Effect of partial hepatectomy on the response of rat liver to aflatoxin B1.

The effect of partial hepatectomy (PH) on aflatoxin B1 (AFB1) action in rat liver has been examined using adult male Fischer 344 rats. The elevated levels of hepatic DNA synthesis, present 26 hr after PH (> 15 times the control level) and 33 hr after PH, are rapidly inhibited by i.p. administration of AFB1. The percentage inhibitions are greater than those observed using intact or sham-operated animals. However, it was possible to demonstrate elevation of DNA synthesis in PH rats treated with AFB1. Rats 2 hr after being treated with AFB1 (0.075 mg/kg) at 24 and 31 hr after PH exhibited levels of DNA synthesis 380 to 400% of those present in sham-operated uninjected controls. After 62 weeks, the livers of the PH rats treated with AFB1 displayed no hepatocellular carcinoma. There was present, however, an increased incidence of lesions believed to be preneoplastic. The differences between the long-term effects of AFB1 and other hepatocarcinogens on the livers of PH rats are discussed in terms of their relative capacities and modes of action in inhibiting DNA synthesis.

Carcinogenicity study with technical-grade dichlorodiphenyltrichloroethane and 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene in hamsters.

Studies conducted by others have revealed that 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE), a proximal metabolite of dichlorodiphenyltrichloroethane (DDT), is a strong hepatocellular carcinogen in mice. Since hamsters appear to be resistant to tumor induction by DDT, we wanted to investigate whether DDE has any neoplastic effect in this species. DDE (99% pure) was mixed into the diet at doses of 500 or 1000 ppm and given to groups of male and female Syrian golden hamsters for life. Another group of animals received a diet containing 1000 ppm technical-grade DDT, and a further group served as control. Groups contained a minimum of 40 hamsters per sex. The tested compounds had no effect on the incidence of tumors at all sites, compared to controls. A specific finding in animals exposed to DDE was the appearance of hepatocellular tumors late in life. They were classified as neoplastic nodules, and the incidence was 15% in females and 47% in males of the 500-ppm DDE dose groups and 21% in females and 33% in males of the 1000-ppm DDE dose groups. None of the untreated or DDT-treated animals had these tumors. Eight animals treated with 1000 ppm DDE and four of those treated with DDT had hyperplastic foci of the liver. In addition, adrenocortical adenomas, spontaneous to Syrian golden hamsters, were more frequent in DDE- and DDT-treated animals than in control animals. These results showing that DDE, but not its parental compound, induces liver cell tumors in hamsters emphasize the importance of this metabolite as a proximal carcinogen of DDT.

Taxing for stormwater drainage systems.

This article evaluates the possibility of creating a tax for urban drainage in order to make the system self-financing. Average costs of implementation and maintenance of the services were used to individualize the charges and definition of the tax. The conventional drainage system was evaluated along with a source control alternative, water detention in tanks on the lot. The magnitude of the values being charged varies in function of the impermeable surface and the density of the urban area. Preserving creeks in natural conditions and using source control approach, are all options with the advantages of lower investment and smaller burden for the users.

Carcinogenicity study of the pesticide fenvalerate in mice.

Fenvalerate is a widely used pesticide, which has been shown recently to be nonmutagenic. We studied its carcinogenicity in a long-term experiment in inbred C57Bl/6 mice given 0, 40 and 80 mg/kg body weight fenvalerate (99% pure) by gavage on 5 days/week for 104 weeks. Survival was decreased especially among females receiving the high dose. Exposure to fenvalerate resulted in a slight increase in the incidence of liver-cell tumours over that in controls only in male mice receiving the high dose. No significant difference in the incidence of other types of tumours was observed in treated groups when compared with controls. Fenvalerate-induced microgranulomas occurred concomitantly in the liver, spleen and lymph nodes of male and female mice, but their overall incidence did not increase with dose. In a separate experiment, groups of SJL/ola female mice were administered two different samples of fenvalerate (92% and 99% pure) once per week for 12 weeks. In animals that received 92% pure compound, the latent period for induction of lymphomas was shortened and their incidence increased, when compared with the group receiving 99% pure fenvalerate and with controls.

Carcinogenicity of some pyrrolic pyrrolizidine alkaloid metabolites and analogues.

Repeated topical doses of dehydromonocrotaline, a putative primary toxic metabolite of the pyrrolizidine alkaloid monocrotaline, followed by repeated treatments with croton oil, produced malignant tumours of the skin in LACA mice. A chemically similar alkylating agent, 2,3-bistrimethylace-toxymethyl-1-methylpyrrole, was carcinogenic without use of a promoter, confirming a preliminary report. Its high activity was due to the intact ester, not to its hydrolysis products. Dehydroretronecine (DHR), a less reactive secondary metabolite of monocrotaline, was also carcinogenic to LACA mouse skin, but it was less active than previously reported in experiments with another strain. Similar carcinogenicity was shown by the synthetic 2,3-bishydroxymethyl-1-methylpyrrole, but not by 2,3-bis-hydroxymethyl-5-methyl-1-phenylpyrrole, which has a high level of antimitotic activity.

Liver-cell tumours in rats fed hexachlorobenzene.

All animals in a group of female Agus rats fed 100 ppm of hexachlorobenzene (HCB) in their diet for up to 90 weeks developed multiple liver-cell tumours whereas none were seen in control rats. There was no evidence of skin lesions or nervous symptoms usually seen with higher doses of HCB. A high incidence of liver-cell tumours was also seen with MRC Wistar female rats fed HCB for 75 weeks.

The inhibitory effects of ethoxyquin on the carcinogenic action of aflatoxin B1 in rats.

Ethoxyquin (EQ), a widely used antioxidant, inhibits the carcinogenic effects of polycyclic aromatic hydrocarbons. The aim of the present study was to determine whether EQ modifies the hepatocarcinogenic effects of aflatoxin B1 (AFB1) in rats. Both compounds were administered in the diet. Rats were fed either EQ for 2 weeks and then AFB1 for 6 weeks, EQ and AFB1 simultaneously or EQ following the cessation of AFB1 treatment. The results indicate that EQ can inhibit the hepatocarcinogenic effects of AFB1 and that the most effective inhibition is obtained when EQ and AFB1 are given simultaneously.

A carcinogenicity study of styrene-7,8-oxide in rats.

Styrene-7,8-oxide (200 mg/kg body wt) was given orally to female BDIV rats on 17th day of pregnancy. Their offspring received 96 weekly doses of styrene oxide (100-150 mg/kg body wt). Following the continuous administration of styrene oxide, an increased incidence, statistically significant, of forestomach tumours was observed in rats of both sexes. The incidence of tumours occurring at other sites was similar in treated and control animals. The present results show that styrene oxide is a direct-acting carcinogen producing benign and malignant tumours of the forestomach.

Carcinogenic effects induced in Wistar rats by combined treatment with technical-grade dichlorodiphenyltrichloroethane and sodium phenobarbital.

A group of 38 female and 39 male outbred Wistar rats were treated with 500 ppm technical-grade dichlorodiphenyltrichloroethane (DDT) in the diet and 500 ppm sodium phenobarbital (PB) dissolved in drinking-water for lifespan. Twenty-three of 29 (79.3%) female and 13/28 (46.4%) male surviving animals developed primary tumours which were detected starting at 65 weeks of age. Most of the liver tumours were neoplastic nodules, but well-differentiated hepatocellular carcinomas were also found in 3 males and 5 females of the exposed animals. No liver-cell tumour was observed in 59 rats exposed to a diet containing 3% olive oil.

Carcinogenicity studies with deltamethrin in mice and rats.

The pesticide Deltamethrin, a synthetic pyrethroid, was studied for carcinogenicity in long-term experiments in mice and rats. Mice were given Deltamethrin by gavage in arachis oil at 0, 1, 4 or 8 mg/kg body wt for 2 years. A group of untreated controls was also available. Rats received 0, 3 or 6 mg/kg body wt. Deltamethrin in arachis oil for 2 years. In mice, an increased incidence of lymphomas was observed in the groups receiving 1 and 4 mg/kg body wt., but not in the group treated with 8 mg/kg body wt. Deltamethrin. In rats, an increased incidence of thyroid tumours was noted, but, no clear dose-response relationship was shown. Deltamethrin does not appear to be carcinogenic in mice or rats, but further studies are needed on the group of compounds to which this substance belongs.

A carcinogenicity study of pesticide dieldrin in hamsters.

Syrian golden hamsters were fed for their lifespan a diet containing 0, 20, 60 and 180 parts per million (ppm) Dieldrin. Tumour-bearing animals totaled 13% among control females and ranged between 3-15% in treated females. Eight per cent of male controls had tumours and between 16-23% of treated males. Incidences of endocrine organ tumours were comparable in all groups. A hepatoma was found in 1 female and 1 male led 180 ppm Dieldrin. The present results show that hamsters tolerate higher doses of Dieldrin than do mice and rats. No significant tumour incidence was observed in treated versus control Syrian golden hamsters.

Influence of ethyl alcohol on the carcinogenic activity of N-nitrosonornicotine.

The present paper describes an experiment designed to investigate the effects of the combined action of different doses of N-nitrosonornicotine (NNN) and ethyl alcohol in BDVI rats. Dose-response relationships of NNN was clearly shown. Ethyl alcohol did not appear to increase, to a great degree, the tumour incidence of NNN. However, ethyl alcohol did shorten the tumour latency period in the groups given NNN in alcoholic solution. In addition, an infiltration of the olfactory tumours to the brain was observed more frequently in both males and females given the high dose of NNN in alcoholic solution.

Influence of hepatic tumors caused by diethylnitrosamine on hexachlorobenzene-induced porphyria in rats.

The response of female BDVI rats bearing diethylnitrosamine(DENA)-induced hepatic tumors to the porphyrinogenic action of hexachlorobenzene (HCB) was studied. (1) The heme pathway operates in these tumors but they were less affected by HCB than the liver. (2) Tumors did not accumulate porphyrins although the surrounding liver accumulated more porphyrins than livers treated with HCB. (3) DENA/HCB livers which developed a well defined tumor showed slightly less porphyrinogen carboxylyase inhibition and delta-aminolaevulinate synthase induction than HCB rats. (4) The results of the present work suggest that endogenously formed porphyrins would be unable to be accumulated by DENA-induced tumors when the tumoral development precedes the onset of the porphyria.

Dengue 3 virus transmission in Africa.

The first known transmission of dengue 3 virus in Africa was documented by virus isolation during an epidemic of dengue-like illness in Pemba, Mozambique, in late 1984 and early 1985. Dengue 3 virus was the only serotype isolated. Most patients appeared to be experiencing secondary flavivirus infections, but whether this was the result of previous dengue, yellow fever, or other flavivirus infection is not known. Two cases of hemorrhagic disease with shock and death were associated with the epidemic.

Carcinogenicity study of the pesticide maleic hydrazide in mice.

The carcinogenicity of the pesticide maleic hydrazide (MH) was studied in C57BL/B6 mice. After subcutaneous (s.c.) administration no significant increase in the incidence of liver-cell tumours was seen over that in solvent-treated controls, and although a statistically significant difference in the incidence of liver-cell tumours was observed between treated and untreated males, this was considered biologically inadequate as evidence of carcinogenic effect. When MH was administered orally, no significant increase in the incidence of liver-cell tumours was seen. These results partially confirm the negative finding of a recent parallel study in rats [1].

A difference between two strains of rats in their liver non-haem iron content and in their response to the porphyrogenic effect of hexachlorobenzene.

Female Agus rats developed hepatic porphyria at a much faster rate than female Porton-Wistar rats when fed a diet containing 0.01% of hexachlorobenzene (HCB). They also showed a greater inhibition of liver uroporphyrinogen decarboxylase [EC 4.1.1.37] activity and a marked stimulation of 5-aminolaevulinate synthetase [EC 2.3.1.37]. The difference between the two strains could not be correlated with differences in the liver concentrations of HCB. However, control Agus rats were found to possess significantly higher levels of total non-haem iron in their livers than the Porton animals. This was particularly apparent after 24 h of starvation and is further evidence for the involvement of iron in the pathogenesis of HCB-induced porphyria. The posterior lobes of the livers from the Agus rats given HCB became porphyric more slowly than the remainder with less severe inhibition of uroporphyrinogen decarboxylase. In contrast to their increased susceptibility to HCB, the Agus rats were less susceptible to another prophyrogenic agent, 3,5-diethoxycarbonyl-1,4-dihydrocollidine.

Characterization and identification of 6 mutagens in opium pyrolysates implicated in oesophageal cancer in Iran.

Previous epidemiological studies have indicated an association between the ingestion of opium pyrolysates, dietary deficiencies, and a high incidence of oesophageal cancer in subjects in north-east Iran. Laboratory studies have shown that pyrolysates of opium and particularly of morphine, a major opium alkaloid, are highly mutagenic in bacteria and induce sister-chromatid exchanges in mammalian cells after metabolic activation. We now report the ability of these pyrolysates to transform Syrian hamster embryo cells in culture and present some evidence for their carcinogenicity in mice and hamsters following topical, subcutaneous, intratracheal and intragastric administration. 6 of the most abundant mutagenic compounds present in morphine pyrolysate were isolated and purified by high-performance liquid chromatography and characterized by gas chromatography/mass spectrometry and 1H-Fourier transform nuclear magnetic resonance spectroscopy. These hitherto unknown compounds, all containing a hydroxy-phenanthrene moiety, were identified as: 3-methyl-3H-naphth[1,2-e]indol-10-ol; 1,2-dihydro-3-methyl-3H-naphth[1,2-e]indol-10-ol; 6-methylaminophenanthren-3-ol; 2-methylphenanthro[3,4-d] [1,3]oxazol-10-ol; 2,3-dimethyl-3H-phenanthro[3,4-d]imidazol-10-ol and 2-methyl-3H-phenanthro[3,4-d]imidazol-10-ol. Mutagenicity in Salmonella typhimurium TA98 of these compounds increased in the order listed, the last compound being 35 times more active than benzo[a]pyrene. The mechanisms, by which these mutagens are formed and metabolically activated are discussed.

Testicular mesotheliomas in rats exposed to N-2-fluorenylacetamide (FAA).

The incidence of testicular mesotheliomas after exposure to the carcinogen N-2-fluorenylacetamide (FAA) was studied in Fischer 344 rats. The animals were fed a carcinogenic diet (containing 0.06% FAA) for 4 weeks and then a control diet for 1 week. This schedule was carried out for 3 complete cycles (12 weeks). A smaller group of rats was treated with FAA for 1 complete cycle only (4 weeks). One group of untreated controls was also available. The surviving rats were sacrificed at 59 weeks of age. The administration of FAA for 3 complete cycles resulted in a high incidence of liver, testis and Zymbal-gland tumors. The testicular tumours were mesotheliomas and occurred in 9/25 rats. No such tumour was observed in animals treated for 1 cycle only or in untreated controls. The high incidence of testicular mesotheliomas, a rare type of tumour in this and other rat strains, suggests an association with the treatment. The present experimental model may be useful in elucidating the mechanisms of the induction of mesothelial tumours of the testis by chemical carcinogens.

Effects of some pyrrolic and dihydropyrrolizine esters on mouse skin: a preliminary study.

Groups of male BALB/c mice were given 33 to 35 treatments during 52 to 54 weeks with 5 ester alkylating agents. Two of these (I and II) were potential metabolites of carcinogenic pyrrolizidine alkaloids; the others (III-V) were chemically similar synthetic compounds. Each dose of 0.5 or 1.0 mumol, in acetone, was applied to the shaved dorsal skin. A control group received acetone. Three skin tumours and 2 preneoplastic lesions were found among 9 mice receiving the compound IV, the agent giving the slowest chemical alkylation reactions. No skin tumours were seen in the other groups. The results suggest that the relationship between carcinogenic potential and alkylating reactivity in this series of compounds should be further investigated.

Carcinogenicity study of 3-(5-nitro-2-furyl)-imidazo(1,2-alpha) pyridine in mice and rats.

3-(5-nitro-2-furyl)-imidazo(1,2-alpha) pyridine was tested for carcinogenicity by long-term administration in the diet to CTM mice at 0.1, 0.2 and 0.4% dose levels and to Wistar rats at 0.2 and 0.4% dose levels, and by short-term intraperitoneal injections to suckling BALB/c mice. The compound was a strong carcinogen. In CTM mice it induced carcinomas of the esophagus and forestomach at all dose levels and thymic lymphosarcomas at the two highest doses. In male and female rats, esophagus and forestomach papillomas were observed at all dose levels, whereas esophagus and forestomach carcinomas and kidney tumors were observed only at the high dose. In female rats, an increased incidence of mammary tumors was seen at the high dose. The treatment of BALB/c suckling mice by intraperitoneal injections did not induce a clear carcinogenic response.