of malathion and malaoxon.

Malathion and its oxygen analogue, malaoxon, are carcinogenic in Osborne-Mendel and Fischer-344 rats. Benign and malignant neoplasms at all sites were increased in Osborne-Mendel and Fischer-344 male and female rats ingesting malathion. Both Osborne-Mendel and Fischer-344 male rats were more susceptible than the female rats. The organ sites were not the same for Fischer-344 and Osborne-Mendel rats. Osborne-Mendel rats developed neoplasms of the endocrine organs, brain, and liver. Fischer-344 rats had neoplasms of the adrenal medulla, organs with squamous cells, lung, and hematopoietic system. Fischer-344 male rats given malathion were more susceptible to chronic renal disease, parathyroid hyperplasia, metastatic calcification, and atrophy of the testes than were Osborne-Mendel male rats. They also had ulcers of the forestomach. Chronic renal disease and atrophy of the testes affected the health of the animals and interfered with the development of neoplasms. Malathion increased the incidence of neoplasms of the liver in B6C3F1 male mice. Male mice also had atrophy of the testes. Benign and malignant neoplasms at all sites, and in the endocrine organs, were increased in Fischer-344 male and female rats ingesting malaoxon. Neoplasms were present in the adrenal medulla, organs with squamous cells, liver, and hematopoietic system. Both male and female Fischer-344 rats receiving malaoxon had chronic renal disease and the male rats had parathyroid hyperplasia and metastatic calcification.

Organ-specific carcinogenesis in rats by methyl- and ethylazoxyalkanes.

Azoxyalkanes are isomeric with nitrosodialkylamines and could be similar in their biochemical and biological actions. To compare the structure-activity relations in the two series, the tumorigenic activities of four azoxyalkanes, azoxymethane, azoxyethane, Z-ethyl-O,N,N-azoxymethane, and Z-methyl-O,N,N-azoxyethane, were compared in male F344 rats by p.o. administration of 0.54 mM and 0.135 mM solutions in drinking water. In most cases, treatment lasted 30 weeks, but at the higher dose of the two ethylazoxy compounds, 24 weeks of treatment were sufficient. Most of the animals died with tumors that could be attributed to the treatments. The two ethylazoxy compounds caused much earlier death from tumors than the corresponding methylazoxy compounds. All four compounds induced a high incidence of liver neoplasms, which were mainly hepatocellular; the two ethylazoxy compounds also induced a large number of hemangiosarcomas in the liver. At both dose levels, azoxyethane induced tumors of the esophagus and nasal cavity, tumors that were not seen in any other group. Other tumors appearing in significant incidence were in the colon and ileum, induced by azoxymethane and Z-ethyl-O,N,N-azoxymethane, and kidney tumors induced by azoxymethane and Z-methyl-O,N,N-azoxyethane. In F344 rats, azoxyethane was similar in carcinogenic activity to its isomer nitrosodiethylamine, whereas azoxymethane was much less potent than nitrosodimethylamine and induced quite different tumors. These results suggest that the biochemical activation of azoxylkanes is different from the analogous nitrosodialkylamines.

Atrial thrombosis involving the heart of F-344 rats ingesting quinacrine hydrochloride.

Quinacrine hydrochloride is toxic for the heart of F-344 rats. Rats treated with 500 ppm quinacrine hydrochloride in the diet all developed a high incidence of left atrial thrombosis. The lesion was associated with cardiac hypertrophy and dilatation and focal myocardial degeneration. Rats died from cardiac hypertrophy with severe acute and chronic congestion of the lungs, liver, and other organs. Seventy percent of rats given 250 ppm quinacrine hydrochloride and 1,000 ppm sodium nitrite simultaneously in the diet had thrombosis of the atria of the heart, while untreated control rats in this laboratory did not have atrial thrombosis. Sodium nitrite in combination with quinacrine hydrochloride appeared to have no additional effect.

The effect of deuterium substitution on carcinogenesis by azoxymethane.

Azoxymethane was synthesized labeled with deuterium in one or other of the two methyl groups. Groups of 20 male F344 rats were given either 4 mg or 1 mg per week of each of the labeled compounds or of unlabeled azoxymethane each week in drinking water, for 30 weeks, after which the animals were kept until they died. All in the high dose groups died earlier with tumors induced by the treatment than did those in the low dose groups. Azoxymethane itself led to earlier death than either of the deuterium-labeled compounds, and methylazoxymethane-d3 seemed to be the least potent compound. The incidence of liver tumors and of kidney tumors was similar in the groups receiving the same dose of all 3 compounds. However, there were fewer tumors of the colon in animals given methyl-d3-azoxymethane than with the other 2 compounds. These results are consistent with the concept that either methyl group of azoxymethane can be oxidized in the course of activation to a proximate carcinogenic agent for liver, kidney or colon of rats, but that oxidation of the methyl group next to the nitrogen bearing oxygen is more important in the induction of colon tumors.

The effect of 3-methyl substitution on the carcinogenicity of nitroso-4-piperidone.

The carcinogenic activity of the 3-methyl derivative of nitroso-4-piperidone was compared with that of the compound without the methyl group, by chronic administration to rats at equimolar doses in drinking water. Nitrosopiperidone induced both liver and esophageal tumors, whereas the 3-methyl derivative induced only tumors of the esophagus in a much shorter time.

Carcinogenicity of dimethoate.

Studies on the carcinogenicity of the insecticide dimethoate in animals were reviewed. Examination of histological sections showed that dimethoate is highly carcinogenic in Osborne-Mendel rats. Neoplasms at all sites, as well as malignant neoplasms, were increased in both low and high doses of dimethoate-treated male rats in the National Cancer Institute study. The malignant neoplasms were both carcinomas and sarcomas. Neoplasms of the endocrine organs, particularly carcinomas, were increased in male and female rats given dimethoate. These carcinomas were observed in the adrenal, thyroid, and pituitary glands. Neoplasms were also increased in the liver of male and female rats and in the reproductive organs of female rats given dimethoate. Male and female rats treated with dimethoate developed monocytic leukemia. There also were toxic changes in rats. Male rats had atrophy of the testes, chronic renal disease, parathyroid hyperplasia, and polyarteritis. Wistar male and female rats given dimethoate by gavage or intramuscularly developed a significant increase in malignant neoplasms, mainly sarcomas, and granulocytic leukemia. AB male and female mice also had an increased incidence of malignant neoplasms and granulocytic leukemia after dermal applications of dimethoate.

Carcinogenesis in rats by asymmetric nitrosamines containing an allyl group.

Four asymmetric nitrosamines containing 1 allyl group were administered to rats in drinking water to aid in understanding the failure of nitrosodiallylamine ( NDAA ) to induce tumors in rats. Three of the compounds were given at equimolar doses, the fourth at somewhat lower dose. All four nitrosamines induced tumors of the esophagus and/or nasal cavity. Nitrosoallylethanolamine (NAE) induced a 30% incidence of hepatocellular carcinomas, while nitrosoallyl -2- hydroxypropylamine induced 70% hepatocellular carcinomas and a much lower dose of nitrosoallyl -2- oxopropylamine induced 80% of hepatocellular carcinomas, several of which metastasized. Nitrosoallyl -2,3- dihydroxypropylamine , which increased the mortality from tumors much more than the other compounds, failed to induce tumors in the liver, but induced a high incidence (85%) of tumors of the esophagus. The conclusion is that the allyl group is not metabolically inert, but that its presence in these molecules modifies their metabolism so as to give rise to tumors in a variety of organs. It does not seem that formation of an allylating agent is the common mechanism of carcinogenesis by these compounds.

Comparison of nitrosocimetidine with nitrosomethylnitroguanidine in chronic feeding tests in rats.

N-Nitrosocimetidine, a nitroso derivative of the drug cimetidine, was given to groups of 20 male and 20 female rats in drinking water at a concentration of 0.5 mM for more than 2 years. The life span of the rats was not decreased compared with untreated control animals, and there was no significant increase in incidence of any tumor that could be attributed to the treatment. In comparison, 45% or more of 20 male rats treated with the analogous nitrosoguanidine, N-nitroso-N-methyl-N'-nitroguanidine, at an equimolar concentration in drinking water developed neoplasms of the glandular stomach. There was some shortening of life span in these animals. An additional group of 20 male rats was given an identical treatment with N-nitroso-N-methyl-N'-nitroguanidine in water, but prepared fresh on alternate days, rather than once a week, to minimize decomposition. These animals died more rapidly than did the previous group and had a higher incidence of neoplasms of the glandular stomach. The neoplasms seen in this organ were usually adenomas or adenocarcinomas, but there were a few hemangiosarcomas and neurosarcomas. There is a possibility that nitrosocimetidine could be formed by interaction of cimetidine with nitrite in the stomach, but the carcinogenic risk arising would be very small based on the negative result of this study.

Carcinogenesis in rats by some hydroxylated acyclic nitrosamines.

A comparison was made of the carcinogenic effectiveness of five hydroxylated nitrosodialkylamines given to female F344 rats in drinking water. Nitroso-2,3-dihydroxypropyl-2-hydroxypropylamine was the most potent carcinogen among those examined, and induced almost exclusively tumors of the upper gastrointestinal tract. Considerably less potent was nitrosobis-(2-hydroxypropyl)amine, which also induced mainly tumors of the esophagus, although several animals also had tumors of the nasal cavity. Nitrosodiethanolamine was weaker again, and induced a high incidence of hepatocellular carcinomas. Nitroso-2-hydroxypropylethanolamine, which can be considered a hybrid of nitrosodiethanolamine, and the bis-hydroxypropyl compound, induced both esophageal tumors and hepatocellular carcinomas, together with some liver angiosarcomas; it appeared to lie in potency between the two symmetrical compounds. In contrast, nitroso-2,3-dihydroxypropylethanolamine was a very weak carcinogen, having little life-shortening effect; it induced hepatocellular carcinomas in only a small number of animals, together with some neoplastic nodules.

Carcinogenesis in rats by nitrosodimethylamine and other nitrosomethylalkylamines at low doses.

Four nitrosomethylalkylamines were given to F344 rats in drinking water at concentrations of 0.22 mM or less. The total doses delivered to each animal were 0.5 and 0.2 mmol of nitrosodimethylamine (NDMA), 0.6 mmol of nitrosomethyl-2-oxopropylamine (NMOP) and nitrosomethyl-2-hydroxy-propylamine (NMHP) and 0.9 mmol of nitrosomethyl-2,3-dihydroxypropylamine (NMDHP). NDMA induced liver neoplasms in most of the animals, including 35% with hemangiosarcomas as well as hepatocellular tumors at the higher dose, but only hepatocellular tumors at the lower dose and the latter group of rats survived longer. NMOP induced a high incidence of esophageal tumors and NMHP induced a high incidence of both esophageal and nasal cavity tumors. NMDHP was the least potent of the 4 carcinogens, and induced lung tumors, neoplastic nodules in the liver, a few esophageal tumors and a few nasal cavity tumors, but after a long induction time.

Dose-response study with N-nitrosodiethanolamine in F344 rats.

A dose-response study of the carcinogenicity of N-nitrosodiethanolamine was conducted in F344 rats. The nitrosamine was administered in drinking-water at a controlled rate (20 ml/rat/day, 5 days/wk) to groups of 16 or 20 rats of each sex. The doses administered were as follows: 2500 mg/litre drinking-water for 45-wk, 1000 mg/litre for 50 wk, 400 mg/litre for 50 wk and 400 mg/litre for 75 wk. Almost all of the treated animals died with hepatocellular carcinomas, of which 20-45% metastasized in each group. The females in each treatment group tended to die earlier, because they received a higher dose per unit body weight, but for each sex there was a dose-related decrease in survival as the carcinogen dose increased. There was a considerable incidence of tumours of the nasal cavity. The incidence of these tumours tended to be higher in males than in females and might be sex- or lifespan-related. A number of rats had cholangiocarcinomas in the liver and there were a few kidney tumours and tumours of the oesophagus in animals given the higher doses. None of these tumours was seen in the untreated controls of either sex, almost all of which outlived the treated animals. It is concluded that N-nitrosodiethanolamine is a carcinogen of considerable potency in rats.

Carcinogenesis in F-344 rats by nitrosobis(2-oxopropyl)amine and related compounds administered in drinking water.

Three asymmetric nitrosamines related to nitrosobis-(2-oxopropyl)-amine (BOP) were given to female F344 rats in drinking water to assess the significance of other alkyl groups on the carcinogenic expression by the 2-oxopropyl group. Nitroso-oxopropylethanolamine (OPE) was weakly carcinogenic, leading to little life-shortening and to induction of tumors (most of them liver neoplasms) in less than half of the treated animals. BOP under these conditions induced a high incidence of hepatocellular carcinomas and hemangiosarcomas of the liver together with lung adenomas in most animals. At the same dose rate nitrosohydroxypropyl-oxopropylamine (HPOP) induced hepatocellular carcinomas, lung carcinomas, and carcinomas of the esophagus with a high incidence; life-shortening was greater with HPOP than with BOP. At a higher dose rate HPOP again induced a high incidence of esophageal carcinomas, and of liver neoplasms, but more animals had hemangiosarcomas than hepatocellular carcinomas. Nitrosodihydroxypropyl-oxopropylamine (DHPOP) increased the mortality rate due to tumors by much more than the other three compounds, but induced mainly tumors of the upper gastrointestinal tract and no neoplasms in the liver. These results do not support the concept that BOP acts through reduction to HPOP, but suggest rather that the nature of the substituents other than 2-oxopropyl in the analogs of BOP has a profound influence on the potency and organ-specificity of the carcinogen. It is probable that pharmacokinetics and the specificity of activation of the particular molecular structures play an important role.

Carcinogenicity and toxicity of 2,4-dichlorophenoxy-acetic acid.

2,4-Dichlorophenoxyacetic acid (2,4-D) is carcinogenic in male and female rats and probably also in mice. Male and female rats ingesting 2,4-D developed increased incidences of malignant neoplasms. Lymphosarcomas were increased in rats of both sexes, and neoplasms of the mammary gland in female rats. Male rats also had carcinomas of the endocrine organs. 2,4-D isooctyl ester was carcinogenic for the lymphoreticular system in female mice. 2,4-D and 2,4-dichlorophenol also were promoters of neoplasms of the skin in mice. Male mice given 2,4-D isopropyl ester developed an increased incidence of neoplasms of the lung. 2,4-D also is mutagenic and teratogenic in animals and causes poisoning in animals and human beings.