Implementation of the INTERGROWTH-21st Project in India.

The South Asian site in the INTERGROWTH-21(st) Project was the city of Nagpur, in Maharashtra State, India, with approximately 4500 births per year among the target population with middle to high socio-economic status. These deliveries are mainly concentrated in 20 small private hospitals, most of which are in the city centre. The sample for the Newborn Cross-Sectional Study (NCSS) was drawn from ten of these hospitals, covering 76% of the target low-risk pregnant population. The Fetal Growth Longitudinal Study (FGLS) sample was recruited from the largest of these institutions, Ketkar Hospital, as well as several ancillary antenatal care clinics. Special activities to encourage participation and raise awareness of the study at this site included translating patient information leaflets into local languages and securing local media interest. Among the unique challenges of the Indian site was the coordination of the large number of hospitals involved in NCSS, a task that required careful planning and organisation by the field teams.

Tumors of the heart and stomach induced in European hamsters by intravenous administration of N-methyl-N-nitrosourea.

One hundred twenty captured European hamsters (Cricetus cricetus L.) were inoculated iv with 1/5, 1/10, or 1/20 the median lethal dose of N-methyl-N-nitrosourea (MNU) once weekly for 18 weeks. MNU induced mainly sarcomas in the heart and squamous cell carcinomas and sarcomas in the stomach. The highest incidence of such tumors was demonstrated by the lowest-dosage group. They were more frequent in males than in females. The effect of MNU was also localized at the site of administration and resulted in squamous cell carcinomas of the oral cavity. The possible fibroblastic or neurogenic origin of the sarcomas was explored.

Tumorigenicity in vivo and induction of mutagenesis and DNA repair in vitro by aclacinomycin A and marcellomycin: structure-activity relationship and predictive value of short-term tests.

The genotoxicity of two new anthracycline antitumor antibiotics, aclacinomycin A and marcellomycin, which are potent cytostatic agents similar to Adriamycin and daunomycin, was investigated in various assays. In contrast to Adriamycin and daunomycin, both agents were devoid of mutagenic activity in the Salmonella-microsome assay as well as in a mammalian cell assay using V79 Chinese hamster cells. In primary rat hepatocytes, aclacinomycin A was active in inducing unscheduled DNA synthesis, whereas marcellomycin was not. After single i.v. doses of the 10% lethal dose, marcellomycin (15 mg/kg) did induce mammary tumors in female Sprague-Dawley rats, whereas aclacinomycin A (15 mg/kg) proved to be nontumorigenic. In conjunction with previous data, these results indicate that: (a) cytostatic and genotoxic properties of anthracyclines can be clearly separated; (b) alkylation of the primary amino group of their sugar moieties can abolish or greatly reduce mutagenic activity; and (c) poor correlations in some instances must be anticipated between in vivo tumorigenicity and activity in in vitro short-term tests as well as among different short-term tests.

Carcinogenic effect of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in European hamsters.

Laboratory-bred European hamsters received intragastric administrations of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) once weekly for 20 weeks. The animals showed mainly squamous cell papillomas and carcinomas of the fore-stomach. The tumour incidence was higher in males (80%) than in females (30%). The average tumour latency was comparatively short (25 weeks).

The carcinogenic effect of bis-(2-oxopropyl)-nitrosamine on Sprague-Dawley rats.

Sprague-Dawley rats received subcutaneous injections of bis-2-oxopropyl)-nitrosamine (BOPN) once weekly for life. The animals developed mainly papillomas and squamous cell carcinomas of the nasal cavity, follicle cell carcinomas of the thyroid gland and papillomas and transitional cell carcinomas of renal pelvis, ureter and urinary bladder. The tumour incidence was 100% in all the 3 treated groups. Survival time, tumour latency and multiplicity showed dose dependency.

The carcinogenic effect of 1,1-diethyl-3-methyl-3-nitrosourea in Syrian golden hamsters.

1,1-Diethyl-3-methyl-3-nitrosourea (Et2MNU) was subcutaneously injected in Syrian golden hamsters once weekly for 52 weeks. The animals developed mainly papillomas and squamous cell carcinomas of the nasal cavity and forestomach and hemangioendotheliomas of the spleen. Although survival time and tumour latency showed dose-dependency, tumour incidence did not.

Investigations on the carcinogenic burden by air pollution in man. Intratracheal instillation studies with benzo[a]pyrene in a mixture of Tris buffer and saline in Syrian golden hamsters.

Syrian golden hamster received intratracheal instillations of 0.125, 0.25, 0.50 or 1.0 mg benzo[a]pyrene (B[A]P) in a mixture of Tris buffer and physiological saline once weekly for life. Papillary polyps, squamous cell papillomas and carcinomas developed in both the larynx and trachea. In addition, bronchiogenic adenomas, adenocarcinomas and squamous cell carcinomas were induced in the lung. The highest incidence of respiratory tract tumours (83%) was seen in hamsters receiving 0.25 mg B[a]P. The results of these investigations are statistically evaluated and discussed.

Investigations on the carcinogenic burden by air pollution in man. Intratracheal instillation studies with benzo(a)pyrene in bovine serum albumin in Syrian hamsters.

The chronic effect of benzo(a)pyrene (B(a)P) administered intratracheally in bovine serum albumin was studied in Syrian golden hamsters. Dose levels of 0.1 mg, 0.33 mg and 1.0 mg of B(a)P induced papillomas and carcinomas of the trachea, stem bronchi and bronchioles. In addition to such tumours, the mucosa of the respiratory tract revealed a variety of atypical epithelial alterations. Although survival time exhibited a dose-dependency, tumour incidence did not. The incidence of respiratory tract tumours was higher in female hamsters than in males. The results of these investigations are statistically evaluated.

The carcinogenic effect of nitrosomethyldodecylamine in European hamsters.

Laboratory-bred European hamsters received nitrosomethyldodecylamine (NMDA) subcutaneously in olive oil once weekly for life. The animals showed mainly mucoepidermoid carcinomas of the lung, carcinomas of the urinary bladder and squamous cell carcinomas and sarcomas at the injection site. The tumour incidence was 90% in males and 70% in females, while the average tumour latency was 32 +/- 6 weeks for both sexes. Males had an average survival time of 29 +/- 17 weeks and females 24 +/- 19 weeks.

Comparative study of the carcinogenic effect of BHP and BAP on NMRI mice.

The carcinogenic effects of N-bis(2-hydroxypropyl)nitrosamine (BHP) and N-bis(2-acetoxypropyl)nitrosamine (BAP) were studied in NMRI mice treated subcutaneously once weekly for life. The highest incidences of tumours were found in the lung (73-100%), in the liver (67-100%) and nasal cavity (0-33%) in both sexes of mice. Data were similar in animals treated with BHP or BAP. These tumours were adenomas, adenocarcinomas and squamous cell carcinomas (nasal cavity and lung) as well as hemangio-endotheliomas and hemangioendotheliosarcomas (liver). The lung tumours were found in the control mice (27-50%) 20 weeks later than in the experimental animals. The rate of malignant neoplasms rose with increasing survival and decreasing dose levels.

The carcinogenic effect of dimethylnitrosamine in laboratory bred European hamsters (Cricetus cricetus).

The carcinogenic effect of dimethylnitrosamine (DMN) s.c. injected at two different dose levels was studied in laboratory bred European hamsters (EH) and data compared to findings for captured EH. Malignant haemangioendotheliomas of the liver and kidney, hepatocellular carcinomas and cholangiocarcinomas were induced. In contrast to the results obtained with wild EH, a large number of the laboratory bred females additionally developed ovarian granulosa cell tumors.

Carcinogenic effect of nitrosomorpholine administered in the drinking water to Syrian golden hamsters.

The long term carcinogenic effect of nitrosomorpholine (NM) was tested in Syrian golden hamsters (Mesocricetus auratus W.). Groups of 30 females and 30 males were given 0.010%, 0.005% and 0.001% NM in their drinking water. The animals developed neoplasms in the larynx, and trachea (papillary polyps, papillomas and epidermoid carcinomas) and in the liver (hepatocellular adenomas and carcinomas). In addition to these, cholangiocellular and endothelial liver tumours were observed. The overall tumour frequency was dose dependent.

The carcinogenic effect of nitrosopiperidine administered in the drinking water of Syrian golden hamsters.

Syrian golden hamsters (Mesocricetus auratus W.) were used to test the long-term carcinogenic effect of nitrosopiperidine (NP). Groups of 30 females and 30 males were given 0.05%, 0.025% and 0.006% NP in their drinking water for life. The animals developed neoplasms in the larynx, pharynx, trachea and forestomach (papillary polyps, papillomas and epidermoid carcinomas) and in the liver (hepatocellular adenomas, carcinomas). In addition, cholangiocellular and endothelial liver tumours and colon adenocarcinomas were observed. The overall tumour frequency was dose-dependent and higher in males than in females.

Implantation of cigarette smoke condensate in the lungs of Syrian golden hamsters.

Different doses of benzo(a)pyrene, cigarette smoke condensate (CSC) and its nitromethane fraction (NMF), in wax pellets, were directly implanted into the lungs of Syrian golden hamsters. Pleomorphic sarcomas were induced in the B(a)P treated animals. Several epithelial proliferative lesions and a few bronchiogenic adenomas were induced in CSC and NMF treated hamsters. A species-specific effect has been observed in this investigation.

Carcinogenic effect of low doses of nitrosopyrrolidine administered in drinking water to Syrian golden hamsters.

Three groups of Syrian golden hamsters each consisting of 30 males and 30 females were given three different doses of nitrosopyrrolidine in their drinking water for the duration of their lives. The animals mainly showed hepatocellular neoplasms. Males were more affected than females and tumor incidence was found to be dose-dependent. No liver tumors were seen in females that received the lowest dose.

A chronic study of praziquantel in Syrian golden hamsters and Sprague-Dawley rats.

Groups of Syrian golden hamsters and Sprague-Dawley rats received 100 mg or 250 mg praziquantel/kg body weight, intragastrically by oral gavage once weekly for 80 weeks and 104 weeks, respectively. In both hamsters and rats the observed differences in tumour incidence, latency and multiplicity revealed no positive dose response effect. Tumours observed corresponded in their origin and morphology to those which develop spontaneously in these species. Haematological and clinico-chemical values were normal. Whereas the average survival time was slightly shortened in rats, female hamsters showed reduced weight gains in the high dose level groups, although water intake and food consumption were increased.

Pathological alterations in Syrian golden hamster lungs after passive exposure to cigarette smoke.

The effects of 2 types of research cigarettes, differing in their total smoke delivery and condensate, were examined as to their histopathological effects of Syrian golden hamster lungs. The animals were passively exposed to the total smoke of the cigarettes once a day, 5 days/week for 1 year. Experimental and control animals were killed one day after termination of exposure. Varying effects on the macrophages of pulmonary alveolar tissue were observed. Infiltration of lung tissue by "Brown cells" was a common pathological alteration. Qualitative and quantitative differences existed between the two cigarette groups with respect to the occurrence of such "Brown cell" clumps. The response of the lung tissue to smoke exposure would appear to be dependent upon the amount of mainstream total particulate matter (TPM), the amount of condensate, the time exposed and the number of cigarettes.

The influence of caffeine on tumour incidence in Sprague-Dawley rats.

Food-grade natural caffeine was given in the drinking-water (available ad lib.) to barrier-maintained specified-pathogen free Sprague-Dawley rats for 2 yr. Groups of 50 animals per sex received levels of 200, 430, 930 and 2000 mg caffeine/litre, while two control groups, each of 50 animals per sex, received plain water. No unusual tumours or sites of origin for neoplastic growth were found in any animal receiving caffeine. Neoplasms found in various organs showed incidences not exceeding those seen in controls. Thus, exposure to caffeine for 2 yr did not enhance or induce neoplasia in the Sprague-Dawley rats.