Lung Cancer Mortality Trends in a Brazilian City with a Long History of Asbestos Consumption.

There are scarce epidemiological studies on lung cancer mortality in areas exposed to asbestos in developing countries. We compared the rates and trends in mortality from lung cancer between 1980 and 2016 in a municipality that made extensive use of asbestos, Osasco, with rates from a referent municipality with lower asbestos exposure and with the rates for the State of São Paulo. We retrieved death records for cases of lung cancer (ICD-9 C162) (ICD-10 C33 C34) from 1980 to 2016 in adults aged 60 years and older. The join point regression and age-period-cohort models were fitted to the data. Among men, there was an increasing trend in lung cancer mortality in Osasco of 0.7% (CI: 0.1; 1.3) in contrast to a mean annual decrease for Sorocaba of -1.5% (CI: -2.4; -0.6) and a stable average trend for São Paulo of -0.1 (IC: -0.3; 0.1). Similar increasing trends were seen in women. The age-period-cohort model showed an increase in the risk of death from 1996 in Osasco and a reduction for Sorocaba and São Paulo State during the same period. Our results point to a need for a special monitoring regarding lung cancer incidence and mortality in areas with higher asbestos exposure.

Neoplastic potential of rat tracheal epithelial cell lines induced by 1-nitropyrene and dibenzo(a,i)pyrene.

Our previous study showed that both 1-nitropyrene (1-NP) and dibenzo(a,i)pyrene (DBP) induced enhanced growth variants (EGVs) in primary cultures of rat tracheal epithelial (RTE) cells exposed in vivo. Cell lines were established from some of the EGVs. Further studies, using anchorage-independent growth in soft agar and tumorigenicity in athymic nude mice, were performed to determine the neoplastic potential of EGVs induced by 1-NP and DBP. Results show that three of five from DBP- and five of five from 1-NP-induced cell lines displayed anchorage-independent growth. The colony forming efficiency (CFE) from DBP-induced cell lines was 0.067 per thousand and CFE from 1-NP-induced cell lines was 0.151 per thousand. There is a significant difference between the two CFEs (mu = 12.08, P<0. 01). Two of five DBP- and five of five 1-NP-induced cell lines produced squamous cell carcinomas (SCC) in nude mice. The rate of tumorigenicity counted by injected sites was 20% (6/30) for DBP-induced cell lines and 57% (17/30) for 1-NP-induced cell lines. There is a significant difference between the results of tumorigenicity from the cell lines induced by the two different compounds (chi(2)=8.53, P<0.01). Neither of the two cell lines from spontaneously developed foci grew in soft agar or produced SCC in nude mice. It seems that the neoplastic potential of transformed RTE cells induced by 1-NP was higher than that of DBP.

[Treatment of malignant tracheo-bronchial tumors. The lost generation]. / Le traitement des tumeurs malignes trachéo-bronchiques. La génération perdue.

250,000 new cases of endobronchial carcinoma are diagnosed each year in France. Risk factors are well known: 80-90% are related to smoking. With an overall 5-year survival rate of only 10%, preventive measures must be our number one priority, especially for young patients, but are their parents a lost generation? Curative therapy has made some progress, particularly with surgery, although only 20% of the patients are potential candidates at diagnosis, and chemotherapy, sometimes in combination with radiotherapy for nonoperable patients. Interesting results have also been achieved with gene therapy where direct intratumoral injection of cytokine genes on recombinant adenoviruses has provided response in certain cases. Interventional bronchoendoscopy provides another promising option as demonstrated by Jeanfaivre and Tuchais who report their results with electrotherapy in this issue of La Presse Médicale.

Increased risk of cancer in the descendants of Syrian hamsters exposed prenatally to diethylnitrosamine (DEN).

Transmission of site-specific tumorigenicity (papillomas in larynx and trachea) of diethylnitrosamine (DEN) to the 2 subsequent generations (F1 and F2) was studied using an outbred strain (Han:AURA) of pregnant Syrian golden hamsters (P generation), which were treated i.p. with 10 mg/kg b.w. of DEN on day 12, 13 or 14 of gestation. Laryngotracheal papillomas were induced by DEN in the P and F1 generations only, while these tumours did not occur in the F2 generation. Spontaneously occurring tumours, including uterine adenocarcinomas, lymphomas, and laryngotracheal neuro-endocrine cell tumours, were observed at higher incidences among the F2 animals derived from the P generation hamsters treated with DEN only on day 13 or 14 of gestation. In the same animals, the ratio of malignant to benign tumours was considerably higher than in controls. In addition, the F2 hamsters derived from the DEN-treated P generation showed more frequent multiple organ involvement in tumorigenesis than the F2 controls. Several uncommon malignant tumours were detected in the F2 offspring, possibly the result of damage caused to germ cells by the prenatal exposure of F1 Syrian hamsters to DEN.

Induction of preneoplastic lesions by sodium arsenite in human fetal respiratory epithelia in organ culture.

The effects of sodium arsenite (As) and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) on epithelia of human fetal trachea and bronchiolar epithelia of human fetal lung were studied by using organ-cultured explants. In epithelium of human fetal trachea, 34 microM MNNG induced hyperplasia, metaplasia, and dysplasia; 1 microM As induced hyperplasia; and 3-9 microM As induced hyperplasia and cellular atypia. In glandular epithelium of human fetal trachea, 34 microM MNNG induced hyperplasia and metaplasia; 1 microM As did not induce obvious changes; and 3-9 microM As induced hyperplasia and epidermoid metaplasia with nuclear atypia. In bronchiolar epithelium of human fetal lung, the induction of dysplasia was observed for 1 microM As. Arsenic-induced preneoplastic lesions support the conclusion of epidemiological studies that arsenic is carcinogenic to human lung.

Effect of acute administration of N-nitrosopyrrolidine to male Syrian golden hamsters.

A protocol has been developed which decreases the time for administration of N-nitrosopyrrolidine (NPYR) to male Syrian golden hamsters from 25 weeks to a single i.p. injection. Animals were divided into five groups: group I received two 0.5-mmol doses on alternate days; group II was given three 0.33-mmol doses on alternate days; group III received a single dose of 0.5 mmol; group IV was given a single dose of 0.25 mmol and group V served as a control and received saline. Preneoplastic and neoplastic changes in the upper respiratory tract and liver were observed in all carcinogen-treated groups. The number of animals with laryngeal and tracheal tumors in the NPYR-treated groups was dose-dependent. Groups I and II, respectively, had 21 of 26 (81%) and 18 of 24 (75%) animals with either laryngeal or tracheal tumors. Groups III and IV showed 4 of 12 (33%) and 3 of 13 (23%) hamsters with these tumors. No laryngeal or tracheal tumors were observed in control animals. These results indicate that a single dose of NPYR is sufficient to induce respiratory tract tumors in Syrian golden hamsters.

Regulation of transformation frequency by exogenous and endogenous growth factors in rat tracheal epithelial cells.

The purpose of our studies was to re-evaluate the rat tracheal epithelial (RTE) transformation system and to identify critical variables that affect the development of enhanced growth variants (EGV). The enhanced growth variant colony, which is a preneoplastic cell variant, is the quantifiable transformation endpoint in RTE cultures. Using a standard protocol the frequency of EGV colony formation was shown to be inversely related to the number of clonogenic cells (CFU) seeded per dish in control cultures as well as in cultures treated with the transforming agent 6-nitrochrysene (6-NC). Experiments showed that the major mechanisms that underlie the CFU density-dependent inhibition of EGV colony formation are depletion of growth factors from and accumulation of autocrine TGF-beta in the media. Thus the cells themselves are creating the selection environment, which allows only the EGVs to survive. The effects of agents such as 6-NC, which increase the frequency of EGV colony formation, are to induce a cellular phenotype that is less susceptible to the selection environment. We showed that TGF-beta-neutralizing antibodies added to the selection media significantly increased EGV colony formation in control cultures but not in 6-NC-exposed cultures. In addition we demonstrated that the development of EGV colonies is much less susceptible to inhibition by (exogenous) TGF-beta in 6-NC-exposed than in control cultures. Thus spontaneous and 6-NC EGV colony formation are distinguishable based on TGF-beta sensitivity. To conduct quantitative cell transformation experiments with RTE cells it is essential that the number of surviving CFU per dish is the same in control and treated cultures. Under the conditions used in the studies described here, 350-500 CFU per culture was found to be the optimum CFU density. Besides 6-NC, agents that have been shown to increase EGV colony frequency under conditions similar to those described here are nitrosamines, NNK, nickel compounds and X-rays.

Invasive tumors derived from xenotransplanted, immortalized human cells after in vivo exposure to chemical carcinogens.

Several chemicals that are found in cigarette smoke or diesel oil engine exhausts, such as benzo[a]pyrene (B[a]P) and 1,6-dinitropyrene (DNP) are carcinogenic in experimental animal models. In the present study, we have exposed in vivo the xenotransplanted immortalized human bronchial epithelial cell line BEAS-2B to the ultimate carcinogen of B[a]P, benzo[a]pyrene diolepoxide (BPDE), to DNP or to the benzo[e]pyrene, a less active compound that has tumor-promoting abilities in mouse skin carcinogenesis bioassays. All three compounds were administered using slow-release beeswax pellets. After a 6 month exposure, BPDE produced two tumors in seven transplants, four tumors were seen in 10 transplants treated with DNP and one tumor was observed in five tracheal grafts exposed to B[a]P. All the neoplasms were well-differentiated invasive adenocarcinomas. Tracheal transplants exposed to beeswax without carcinogen did not show any evidence of neoplastic growth, and their luminal surfaces were lined by a single or double layer of cuboidal cells. All lines derived from the adenocarcinomas showed increased in vitro resistance to serum-induced terminal differentiation, gelatinolytic activity, s.c. tumorigenicity and invasive growth in an in vivo assay. When these cell lines were compared with previously described tumor cell lines derived from xenotransplants exposed to cigarette smoke condensate, it became clear that the latter exhibited a more aggressive invasive behavior. Nevertheless treatment with the three chemicals gave rise to tumor cell lines that exhibited a similar invasive behavior in vivo, and were able to penetrate early into the wall of the tracheal transplants in which they were seeded. These data indicate that this system based on xenotransplanted bronchial epithelial cells is a very relevant model to identify human carcinogens and to study mechanisms of bronchogenic cancer pathogenesis.

Failure of ozone and nitrogen dioxide to enhance lung tumor development in hamsters.

We tested the hypothesis that the two common oxidant air pollutants, ozone and nitrogen dioxide, modulate the development of respiratory tract tumors in Syrian golden hamsters. The animals received subcutaneous injections of the carcinogen diethylnitrosamine (20 mg/kg) twice a week while being exposed continuously to an atmosphere of 0.8 parts per million (ppm)* of ozone or 15 ppm of nitrogen dioxide. Animals were killed 16 weeks or 24 to 32 weeks after the beginning of the treatment. Ozone delayed the appearance of tracheal tumors and reduced the incidence of tumors in the lung periphery. A suspected neuroendocrine differentiation of those lung tumors could not be established by immunocytochemistry due to overfixation of tissues. On the other hand, ozone seemed to mitigate development of hepatotoxic lesions mediated by diethylnitrosamine. In animals treated with diethylnitrosamine and exposed to nitrogen dioxide, fewer tracheal tumors and no lung tumors were found. Only a few lung tumors were produced in animals treated with diethylnitrosamine and kept in an atmosphere of 65% oxygen. The previously observed neuroendocrine nature of tumors induced by simultaneous exposure to diethylnitrosamine and hyperoxia could not be established because the long fixation of tissues precluded immunocytochemical stains. Animals treated with diethylnitrosamine and kept in filtered air while being housed in wire-mesh cages developed fewer lung tumors than animals given the same treatment and kept on conventional bedding in shoebox cages. Although all inhalants tested are known to produce substantial cell proliferation in the respiratory tract, it was not possible to document whether this would enhance lung tumor development. The role of the two common air pollutants, ozone and nitrogen dioxide, as possible additional risks in the pathogenesis of lung cancer in animals continues to remain uncertain.

Effects of formaldehyde on xenotransplanted human respiratory epithelium.

A laboratory animal model that permits the exposure of xenotransplanted human respiratory epithelium to formaldehyde was used to study the effects of formaldehyde alone or in combination with the ultimate carcinogenic metabolite of benzo[a]pyrene, benzo[a]pyrene diol epoxide. Epithelial cells obtained from autopsies of full-term human fetuses or infants less than one year old were isolated, amplified in primary cultures, and then inoculated into rat tracheas from which the epithelial layer had been removed. These tracheas then were sealed and transplanted subcutaneously into irradiated athymic nude mice. Four weeks after transplantation, the tracheal lumen was completely covered by epithelium, most of which was of the mucociliary respiratory type. At this stage, tracheal transplants containing tracheobronchial epithelium from 20 different human infant donors were exposed to silastic devices containing 0, 0.5, 1, or 2 mg of formaldehyde. The tracheal transplants were examined histologically 2, 4, 8, or 16 weeks after transplantation. Before being killed, all animals were injected with a single pulse of tritiated thymidine. Important epithelial alterations were seen in the transplants treated with formaldehyde, with a maximum effect visible two weeks after exposure. In most cases, the highest dose of 2 mg produced numerous areas of epithelial erosion and inflammation; however, this effect was not as evident with the lower doses. All doses produced areas of hyperplastic epithelium alternating with areas of atrophic epithelium. Although the differences in predominance of different types of epithelium were not clearly dependent on dose, the labeling index showed dose dependence between two and four weeks after the initiation of exposure. The maximum mean labeling index was three to four times higher than normal, although in some focal hyperplastic-metaplastic lesions the labeling index increased up to 20 times. These studies show that formaldehyde, although toxic at higher doses, is able to elicit at lower doses a proliferative response of the human infant tracheobronchial epithelium that is not preceded by a massive toxic effect. Similar studies were performed using xenotransplanted human adult nasal respiratory epithelium (Study 2). The response pattern was very similar to that of the xenotransplanted human tracheobronchial epithelium from human infants (Study 1). In Study 3, using cells obtained from 11 human infant tracheobronchial epithelia, the formaldehyde applied simultaneously or sequentially with benzo[a]pyrene diol epoxide did not induce epithelial alterations different from those observed with formaldehyde treatments alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Lung cancer and hydrogen chloride exposure: results from a nested case-control study of chemical workers.

There are few epidemiologic data available to address the question of potential carcinogenic effects of hydrogen chloride (HCl) exposure on humans. An opportunity arose to augment a nominal HCl exposure classification that had been done earlier for a nested case-control study of lung cancer among a cohort of chemical manufacturing employees. Working from first-hand knowledge of the relevant chemical processes and limited HCl monitoring data, a certified industrial hygienist estimated average exposures for each of the job assignments of 308 lung cancer cases and 616 comparison workers. The risk of lung cancer was then analyzed in relation to several measures of HCl exposure, including duration, a cumulative exposure score, highest average exposure, and latency. None showed evidence of an association between HCl exposure and lung cancer. This is consistent with the limited rodent bioassay data, which also failed to find a tumorigenic response from HCl. Thus, even at high level occupational exposures (up to 3000 micrograms/m3 for several years) there is no evidence that HCl is a human carcinogen.

Cell-specific alterations in glycoconjugates in the development of squamous metaplasia induced by benzo[a]pyrene in hamster tracheal explants.

Squamous metaplasia of tracheal mucosa, putative preneoplastic lesions, involves replacement of normal mucociliary epithelium with epidermoid lesions. Alterations in cell differentiation and neoplasia accompany changes in glycoconjugates at the plasma membrane. Lectins which bind to specific cell surface glycoconjugates are used to elucidate such alterations. We have used peanut agglutinin (PNA) and concanavalin A (Con A) as specific molecular probes to elucidate cell specific alterations in the development and progression of squamous metaplasia in the hamster tracheal explants induced by benzo[a]pyrene (BP), a component of cigarette smoke. The tracheal explants were cultured in serum-free chemically defined medium and treated with BP (7.5 micrograms/ml) for up to 15 days. At this time, 80-90% of the carcinogen treated explants exhibited epidermoid lesions at various stages of development. The untreated control explants maintained normal pseudostratified epithelium. In these explants, PNA and Con A exhibited moderate reaction in the cytoplasm of luminal mucociliary cells; the basal cells showed no reaction. In early metaplastic lesions PNA and Con A stained only the cytoplasm of luminal cells; the metaplastic cells along the basal lamina were negative. In well-developed lesions, in which the luminal mucociliary layer was still intact overlying the lesions, the metaplastic epithelium remained unreactive with the lectins. In highly advanced lesions exhibiting cornification, and in which the mucociliary layer was sloughed, the metaplastic lesions showed strong reaction with both the lectins. The reaction was limited mainly to the plasma membrane of the metaplastic cells. These results show that induction and progression of the BP induced lesions accompany dynamic cell specific alterations in glycoconjugates. The epidermoid lesions acquire glycoconjugates rich in beta-D-galactose and D-mannose. These results are also consistent with the basal cell origin of the metaplastic lesions.

Promoting effect of sodium chloride solution mist on the induction of papillomas on Syrian hamster tracheal mucosa following administration of diethylnitrosamine.

The promoting effect of NaCl solution mist was studied in the induction of papillomas on Syrian hamster trachea following single subcutaneous injection of diethylnitrosamine (DEN). Sixty male hamsters were divided into three groups. Group A; Exposure to a 5% NaCl solution mist for 32 weeks following single subcutaneous injection of DEN at a dose of 3 mg/100 g body weight. Group B; Subcutaneous DEN injection alone. Group C; Exposure to the NaCl mist for 32 weeks alone. Total numbers of papillomas on the trachea in each group were 107 in group A, 64 in group B, and 0 in group C (P less than 0.05 between group A and B, P less than 0.01 between either groups A or B and C). Comparing the incidence of large papillomas with a diameter of more than 2 mm, that in group A hamsters was significantly greater than that of group B (22 large papillomas vs. 8 large papillomas, P less than 0.01). No difference in the effects on the epithelial cells of the nasal cavity, the bronchial or the alveolar cells in the lung was recognized between groups A and B. The hamsters in group C were not observed to have any changes in any of the respiratory organs. Inhalation of NaCl solution mist is considered to have a promoting effect on the induction of papillomas in the hamster trachea following DEN injection.

Preneoplastic transformation of rat tracheal epithelial cells by ozone.

The transforming potency of ozone for rat tracheal epithelial (RTE) cells exposed in vivo or in vitro was determined. RTE cells isolated from rats exposed to ozone (0, 0.14, 0.6, or 1.2 ppm, 6 hr/day, 5 days/week for 1, 2, or 4 weeks) showed no increase in the frequency of preneoplastic transformation compared to cells isolated from unexposed rats, although ozone-induced morphologic changes were observed in exposed tracheas. In contrast, preneoplastic variants of RTE cells were induced by multiple, but not single, exposures of RTE cells to ozone in culture. RTE cells exposed biweekly to ozone (approximately 0.7 ppm for 40 min, nine total exposures) had approximately twofold increases in the frequency of preneoplastic transformation compared to that of concurrent controls exposed to air. Single, 40-min exposures to ozone (approximately 1 or approximately 10 ppm) did not induce preneoplastic variants. However, single, 40-min exposures of RTE cells to approximately 10 ppm ozone did result in approximately 40% decreases in colony-forming efficiency. In addition, single, 40-min exposures of RTE cells to approximately 1 ppm ozone reduced the transforming potency of a subsequent exposure to the direct-acting chemical carcinogen N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). When multiple ozone exposures followed exposure to MNNG (approximately 0.7 ppm ozone for 40 min, nine biweekly exposures), an additive (or possibly a multiplicative) effect of ozone on MNNG-induced preneoplastic transformation was seen. These results demonstrate that ozone can, under some conditions, induce preneoplastic variants of RTE cells. In addition, depending on the sequence or combinations of exposures, ozone can reduce or, possibly, increase, the transforming potency of the carcinogen MNNG for rat tracheal cells in culture.

Formaldehyde exposure and respiratory cancer among woodworkers--an update.

Respiratory cancer was examined in relation to occupational formaldehyde exposure in a case-referent study (136 cases, 408 referents) nested in a woodworker cohort. Plant- and time-specific job-exposure matrices were constructed for formaldehyde exposure. Over 3 ppm-months of formaldehyde exposure was associated with an odds ratio of 1.4 [90% confidence interval (90% CI) 0.5-4.1]. The odds ratios for lung cancer were near unity, the excess risk concentrating on the upper respiratory tract. That for combined exposure to formaldehyde-phenol exposure (all respiratory cancers) was 1.6 (90% CI 0.6-4.4) but 1.0 for formaldehyde only. No consistent exposure-response patterns emerged for the level, duration, or cumulative exposure. The results are hardly more than debatable support for the hypothesis concerning formaldehyde as a carcinogen in humans, the possible risk seemingly concentrating on the upper respiratory tract rather than the lung.

[Effects of As2O3, MNNG and B(a)P on epithelia of human fetal tracheae and rat tracheae in organ culture].

The effects of As2O3, MNNG and B(a)P on epithelia of human fetal tracheae and rat tracheae in organ culture were studied. In human fetal trachea, a small dose of arsenic (1 mumol As) induced hyperplasia of the epithelium; 3-9 mumol As induced hyperplasia and cellular atypia in the epithelium, and hyperplasia and squamous metaplasia in the adenoepithelium. Similar effects were not observed in rat tracheae. MNNG and B(a)P induced hyperplasia, squamous metaplasia and dysplasia in human fetal tracheal and rat tracheal epithelia respectively, and MNNG also induced hyperplasia and squamous metaplasia in human fetal tracheal adenoepithelium. The data suggest that 1) arsenic may be carcinogenic to the human respiratory tract but not to the rat; and 2) human tissues in organ culture are very useful for detecting carcinogens and for studying carcinogenesis.

Neoplastic and potentially prenoeplastic changes in the upper respiratory tract of rats and mice.

The National Toxicology Program (NTP) database was examined for tumor incidences and chemicals producing tumors in the nasal cavity, larynx, or trachea. Slides from appropriate studies were then examined in an attempt to unify terminology and make comparisons between induced and spontaneous tumors and hyperplastic or preneoplastic lesions produced in the upper respiratory system. An attempt was also made to compare the species affected, route of administration, and tumor types produced by different chemicals. The results are not meant to be all inclusive of the NTP database but to be representative of observed trends. General conclusions that emerged from this review were that rats are much more susceptible to epithelial tumors of the nasal cavity than mice; that only mice have been reported to have chemically induced hemangiomas and hemangiosarcomas of the nasal cavity; that tumors of the olfactory epithelium and squamous cell tumors of the respiratory epithelium are almost uniformly malignant and invasive, while other tumors of the respiratory epithelium are typically less invasive; that most chemically induced tumors of the olfactory region, either mesenchymal or epithelial, do not require an inhalation route of exposure but appear to occur by systemic targeting of this region; and that a uniform nomenclature for tumors of the nasal cavity is needed.

Upper respiratory tract tumors in Cpb:WU (Wistar random) rats.

A survey is given of upper respiratory tract tumors in Cpb:WU (Wistar random) rats. Data were collected from ten 24- to 30-month toxicity/carcinogenicity studies and from one 12-month study. Nasal tumors may lead to dyspnea, mouth breathing, and nasal discharge. These clinical signs mainly occurred in rats bearing squamous cell carcinomas. The large nasal tumors were often osteolytic, they invaded the subcutis over the premaxilla, resulting in swellings on the back of the nose, and extended into the brain. The incidence of nasal tumors in untreated male controls was 1.1% (7/661), the tumors invariably being squamous cell carcinomas. There were no nasal tumors found in untreated female controls. The type of compound-induced nasal tumor most frequently observed was adenocarcinoma (of the olfactory epithelium) followed, in order of decreasing incidence, by squamous cell carcinoma, carcinoma in situ, polypoid adenoma, Schwannoma, and carcinosarcoma. It was proposed that adenocarcinomas of the olfactory epithelium should be classified as neuroepitheliomas. It was also suggested that squamous cell carcinomas, seen in association with necrotizing inflammation of an incisor tooth, should be considered as part of the malocclusion syndrome. No spontaneous tracheal tumors were observed, and only one out of 422 untreated female controls (0.2%) was seen to have a laryngeal tumor, an adenoma. Induced laryngeal tumors included carcinoma in situ, squamous cell carcinoma, and adenocarcinoma. Squamous cell carcinoma was the only type of treatment-related tracheal tumor found. The incidences of induced laryngeal and tracheal tumors were very low, and in no case were these tumors statistically significantly different from the respective incidences in controls.

Successful chemotherapy of experimental neuroendocrine lung tumors in hamsters with an antagonist of Ca2+/calmodulin.

The chemotherapeutic effect of B859-35, the (-)-enantiomer of dihydropyrine 3-methyl-5-3-(4,4-diphenyl-1-piperidinyl)-propyl-1,4-dihydro-2,6-dimethy l-4- (3-nitrophenyl)-pyridine-3,5-dicarboxylate-hydrochloride (niguldipine), was tested on tumors induced in Syrian golden hamsters by N-nitrosodiethylamine (DEN). Peripheral pulmonary adenomas/adenocarcinomas were induced in hamsters maintained under ambient air conditions by multiple s.c. injections of DEN for 20 weeks. We have reproducibly shown that within this time interval lung adenomas develop in a significant number of the animals. The carcinogen treatment was discontinued at this point and one group of these hamsters was given B859-35 intragastrically 5 days/week for 20 weeks while the second group of such tumor-bearing hamsters were kept for an identical time interval without further treatment. Neuroendocrine lung tumors were induced in hamsters maintained in an atmosphere of 60% O2 by multiple s.c. injections of DEN for 8 weeks. We have reproducibly shown that within this short time interval neuroendocrine lung tumors develop in a significant number of the animals. The carcinogen treatment was discontinued at this point and the animals were returned to ambient air conditions. One group of these tumor-bearing hamsters was then given B859-35 intragastrically 5 days/week for 20 weeks while a second group of these hamsters was kept untreated for an identical time interval. A control group was given s.c. injections of saline for 20 weeks under ambient air conditions. A dramatic and selective anticarcinogenic effect of B859-35 was observed on the neuroendocrine lung tumors and nasal cavity tumors induced by DEN/hyperoxia while tumors of larynx/trachea were not affected. B859-35 had no effect on peripheral adenomas/adenocarcinomas, nasal cavity tumors, papillary polyps of larynx/trachea, or liver tumors induced by DEN under ambient air conditions.