Geroprotective effect of ala-glu-asp-gly peptide in male rats exposed to different illumination regimens.

Exposure of male rats to permanent or natural illumination of North-Western Russia accelerated their death in comparison with animals exposed to standard (12 h) light. Permanent illumination promoted the development of spontaneous tumors in comparison with the standard photoregimen. Injection of epithalone (synthetic Ala-Glu-Asp-Gly peptide; subcutaneously 0.1 microg/rat 5 times a week from the age of 4 months until natural death) virtually did not change the mean lifespan of male rats, but was associated with a significant (p<0.05) normalization of population aging rate and hence, time of mortality rate doubling in groups exposed to natural or constant illumination. Epithalone injected to rats exposed to any photoregimen significantly inhibited the development of spontaneous tumors, primarily testicular leydigomas and leukemias.

Effect of Ala-Glu-Asp-Gly peptide on life span and development of spontaneous tumors in female rats exposed to different illumination regimes.

The effects of Ala-Glu-Asp-Gly peptide (Epithalon) on the life span and development of spontaneous tumors were studied in female rats exposed to standard, natural for North-Western Russia, and constant illumination. The mean life span of animals exposed to constant or natural illumination decreased by 13.5 and 25.5%, the maximum by 9 and 7 months, respectively, and spontaneous tumors developed much more rapidly than in animals living under conditions of the standard light regimen. Epithalon (0.1 microg daily 5 times a week from the age of 4 months) did not change the life span of rats living under conditions of standard day/night regimen, while in rats exposed to the natural and constant light it promoted prolongation of the maximum life span by 95 and 24 days, respectively. Epithalon prolonged the mean life span of the last 10% of rats exposed to natural and constant illumination, treated with Epithalon, by 137 and 43 days, respectively. This peptide exhibited virtually no effect on the development of spontaneous tumors in rats exposed to standard and constant illumination, but significantly inhibited their development in rats exposed to natural light.

Melatonin increases both life span and tumor incidence in female CBA mice.

From the age of 6 months until their natural deaths, female CBA mice were given melatonin with their drinking water (20 mg/l) for 5 consecutive days every month. Intact mice served as controls. The results of this study show that the consumption of melatonin did not significantly influence food consumption, but it did increase the body weight of older mice; it did not influence physical strength or the presence of fatigue; it decreased locomotor activity and body temperature; it inhibited free radical processes in serum, brain, and liver; it slowed down the age-related switching-off of estrous function; and it increased life span. However, we also found that treatment with the used dose of melatonin increased spontaneous tumor incidence in mice. For this reason, we concluded that it would be premature to recommend melatonin as a geroprotector for long-term use.

Long-live euthymic BALB/c-nu mice. II: spontaneous tumors and other pathologies.

This paper is the second of a series aimed to show the main physiological and pathological characteristics of male euthymic BALB/c-nu mice, a long-live strain of BALB/c mice bred in our own Institute. The previous paired paper Piantanelli (Mech. Ageing Dev. (2001)) has been devoted to a survival study up to advanced ages highly interesting for studies on successful aging. In the present paper we report first data of a cross-sectional study on 4,15,22,28 and 34 months-old mice, dealing with tumors and other relevant pathologies. Results have shown that tumors or other pathologies can hardly be detected up to the age of 22 months. At 34 months of age about 40% of mice revealed a variety of neoplasia and other diseases are clearly detectable. These results suggest that a significant increase in longevity could be a factor increasing the risk of tumor development; thus, caution has to be paid in studies on mice utilized for long term carcinogenicity assay, where animals are sacrificed at the age of 18 months, according to the International Program. Finally, animals of the same chronological age have been subdivided in clusters according to their presumptive longevity, estimated taking advantage of the relationship between body weight and age-at-death found in the paired longitudinal study. This subdivision will be helpful in interpreting inter-individual variability of the biological parameters checked in these animals.

The effect of light regimen and melatonin on the development of spontaneous mammary tumors in HER-2/neu transgenic mice is related to a downregulation of HER-2/neu gene expression.

OBJECTIVES AND DESIGN: The effect and the mechanism of light regimen and melatonin on the development of mammary tumors in HER2/neu transgenic mice were investigated. Female HER-2/neu mice starting from the age of 2 months were kept under standard light/dark regimen (LD) or constant light illumination (LL) and a part of each group was given melatonin (20 mg/l) during the night time. RESULTS: The exposure to LL failed to change the incidence of spontaneous mammary adenocarcinoma development, the size of mammary tumors, as well as the incidence and size of lung metastases. However, the number of tumors per mouse was significantly increased in the LL group as compared to the LD group. The number of mice bearing 4 and more tumors was higher in the LL group than in the LD group, whereas the number of mice bearing 1 to 3 tumors was lower in the LL group in comparison with the LD group. Melatonin decreased the incidence and size of mammary adenocarcinomas, and the incidence of lung metastases in the LD group but not in the LL group. The mean number of tumors per mouse was not changed by melatonin treatment in both light regimens. The number of mice bearing 4 and more tumors was reduced by melatonin more significantly in the LL group than in LD group. Melatonin treatment resulted in a 2.5-fold reduction in the expression of HER-2/neu mRNA in mammary tumors from HER-2 /neu transgenic mice. CONCLUSION: The data demonstrate the influence of the LD light regiment and melatonin treatment in the development of spontaneous mammary tumors in HER-2/neu mice suggesting a melatonin-dependent modulation of HER-2/neu gene expression in mammary adenocarcinoma.

Melatonin and colon carcinogenesis. IV. Effect of melatonin on proliferative activity and expression of apoptosis-related proteins in the spleen of rats exposed to 1,2-dimethylhydrazine.

The suppression of 1,2-dimethylhydrazine (DMH)-induced colon carcinogenesis by melatonin was previously demonstrated. The objective of the present work was to evaluate histologically and immunohistochemically the splenic immune response to the induced cancer and to melatonin. Spleens from rats, either untreated, injected with DMH, fed with melatonin or treated with both carcinogen and melatonin, were studied. The exposure to the carcinogen and the consequential carcinogenesis resulted in splenic changes that reflected the insufficiency of the immune response, as manifested in significant reduction of the white pulp and the simultaneous expansion of the red pulp. The effects of melatonin on most splenic components were inverse to those of DMH. The anti-carcinogenic properties of melatonin were evidenced from the reversal of the inhibitory effects of DMH, especially when the densities of lymphocytes in different parts of the spleen were compared. The combined treatment of the rats with DMH and melatonin resulted in the expansion of the splenic zones by 106% to 125%, compared to those from DMH-treated rats, and the numbers of CD8+ lymphocytes and Fas-positive cells increased sharply. Therefore we conclude that anti-carcinogenic effects of melatonin are related to activation of several elements of the host's lymphatic system.

Inhibitory effect of melatonin on 7, 12-dimethylbenz[a]anthracene-induced carcinogenesis of the uterine cervix and vagina in mice and mutagenesis in vitro.

Forty female CBA mice aged 3-4 months were exposed twice a week during 2 months to intravaginal applications of polyurethane sponges impregnated with 0.1% solution of 7,12-dimethylbenz[a]anthracene (DMBA) in triethyleneglycol. Three hours after each application the sponges were taken out. Starting from the day of the 1st DMBA application a part of mice was exposed five times a week during 4 months with melatonin in tap water (20 mg/l) given at night time (from 18:00 to 09:00 h). Additional 20 female CBA mice were intact and served as a control. All mice were sacrificed in 6 months after start of the experiment. Seven of 20 mice exposed to DMBA alone developed malignancies in the vagina and cervix uteri and two mice developed benign cervical tumors. No malignancies in vagina and uterine cervix and three vaginal papillomas were observed in mice exposed to DMBA+melatonin. There were no any tumors in intact controls. Two in vitro tests were used for mutagenicity studies: the Ames test (strains TA 97 and TA 98 of Salmonella typhimurium) and the single cell gel electrophoresis assay (SCGE assay or COMET assay) performed on CHOK1 cells. In tested strains melatonin significantly reduced the mutagenicity of DMBA. In the SCGE assay preincubation with melatonin led to a strong inhibition of clastogenic activities of DMBA. Thus, our data indicate that pineal indole hormone melatonin inhibits cervical and vaginal carcinogenesis induced by DMBA in mice and possess antimutagenic and anticlastogenic effect in vitro.

Melatonin and colon carcinogenesis. III. Effect of melatonin on proliferative activity and apoptosis in colon mucosa and colon tumors induced by 1,2-dimethylhydrazine in rats.

Forty-eight two-month-old outbred female LIO rats were injected weekly with a single dose of 1,2-dimethylhydrazine (DMH; 21 mg/kg of body weight) administered s.c. for 15 consecutive weeks. From the day of the 1st injection of the carcinogen the part of rats were given five days a week during the night time (from 18.00 h to 08.00 h) melatonin dissolved in tap water, 20 mg/l. 10 rats were treated similarly with solvents and served as control. The experiment was terminated 6 months after the first injection of the carcinogen. Colon tumors (mainly adenocarcinomas) developed in a hundred percent of rats exposed both to DMH or to DMH plus melatonin. However, descending colon carcinomas were observed in 65 % of rats exposed to DMH plus melatonin against 100% in those exposed to DMH alone (p < 0.01). The multiplicity of colon tumors was also reduced in rats under the influence of melatonin. This effect is correlated with the significant inhibitory effect of the pineal hormone on mitotic index and with stimulating effect of melatonin on the relative number of apoptotic cells (TUNEL-method) in colon tumors. Long-term treatment with melatonin was followed also by the decrease in the area of lymphoid infiltrates in the colon mucosa of tumor-bearing rats.

Inhibitory effect of synthetic interferon inductor Cycloferone on 1,2-dimethylhydrazine-induced colon carcinogenesis in rats.

The effect of a synthetic interferon inductor Cycloferone on colon carcinogenesis was firstly studied in rats. Seventy-five 2-month-old outbred female LIO rats were subdivided into three groups and were weekly exposed to 15 s.c. injections of 1,2-dimethylhydrazine (DMH) at a single dose of 7 mg/kg body wt. From the day of the fist injection of DMH rats from group 2 were given weekly i.p. injections of Cycloferone (62.5 mg/kg) until the end of the experiment. DMH-treated rats (group 3) were exposed to weekly i.p. injections of Cycloferone (62.5 mg/kg) starting in the week after the last injection of the carcinogen. Rats from group 1 were exposed to DMH and treated weekly with 0.2 ml i.p. of normal saline. Additional groups of rats were treated weekly with Cycloferone (62.5 mg/kg) or with 0.2 ml of saline. The experiment was ended 6 months after the first injection of DMH. In DMH-treated rats (groups 1, 2 and 3) colon adenocarcinomas developed in 87, 61 and 59%, respectively. The number of colon tumors per tumor-bearing rat was 2.5, 1.9 and 1.3 in groups 1, 2 and 3, respectively. Treatment with Cycloferone significantly inhibits carcinogenesis in ascending and descending colon. The incidence of tumors of the rectum was decreased in the group 2 as compared with the group 1. There were no cases of tumors of rectum in rats from group 3. The treatment with Cycloferone alone as well as with normal saline failed to induce any tumors in rats. Thus, our results demonstrated inhibitory effect of Cycloferone on colon carcinogenesis induced by DMH in rats.

Prevention of spontaneous and chemically induced carcinogenesis using activated carbon fiber adsorbent. II. Inhibitory effect of the activated carbon fiber adsorbent 'Aqualen' on N-methyl-N'-nitro-N-nitrosoguanidine-induced gastric carcinogenesis in rats.

Two-month-old female LIO rats were given N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) with tap water in a concentration of 100 mg/l for 12 months (groups 1 and 2) or were kept without the carcinogen treatment (groups 3 and 4). From the first day of exposure to MNNG rats from groups 2 and 3 were given activated carbon fiber adsorbent Aqualen in their diet five times per week together with lab chow in a daily dose of 100 mg/kg of body weight. The experiment was finalized 16 months after first exposure to the carcinogen. The total stomach adenocarcinoma incidence was 43% in group 1 and 39% in group 2, whereas invasive stomach adenocarcinomas occurred in 36% and 8% of rats from groups 1 and 2, respectively (P < 0.05). Tumors other then stomach sites (duodenum and liver) only developed in rats from group 1 (29%). No lesions were observed in rats exposed to Aqualen without MNNG. Thus, our results demonstrate the inhibitory effect of the activated carbon fiber adsorbent Aqualen on stomach carcinogenesis in rats.

Prevention of spontaneous and chemically induced carcinogenesis using activated carbon fiber adsorbent. III. Inhibitory effect of the activated carbon fiber adsorbent 'Aqualen' on 1,2-dimethylhydrazine-induced intestinal carcinogenesis in rats.

Two-month-old outbred female LIO rats were exposed weekly to 15 (experiment I, groups 1, 2 and 3) or to 5 (experiment II, groups 4, 5 and 6) subcutaneous injections of 1,2-dimethylhydrazine (DMH) at a single dose of 21 mg/kg of body weight. From the day of the first injection of the carcinogen, the rats from groups 2, 3, 5 and 6 were given Aqualen in their diet. In both experiments rats were fed Aqualen five times per week together with lab chow at the daily dose of 0.1 g/kg (groups 2 and 5) or 1.0 g/kg (groups 3 and 6) of body weight. Additionally, other rats were not exposed to the carcinogen and served as an intact control (group 7) or were given Aqualen with the diet at the daily dose of 0.1 g/kg (group 8) or 1.0 g/kg (group 9). These experiments were finalized 6 months after the first injection of DMH. In experiments I and II, the majority of tumors were localized in the descending colon. Tumors of the small intestines developed only in rats from experiment I. The total incidence of colon tumors as well as tumors in different parts of the colon and the mean number of tumors per rat were much higher in rats from all groups in experiment I than in the rats from experiment II. In experiment I supplementation of Aqualen to the diet was followed by a decrease in the incidence of tumors in the ascending colon and by a decrease in the number of tumors per rat in both ascending and descending colons regardless of the dose of the enterosorbent. In experiment II the effect of Aqualen was stronger than in experiment I -- the enterosorbent decreased both the tumor incidence and the multiplicity in the total colon, its ascending and descending parts and in the rectum. In experiments I and II the percentage of small colon tumors among rats exposed to Aqualen (groups 2, 3, 5 and 6) was higher than that of the controls (groups 1 and 4). Most of detected intestinal tumors were classified as adenocarcinomas. The level of tumor differentiation was higher in rats exposed to Aqualen. There were no pathological changes observed in rats exposed to Aqualen without DMH. Carcinogen treatment resulted in an increase of serum glucose and cholesterol levels whereas Aqualen normalized these changes. Thus, our results demonstrate the inhibitory effect of activated carbon fiber adsorbent Aqualen on intestinal carcinogenesis in rats.

Melatonin and colon carcinogenesis. II. Intestinal melatonin-containing cells and serum melatonin level in rats with 1,2-dimethylhydrazine-induced colon tumors.

Two-month-old outbred female LIO rats were injected weekly with a single dose of 1,2-dimethylhydrazine (DMH; 21 mg/kg of body weight) administered s.c. for 15 consecutive weeks. From the day of the 1st injection of the carcinogen the part of rats were given five days a week during the night time (from 18.00 h to 08.00 h) melatonin dissolved in tap water, 20 mg/l. The experiment was terminated in 6 months after the first injection of the carcinogen. The concentration of melatonin in the serum was estimated by radioimmunoassay in rats exposed to DMH alone or in intact control rats in the morning (between 10.00 and 11.00 hours) and night (between 24.00 and 01.00 hours) time. Number of melatonin-containing cells (M-cells) and their optical density were estimated by immunohistology in normal mucosa of glandular stomach, duodenum, ileum and descending colon of tumor-bearing animals from groups exposed to DMH or DMH+melatonin. It was shown that serum melatonin levels in rats with colon tumors was increased as compared with controls. However there was no diurnal rhythm of serum melatonin of colon tumor-bearing animals as compared to intact controls. The number of M-cells was decreased in all tissues studied in rats with DMH-induced colon tumors in comparison to corresponding controls: by 2.0 times in stomach, by 1.8 time in duodenum, by 1.3 times in ileum, and by 1.8 times in colon. In ileum and colon of rats treated with DMH+melatonin the number of M-cells was similar to control level whereas in stomach and duodenum this number was significantly higher than that in rats treated with DMH alone, but less than in corresponding controls. Relative content of melatonin in enterochromaffin cells of all parts of gastrointestinal tract evaluated as optical density of the cells and was decreased in rats exposed with DMH alone in comparison to the controls and was normalized and similar to the norm level in rats treated with DMH+melatonin. Thus, exogenous melatonin prevent a decrease in numbers of melatonin-containing cells as was observed in gastrointestinal tract (GIT) of rats exposed to DMH. This preventive action of melatonin correlated well with its anticarcinogenic effect.

Prevention of spontaneous and chemically-induced carcinogenesis using activated carbon fiber adsorbent. I. Effect of the activated carbon fiber adsorbent 'Aqualen' on spontaneous carcinogenesis and life-span in mice.

Female SHR mice were fed the activated carbon fiber adsorbent Aqualen beginning at the age of 3 months through their life. Mice were fed Aqualen five times per week together with lab chow at a daily dose of 100 mg/kg b.w. The addition of Aqualen into food did not significantly influence the dynamics of body weight and the mean life-span of the animals. At the same time, the age at 90% mortality of mice was 4 months longer in the group exposed to Aqualen. There were no statistically significant differences in the incidence of all tumors and malignant tumors in the group of mice treated with Aqualen as compared with the control group. However, in the group of mice exposed to Aqualen, there was a 1.4 times reduction of the mean number of tumors per mouse. Feeding mice with the adsorbent led to a 4 months longer life-span in animals with any tumors and to a 5 months longer life-span in animals bearing malignant tumors (P < 0.05). No carcinogenic effect of Aqualen was found. It could be supposed that Aqualen has some geroprotective and anticarcinogenic properties.

Melatonin and colon carcinogenesis: I. Inhibitory effect of melatonin on development of intestinal tumors induced by 1,2-dimethylhydrazine in rats.

The effect of pineal indole hormone melatonin on colon carcinogenesis was firstly studied in rats. Two-month-old outbred female LIO rats were weekly exposed to 15 (experiment 1, groups 1 and 2) or to five (experiment 2, groups 1 and 2) s.c. injections of 1,2-dimethylhydrazine (DMH) at a single dose of 21 mg/kg of body weight. From the day of the first injection of the carcinogen DMH, the rats from groups 2 (experiments 1 and 2) were given melatonin five days a week during the night-time (from 18:00 h to 8:00 h), dissolved in tap water at 20 mg/l. The experiment was finalized in 6 months after the first injection of DMH. In both experiments the majority of tumors were localized in the descending colon. Tumors of the small intestines developed only in rats from experiment 1. Total incidence of colon tumors as well as tumors in different parts of the colon and the mean number of tumors per rat were much higher in rats from both groups in experiment 1 than that in rats from experiment 2. In experiment 1 melatonin failed to influence the total incidence of colon tumors. However, incidence of carcinomas in the ascending colon was significantly reduced (P < 0.01). The multiplicity of total colon tumors per rat, as well as the mean number of tumors, ascending and descending colon per rat, was also decreased under the influence of melatonin (group 2 vs group 1, P < 0.01). In the same experiment, melatonin slightly decreased the depth of tumor invasion and increased number of highly differentiated colon carcinomas induced by DMH. The percentage of small tumours in the descending colon among rats from group 2 was higher than that of group 1. Treatment with melatonin was also followed by a decrease in the multiplicity of DMH-induced tumors of the duodenum (group 2 vs group 1, P < 0.05) and by a decrease in the incidence of jejunum and ileum tumors (group 2 vs group 1, P < 0.05). In experiment 2, the inhibitory effect of melatonin on DMH-induced colon carcinogenesis was much more expressed than that in experiment 1. Thus, in group 1 the incidence of total colon tumors, ascending and descending colon tumors, was significantly decreased in comparison with group 2; also melatonin reduced the number of tumors per rat in the ascending and descending colon. The number of colon tumors that invaded only mucosa was significantly higher in group 2 than in group 1, P < 0.05. The ratio of highly differentiated tumors was increased (P < 0.05) and the ratio of low-differentiated tumors was decreased (P < 0.05) in rats exposed to melatonin (group 4) as compared with group 3. The number of large size tumors in the ascending and descending colon was decreased whereas the number of small size tumors (<10 mm2) was increased in those parts of the colon that were under the influence of melatonin in experiment 2. Thus, our results demonstrate the inhibitory effect of melatonin on intestinal carcinogenesis induced by DMH in rats.

Effect of video display terminal irradiation on urethane-induced lung carcinogenesis in mice.

Female Swiss-derived SHR mice were exposed intraperitoneally to 4 injections of 1% urethane at the Ist, 8th, 54th and 61st days of the experiment (a single dose was 20 mg per mouse). Groups of mice starting from the Ist day were also exposed 5 days per week to 1 hour irradiation of video display terminal (VDT) or VDT+ screen filter (SF). The distance from VDT screen and bottom of animal cage was 38 cm. The experiment was finalized in 1 year. Longterm exposure of urethane-treated mice to both VDT or VDT+SF was followed by slight decrease in survival time of lung tumor-bearing animals. The tendency to increase of the incidence of lung tumors and the number of lung tumor per mouse was observed in mice exposed to urethane + VDT as compared to those exposed to urethane alone. The incidence of lung tumors and lung tumor multiplicity were significantly decreased in mice treated with urethan and VDT+SF in comparison to mice exposed to urethane + VDT. Thus, a slight promoting effect of VDT-induced irradiation on lung tumorigenesis was observed induced by urethane in mice, and SF alleviated this effect. The dose of urethane in these experiments was rather high to show more clearly the effect of VDT irradiation on lung carcinogenesis.

Individual values of excretion of benzo[a]pyrene metabolites and susceptibility to its carcinogenic effect in rats.

In white outbred LIO rats exposed to multiple intraperitoneal (i.p.) doses (10 mg/kg) of benzo[a]pyrene (BP) in the form of a water-lipid emulsion, individual peculiarities of the excretion of its metabolites, BP-7,8-diol and 3-hydroxy-BP (3-OH-BP) in urine and feces were detected and compared with the carcinogenic effect. Parameters of BP metabolite excretion differed from those found in our previous experiments with rats exposed to single high i.p. doses of BP (100 and 200 mg/kg), dissolved in sunflower oil [11,12]. In comparison with our previous observation, in the present study, the carcinogenic effect was considerably weaker (5/22 versus 10/19). The rats that developed tumours of internal tissues (four peritoneal malignant histiocytomas and one lung lymphosarcoma), excreted higher quantities of BP-7,8-diol in the urine than other rats. The possible implication of monitoring excretion of BP metabolites for predicting individual susceptibility to its carcinogenic effect is discussed.

Individual levels of activity of O6-alkylguanine-DNA alkyltransferase in monkey gastric mucosa during chronic exposure to a gastrocarcinogen N-ethyl-N'-nitro-N-nitrosoguanidine.

The activity of a DNA repair enzyme, O6-alkylguanine-DNA alkyltransferase (AGT), was studied in gastric mucosa of 15 Macaca fascicularis monkeys before and during chronic oral exposure to the ethylating carcinogen N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG) in order to investigate possible causes of inter-individual differences in susceptibility to its gastrocarcinogenic effect. A wide range of AGT activity (307-1903 fmol/mg protein, mean 695) was found before treatment and it decreased during the first year of exposure (means 627, 479 and 452 fmol/mg protein respectively at 6, 12 and 18 months after the beginning of the experiment). The carcinogenesis study is under way and to date four monkeys with low initial AGT level in gastric mucosa died of gastric cancer. The relevance of AGT level measurement for prediction of individual susceptibility to ENNG is discussed.

Biomarkers of individual susceptibility to carcinogens: application for biological monitoring.

In order to develop new markers of individual susceptibility to various human carcinogens, we studied some parameters of formation and metabolism of carcinogens, as well as DNA adducts formation and DNA repair in animals and humans. Following an i.p. administration of benzo(a)pyrene (BP) to the rats, levels of urinary excretion of BP-7,8-diol correlated with tumour latency. A high correlation was found between excretion of this metabolite and BP-DNA adducts level in the liver. Healthy smokers excreted higher quantities of BP-7,8-diol, than smoking lung cancer patients, thus confirming the suggestion on existence of cancer-prone phenotype. N-nitroso compounds formed most efficiently in stomach juice of children with superficial gastritis who therefore could be at high risk of stomach cancer. N-ethyl-N'-nitro-N-nitrosoguanidine induced stomach cancer earlier in monkeys with a low level of DNA repair enzyme, O6-alkylguanine-DNA alkyltransferase (AGT) in gastric mucosa. Overall, these markers can be helpful in predicting individual susceptibility to carcinogens.

Biomarkers for individual susceptibility to carcinogenic agents: excretion and carcinogenic risk of benzo[a]pyrene metabolites.

In rats exposed to a single intraperitoneal dose of 200 mg/kg of the environmental carcinogen benzo[a]pyrene (BP) in sunflower oil, significant individual variations in excretion of the BP activation (BP-7,8-diol) and deactivation (3-OH-BP) derivatives were found. Most rats developed peritoneal sarcomas. Only the levels of BP-7,8-diol excreted in the urine correlated directly with the latency of tumor formation. After a similar exposure to a dose of 100 mg/kg BP, Macaca fascicularis monkeys excreted smaller quantities than rats of both metabolites. After rats were given 10 intraperitoneal injections each of 10 mg/kg of BP in a water-lipid emulsion, the excreted levels of both metabolites after the first, fifth, and tenth injection were lower than those of the rats that received 200 mg/kg. BP metabolites were also detected in the urine of lung cancer patients who were heavy smokers. The applicability of monitoring the excretion of the BP metabolites to predicting individual cancer risk is discussed.