Comparative dose-response tumorigenicity studies of dibenzo[alpha,l]pyrene versus 7,12-dimethylbenz[alpha]anthracene, benzo[alpha]pyrene and two dibenzo[alpha,l]pyrene dihydrodiols in mouse skin and rat mammary gland.

Comparative studies were conducted of the tumor-initiating activity in mouse skin and carcinogenicity in rat mammary gland of dibenzo[a,l]pyrene (DB[a,l]P) versus 7,12-dimethyl-benz[a]anthracene (DMBA), the most potent recognized carcinogenic polycyclic aromatic hydrocarbon (PAH); benzo[a]pyrene (B[a]P), the most potent recognized carcinogenic environmental PAH; DB[a,l]P 8,9-dihydrodiol, the K-region dihydrodiol; and DB[a,l]P 11,12-dihydrodiol, precursor to the bay-region diolepoxide. The tumor-initiating activity of DB[a,l]P and B[a]P was compared in the skin of female SENCAR mice at doses of 300, 100 and 33.3 nmol. The mice were promoted with 12-O-tetradecanoylphorbol-13-acetate (TPA) twice-weekly for 13 weeks. DB[a,l]P at all doses induced significantly more tumors than B[a]P at the corresponding dose, with a significantly shorter latency. Subsequently, the tumor-initiating activity of DB[a,l]P was compared in the skin of female SENCAR mice to that of DMBA, B[a]P, DB[a,l]P 8,9-dihydrodiol and DB[a,l]P 11,12-dihydrodiol at doses of 100, 20 and 4 nmol. The mice were promoted with TPA twice-weekly for 24 weeks. In addition, groups of mice were initiated with 100 nmol of DB[a,l]P, DMBA, B[a]P, DB[a,l]P 8,9-dihydrodiol or DB[a,l]P 11,12-dihydrodiol and kept without promotion. This experiment showed that in the mouse skin, DB[a,l]P and DB[a,l]P 11,12-dihydrodiol displayed similar tumor-initiating activity with a response inversely proportional to the dose, presumably due to the toxicity of the compounds. At the high dose they elicited tumors earlier than DMBA, though DMBA produced a much higher tumor multiplicity. At the low dose, DMBA, DB[a,l]P and DB[a,l]P 11,12-dihydrodiol exhibited similar tumorigenicities. DB[a,l]P 8,9-dihydrodiol was a marginal tumor initiator. Once again, DB[a,l]P was by far a much stronger tumor initiator than B[a]P. Female Sprague-Dawley rats were treated with 1.0 or 0.25 mumol of DB[a,l]P, DMBA or B[a]P by intramammillary injection at eight teats. DB[a,l]P at both doses was a more potent carcinogen than DMBA at the corresponding dose in the rat mammary gland. B[a]P was a marginal mammary carcinogen, eliciting only a few fibrosarcomas. Thus, these data suggest that DB[a,l]P is the strongest PAH carcinogen ever tested.

Improvement of silent myocardial ischaemia and reduction of plasma fibrinogen during nisoldipine therapy in occult coronary arterial disease.

The effect of the long-acting calcium channel blocking agent, nisoldipine, on silent myocardial ischaemia due to occult atherosclerotic coronary arterial disease has been evaluated in 12 asymptomatic patients (seven diabetics and five claudicants), none of whom had any history suggestive of ischaemic chest pain or previous myocardial infarction. All patients had normal resting electrocardiograms but positive exercise testing using 16-lead electrocardiographic mapping of the chest wall. They also had silent episodes of ST-segment depression during 24-hour ambulatory (Holter) monitoring. The study was of double-blind, cross-over design with four weeks randomised nisoldipine 10 mg twice daily versus placebo twice daily. Both the exercise test and Holter monitoring were carried out before entry to the trial and at the end of each randomised active and placebo phase. Plasma fibrinogen was also estimated at entry to the trial and at the end of each randomised phase. There were significant reductions in the magnitude (P less than 0.001) and duration (P less than 0.001) of depression of the ST segment on exercise testing and in the number of episodes (P less than 0.01), magnitude (P less than 0.001) and duration (P less than 0.02) of ST-segment depression on Holter monitoring at the end of the nisoldipine phase as compared to the randomised placebo phase. A significant reduction in plasma fibrinogen was also noted at the end of the nisoldipine phase (P less than 0.001). This study demonstrates the efficacy and usefulness of nisoldipine in treating myocardial ischaemia due to occult coronary arterial disease in asymptomatic subjects presenting with diabetes mellitus or intermittent claudication. Its use was associated with reduction in plasma fibrinogen.

Doppler ultrasound in assessing systolic left ventricular function in cardiovascular patients.

Determination of left ventricular (LV) function is of vital importance in cardiovascular medicine and surgery. Various methods have been introduced to achieve this goal but a noninvasive method is more appropriate as it could be used during exercise to follow-up patients and study the response to medical or surgical intervention. The Doppler ultrasound technique of transcutaneous aortovelography (TAV) has been introduced as a successful approach using a 2 MHz transducer to measure the aortic blood velocity in the aortic arch. From the Doppler ultrasound signals the systolic velocity integral is derived (Sd; the stroke distance which is an index of stroke volume) and its percentage change at maximal-tolerated supine exercise (% delta Sd). The latter was found to be a function of LV ejection fraction and thus proved to be a useful approach to assess LV function in patients with coronary artery disease. Using TAV it was found that coronary artery bypass grafting improves LV function during exercise (rather than at rest) irrespective of the presence of a history of myocardial infarction prior to the operation. In patients with intermittent claudication assessment of LV function proved of great use. The % delta Sd was significantly lower in claudicants with positive stress ECG tests than those with negative test. There was a linear correlation (r = 0.51) between the % delta Sd and the percentage change in the ankle/brachial systolic blood pressure index in response to standard 1 minute of exercise. Assessment of LV function in cardiovascular patients is thus of great clinical importance and provides more insight into the mechanism of the disease and assess the response to management.

Tumor-initiating activity in mouse skin and carcinogenicity in rat mammary gland of dibenzo[a]pyrenes: the very potent environmental carcinogen dibenzo[a, l]pyrene.

Comparative studies of tumor-initiating activity in mouse skin and carcinogenicity in rat mammary gland were conducted with several dibenzo[a]-pyrenes (DBPs). SENCAR mice were initiated with DB[a, e]P, DB[a, h]P, DB[a, i]P, DB[a, l]P and anthanthrene, and promoted with tetradecanoyl-phorbol acetate. The same compounds were tested by intramammillary injection in female Sprague-Dawley rats. Anthanthrene was inactive in both mouse skin and rat mammary gland. DB[a, e]P was a very weak tumor-initiator in mouse skin and was inactive in rat mammary gland. DB[a, h]P induced twice as many papillomas in mouse skin as DB[a, i]P, although both compounds exhibited similar tumor latencies and percentages of tumor-bearing mice. These two compounds induced similar numbers of mammary tumors, but treatment of the rats with DB[a, i]P resulted in a significantly larger number of adenocarcinomas. DB[a, l]P was toxic to both the mice and rats. Treatment of mouse skin with this compound led to an erythema, which delayed the beginning of promotion until the 3rd week after initiation. Despite this delay, papillomas began appearing 5 weeks after initiation with DB[a, l]P and the number of tumors increased rapidly. The compound was so toxic in the rats that half of the animals died in the first 9 weeks and the remaining animals were sacrificed after 15 weeks. Nonetheless, DB[a, l]P was the strongest carcinogen tested, inducing seven tumors per rat within 10 weeks. These results demonstrate that DB[a, l]P, which is present in tobacco smoke, is an extremely potent carcinogenic aromatic hydrocarbon. Furthermore, some of these compounds can serve as useful models for elucidating their mechanisms of activation.

Tumorigenicity of 6-halogenated derivatives of benzo[a]pyrene in mouse skin and rat mammary gland.

Studies of the tumorigenicity of 6-halogenated derivatives of benzo[a]pyrene (BP) can provide evidence about the role of the 6 position in the carcinogenic activation of BP. Female Swiss and A-strain mice were treated on the skin with BP, 6-fluorobenzo[a]pyrene (6-FBP), 6-chlorobenzo[a]pyrene (6-C1BP), 6-bromobenzo[a]pyrene (6-BrBP) and 6-iodobenzo[a]pyrene (6-IBP) by repeated application, and in some cases by initiation-promotion. While BP was more potent than 6-FBP, only these two compounds exhibits tumor-initiating and carcinogenic activity in mouse skin. Female Sprague-Dawley rats were treated with BP, 6-FBP, 6-ClBP, and 6-BrBP by intramammillary injection. BP and 6-FBP induced high levels of mammary epithelial tumors and fibrosarcomas. 6-ClBP elicited only a high percentage of fibrosarcomas, whereas 6-BrBP induced a few adenocarcinomas. These results indicate that chloro or bromo substitution at C-6 in BP reduces or eliminates carcinogenic activity. Conversely, 6-FBP, from which the fluoro substituent has been chemically and metabolically removed by one-electron oxidation, displays a moderate carcinogenic activity which is consistent with activation by either one-electron oxidation or monooxygenation.

Tumor-initiating activity in mouse skin and carcinogenicity in rat mammary gland of fluorinated derivatives of benzo[a]pyrene and 3-methylcholanthrene.

Comparative studies of tumor-initiating activity in mouse skin and carcinogenicity in rat mammary gland were conducted with benzo[a]pyrene (BP) and 3-methylcholanthrene (MC) derivatives. SENCAR mice were initiated with BP, 6-fluorobenzo[a]pyrene (6-FBP), 6-methylBP, 7-FBP, 8-FBP, 9-FBP, 10-FBP, or 10-azaBP and promoted with tetradecanoyl phorbol acetate. The same compounds plus BP 7,8-dihydrodiol were tested by intramammillary injection in female Sprague-Dawley rats. Tumor-initiating activity in mice and/or carcinogenicity in rats were observed for BP, 6-methylBP, 6-, 7-, 8-, and 10-FBP, whereas 9-FBP was inactive in both experiments and 10-azaBP was only marginally active in the mammary gland. BP 7,8-dihydrodiol was carcinogenic in rat mammary gland, although it was less potent than BP. MC, 8-FMC, 10-FMC, and 3-methylcholanthrylene were also tested in Sprague-Dawley rats by intramammillary injection. All compounds were carcinogenic, with MC displaying the most potent activity. The less potent carcinogenic activity of BP 7,8-dihydrodiol in the mammary gland, compared with BP, and the moderate-to-weak tumor-initiating and/or carcinogenic activity of 7-, 8-, and 10-FBP suggest that the bay-region diol-epoxide pathway does not play a significant role in the activation of BP in these two target tissues. Similarly, the carcinogenic activity of 8-FMC and 10-FMC, in which the bay-region diol-epoxide pathway is blocked, suggests that this mechanism of activation is not important in the carcinogenicity of MC in rat mammary gland.

Assessment of the effect of coronary artery bypass grafting on left ventricular performance by Doppler measurement of the aortic blood velocity during exercise.

The effect of coronary artery bypass grafting (CABG) on left ventricular (LV) function is studied noninvasively in 30 male patients with a mean age o 55.4 years using the continuous-wave Doppler technique of transcutaneous aortovelography (TAV). With a transducer applied in the suprasternal notch the main-stream aortic blood velocity recordings were obtained before and at maximum-tolerated supine exercise both prior to, and six weeks after, CABG. From the TAV recordings the stroke distance (Sd: or the systolic velocity integral which is a measure of the stroke volume) and minute distance (Md: or the measure of cardiac output) were derived as well as the percentage changes in these parameters with exercise (% delta Sd and % delta Md successively). Whereas no significant change following CABG was observed in the resting values for Sd, a significant improvement in the maximal exercise values for Sd and Md as well as the % delta Sd and % delta Md was noticed after CABG (p less than 0.001). Prior to CABG the % delta Sd (an indicator of left ventricular function) was significantly lower in 13 patients with a history of an old myocardial infarction (MI). The % delta Sd in these 13 patients was also significantly lower than that in the 17 patients without a history of MI though the improvement in the % delta Sd following CABG was similar in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Non-invasive assessment of left ventricular function in coronary artery disease by Doppler stress testing.

Left ventricular (LV) function in 62 patients presenting with chest pain typical of angina was studied non-invasively at rest and at maximum-tolerated supine exercise using the continuous-wave Doppler technique of transcutaneous aorto-velography (TAV). The signals were analysed to derive peak velocity (Vp), systolic velocity integral [an index of stroke volume or stroke distance (Sd)], and minute distance (Md; index of cardiac output = Sd X heart rate). Comparison was made with results obtained from 66 normal volunteers. The percentage change in stroke distance with exercise (% delta Sd) was significantly related to the resting ejection fraction (EF) calculated from left ventriculography (r = 0.84), and was below 6% (lowest value observed in normal volunteers) in all of the 23 patients with coronary artery disease (CAD) whose EF was below 60%. No significant difference was observed in the % delta Sd between normal individuals and the 12 patients presenting with chest pain but who had normal coronary arteriograms. However, the % delta Vp, delta % Sd and % delta Md in the 50 patients with CAD were significantly lower than the normal individuals and the 12 patients with normal coronary arteriograms. Lower TAV measurements were observed with exercise, rather than at rest, with increasing number of coronary arteries with significant stenoses and the presence of history of myocardial infarction (linear trend p less than 0.003). These results suggest that Doppler recording of aortic blood velocity with exercise is a clinically useful non-invasive technique for studying LV performance in patients with CAD.(ABSTRACT TRUNCATED AT 250 WORDS)

Non-invasive assessment of changes in aortic blood velocity and its derivatives with exercise in normal subjects by Doppler ultrasound.

Using the continuous-wave Doppler technique of transcutaneous aortovelography (TAV), aortic blood velocity was measured in 66 normal individuals at rest and during maximum voluntary supine exercise. Stroke distance (the systolic velocity integral: a measure of stroke volume), minute distance (a measure of cardiac output=stroke distance times heart rate) and peak velocity increased significantly with exercise, but flow time shortened slightly. Stroke distance was found to rise to a plateau of 24% above the resting value at low work rates during exercise. This relatively undemanding noninvasive technique for measuring haemodynamic response to physiological stress may prove valuable in the assessment of left ventricular function. Our results in normals are consistent with findings by other techniques and provide a basis for clinical comparisons.

Carcinogenicity of 1-(2-hydroxyethyl)-1-nitrosourea and 3-nitroso-2-oxazolidinone administered in drinking water to male MRC-Wistar rats: induction of bone, hematopoietic, intestinal, and liver tumors.

A previous report was made on the carcinogenicity of 1-(2-hydroxyethyl)-1-nitrosourea [(HENU) CAS: 13743-07-2] in rats. Because the cyclic nitrosocarbamate 3-nitroso-2-oxazolidinone (NOZ) is readily produced during the synthesis of HENU and can be confused with HENU, HENU was retested and NOZ was tested for carcinogenicity. Improved syntheses of both compounds are described. They were administered in drinking water to male MRC-Wistar rats for 1 year, starting at 3 or 9 weeks of age. The HENU-treated rats showed incidences of 48% for bone tumors, 32% for intestinal tumors (mostly duodenal adenocarcinomas), and 53% for lymphoma-leukemia. Of the bone tumors, which were evaluated microscopically and radiologically, 68% were osteosarcomas and 32% were osteoblastomas. The skeletal distribution of these tumors was similar to that of human osteosarcoma, with the tumors occurring most frequently in the lower limbs near the knees. Of the hematopoietic tumors, the majority were lymphoblastic lymphoma-leukemia, which showed a diffuse organ distribution resembling human B-cell (Burkitt's-like) lymphoblastic lymphoma-leukemia, and differed from the usual type of convoluted T-cell lymphoma-leukemia induced by other nitrosoureas in rats and mice. NOZ induced intestinal tumors (mostly duodenal adenocarcinomas) in 80% and liver tumors (mostly hepatocellular adenomas) in 53% of the rats.

Effects of dietary selenium on bis(2-oxopropyl)nitrosamine-induced carcinogenesis in Syrian golden hamsters.

In studies designed to determine the influence of dietary Se on pancreatic carcinogenesis, Syrian golden hamsters were fed unsupplemented torula yeast diet or diet supplemented with 0.1 or 5.0 ppm Se, from sodium selenite, starting at 4 weeks of age until the termination of the study. In separate groups, hamsters were given the diet supplemented with 0.1 ppm Se until 5 days after carcinogen treatment. Then they were fed either the unsupplemented diet or the diet supplemented with 5.0 ppm Se until the end of the experiment. N-Nitrosobis(2-oxopropyl)amine (BOP; CAS; 60599-38-4) treatment was given as a single sc injection of 20 mg/kg (body wt) at 8 weeks of age, and surviving hamsters were killed 50 weeks later. As a measure of Se status, glutathione peroxidase (GSHPX) activities were determined in plasma, erythrocytes, and liver. Values were elevated in animals fed higher levels of dietary Se. BOP treatment depressed plasma GSHPX at 24 hours and elevated erythrocyte and liver values at 4 weeks. Pancreatic ductular adenoma yields were inhibited with each elevation of dietary Se in female hamsters fed the diets, both before and after BOP administration, and were further inhibited in females that were fed diets containing 0.1 ppm Se before BOP administration and that were changed to the unsupplemented or 5.0-ppm-supplemented diets after BOP was given. Pancreatic ductular adenoma yields were highest in all male groups given diets of 0.1 ppm Se before BOP administration, irrespective of the Se level after BOP was fed. Adenoma yields in males were lowest in hamsters fed unsupplemented diet, both before and after BOP treatment. Pancreatic carcinoma yields were low and not influenced by dietary Se. The incidence of hepatic necrosis was elevated in BOP-treated hamsters fed the unsupplemented diet, and that of biliary cystic adenomas was highest in the group fed 0.1 ppm Se before and after BOP treatment.

Test of catechol, tannic acid, Bidens pilosa, croton oil, and phorbol for cocarcinogenesis of esophageal tumors induced in rats by methyl-n-amylnitrosamine.

Catechol (CAS: 120-80-9), given in drinking water to rats, was the most effective of 5 phenols in enhancing [3H]thymidine incorporation [( 3H]dThd-l) into esophageal DNA. To test for esophageal cocarcinogenesis, groups of 30 male MRC-Wistar rats received 3 weekly ip injections of 25 mg methyl-n-amylnitrosamine [(MNAN) CAS: 13256-07-0]/kg. From the time of the first MNAN injection, each group also received catechol, tannic acid (CAS: 1401-55-4), dried leaves of Bidens pilosa L., or croton oil (CAS: 8001-28-3) (respectively, 2, 10, 50, and 2 g/kg semipurified diet), or were given 20 ip injections of 6 mg phorbol (CAS: 17673-25-5)/rat. The rats were killed after 20-45, 46-52, or 53-72 weeks (subgroups A, B, and C). In the group given MNAN alone, most esophageal papillomas developed during the first 45 weeks. Both catechol and B. pilosa significantly increased the esophageal papilloma multiplicity (No. of papillomas/rat) induced by MNAN, with a maximum tumor yield of 2.2 times that in the corresponding subgroup treated with MNAN alone. Papilloma multiplicity increased from subgroup A to subgroup C in the MNAN plus B. pilosa group but not in the MNAN plus catechol group. No tumors were induced by the test cocarcinogens given without MNAN. We concluded that a) an increased esophageal [3H]dThd-I indicates potential cocarcinogenicity and b) catechol and B. pilosa were weak esophageal cocarcinogens. These results support the view that catechol in cigarette smoke and B. pilosa as eaten in South Africa contribute to the etiology of human esophageal cancer.

The value of exercise-induced U-wave inversion on ECG chest wall mapping in the identification of individual coronary arterial lesions.

Exercise-induced U-wave inversion on chest wall mapping was compared with coronary arteriographic findings in 160 consecutive patients who presented with chest pain suggestive of ischaemic heart disease. ECG recordings were made from 16 points on the chest wall before, during and after exercise. None of the 27 patients with normal coronary arteriograms developed U-wave inversion during or after exercise (specificity = 100%). In 21 (all males) of the 133 patients (15.8%) with significant coronary arterial lesions, U-wave inversion on exercise was noticed on different coronary artery territories on the chest wall map, and its localization was correlated with angiographic evidence of individual coronary arterial lesions (100% projection rate). In 9 patients (6.8%) this sign was observed in the absence of any ST segment changes or Q waves. Exercise-induced U-wave inversion was the sole ECG criterion reflecting a lesion of the left anterior descending artery in 12 cases (9%), of the circumflex in 6 cases (4.5%), and in only one case of right coronary artery disease. This sign was not detectable in the conventional V5 site in 9 cases (7.1%) with significant disease of the left anterior descending coronary artery. These nine patients showed U-wave inversion on other areas of the left anterior descending coronary artery territory on exercise. Exercise-induced U-wave inversion disappeared in all the ten patients who underwent coronary artery bypass graft surgery. It is suggested that exercise-induced U-wave inversion shown on chest wall mapping is a reliable indicator of coronary artery disease, which disappears after myocardial revascularization, and in addition, aids identification of individual coronary arterial lesions.

Lack of inhibition by retinoids of bis(2-oxopropyl)nitrosamine-induced carcinogenesis in Syrian hamsters.

Syrian hamsters were treated with either a low (10 mg/kg body weight) or high (40 mg/kg body weight) single dose of bis(2-oxopropyl)nitrosamine (BOP) and beginning 1 week later fed either low (0.2 mmol/kg diet) or high (0.4-1.0 mmol/kg diet) levels of one of four retinoids [13 cis retinoic acid (13-cis-RA), N-ethylretinamide (ERA), N-(2-hydroxyethyl)retinamide (OHERA) or N-(phenyl)retinamide (PRA)] for periods of 40 or 50 weeks. The high retinoid levels (0.4-1.0 mmol/kg diet) fed following the highest BOP treatment enhanced pancreatic carcinoma yields (average number/effective animal) in males fed all four retinoids, and in females fed ERA and 13-cis-RA. Enhanced adenoma yields were also seen in all groups when high retinoid levels were fed following 40 mg BOP/kg body weight. However, these retinoid levels caused an increased adenoma yield in male hamsters only and did not modify carcinoma yields when fed following 10 mg BOP/kg body weight. Similarly, tumor yields at extra-pancreatic sites were elevated in retinoid-fed hamsters of both sexes after 40 mg BOP/kg body weight and in males fed ERA and 13-cis-RA after 10 mg BOP/kg body weight when retinoids were given at the high levels (0.4-1.0 mmol/kg diet). Increased incidences of bile duct and liver tumors in particular were found in hamsters given 40 mg BOP/kg body weight. Consumption of retinoid levels of 0.4 mmol/kg diet and above was also associated with a high incidence of liver cell necrosis, ovarian cysts and ovarian hemorrhage. Retinoids (ERA, OHERA, and PRA) fed at the low level (0.2 mmol/kg diet) following the low BOP dose did not enhance carcinogenesis in the pancreas or at other sites and did not cause alterations in morphologic observations.

Liver and forestomach tumors and other forestomach lesions in rats treated with morpholine and sodium nitrite, with and without sodium ascorbate.

Administration to rats of ascorbate with morpholine and nitrite was previously shown to inhibit the liver tumor production and to enhance the induction of forestomach tumors, as compared to treatment with morpholine and nitrite. In a repetition of this experiment, 10 g morpholine/kg in the diet and 2 g sodium nitrite/liter in the drinking water were administered for life to male MRC-Wistar rats without (group 1) or with (group 2) 22.7 g sodium ascorbate/kg in the diet. Group 3 was untreated. Group 2 showed a lower liver tumor incidence with a longer latency than group 1, indicating a 78% inhibition by ascorbate of in vivo N-nitrosomorpholine (NMOR) formation. The incidence of forestomach papillomas was 3% in group 1, 38% in group 2, and 8% in group 3. The difference between groups 1 and 2 was not significant due to the shorter life-span of group 1. Group 1 and especially group 2 had more forestomach hyperplasia and hyperkeratosis than group 3. Ascorbate might have enhanced induction of these lesions because of an action synergistic with that of NMOR. However, it is most likely that the lowered NMOR dose and concomitantly increased survival produced by the ascorbate were solely responsible for the increased incidence of forestomach papillomas and other lesions in group 2.

Electrocardiographic chest wall mapping in the diagnosis of coronary artery disease.

Chest wall mapping of ST segment changes, inverted U waves, and Q waves using 16 electrocardiographic electrodes was performed at rest and during and after bicycle ergometry in 150 patients presenting with chest pain suggestive of angina. All patients underwent coronary angiography. The presence or absence of appreciable coronary artery disease (greater than or equal to 50% stenosis) was detected with a sensitivity of 98% and a specificity of 88%. The identification of lesions in individual coronary arteries was also possible with a sensitivity and specificity of 87% and 85% respectively for the territory of the left anterior descending and diagonal artery, 71% and 85% respectively for the right coronary artery, and 85% and 80% respectively for the circumflex artery. This test appears to be a reliable non-invasive screening method for selecting patients for angiography.

Modifying factors in pancreatic carcinogenesis in the hamster model. I. Effect of protein-free diet fed during the early stages of carcinogenesis.

The role of protein in pancreatic carcinogenesis was examined in outbred Syrian golden hamsters treated with the pancreatic carcinogen N-nitrosobis(2-oxopropyl)amine (BOP) and fed a purified protein-free diet (PPFD). The PPFD was fed for 28 days from 8 weeks of age; before and after animals were fed PPFD, they were given a commercial diet (CD). BOP was given before PPFD feeding (group 1) or at 18 days (group 2) and 28 days (group 3) from the beginning of the PPFD feeding. BOP-treated control hamsters (group 4) were pair-fed a purified control diet (PCD) instead of PPFD. All animals fed PPFD and PCD were returned to a CD for the rest of the experiment, which was terminated in each group 52 weeks after BOP treatment. The results showed a highly significant reduction of tumor incidence (P less than 0.0001) in hamsters that received PPFD, when compared to those fed PCD, regardless of the time of carcinogen administration during the dietary regimen. Hamsters treated with BOP at 18 days of PPFD (group 2) developed neither benign nor malignant pancreatic tumors. The inhibition of pancreatic neoplasms was not related to reduced calorie consumption, since this occurred in the BOP-treated hamsters that were pair-fed the PCD diet. The results indicated that both the initiation and promotion of pancreatic carcinogenesis with BOP in hamsters can be inhibited by lack of protein in the diet given for 4 weeks during the early stages of the neoplastic process.

Syncarcinogenic effect of the environmental pollutants cyclopenteno[cd]pyrene and benzo[a]pyrene in mouse skin.

Benzo[a]pyrene (BP) and cyclopenteno[cd]pyrene (CPEP) are widespread environmental pollutants. CPEP is a relatively potent carcinogen in mouse skin with an activity second only to BP among environmental aromatic hydrocarbons. We have studied the combined application of BP and CPEP on mouse skin to determine their possible synergistic carcinogenic effect. Nine-week-old female Swiss mice in groups of 30 were treated on the back with high (H), medium (M) and low (L) doses, respectively, of 20 (H), 6.6 (M) or 2.2 (L) nmol BP or 200 (H), 66.6 (M) or 22.2 (L) nmol CPEP in 50 microliters acetone twice weekly for 48 weeks. Other groups received BP-H + CPEP-H, BP-M + CPEP-M, BP-L + CPEP-L, BP-H + CPEP-L, BP-M + CPEP-L, BP-L + CPEP-H, or BP-L + CPEP-M. A significant, 3- to 7-fold syncarcinogenic effect occurred when BP-M + CPEP-M were administered together. A smaller, but significant, synergistic effect (1.2- to 3.8-fold) was also observed when BP-M + CPEP-L or BP-L + CPEP-M was applied. Because of the syncarcinogenic effect of BP and CPEP, their abundance in engine emissions and ambient air samples may present a major source of carcinogenic risk.

Carcinogenicity test of acetoxime in MRC-Wistar rats.

Acetoxime was tested for carcinogenicity by chronic administration in the drinking water to male and female outbred MRC-Wistar rats. The dose of 1.0 g/liter was administered 5 days/week for 18 months (total dose, 6.2--7.0 g/rat). The test compound induced benign hepatocellular adenomas in 80% of the males but did not produce tumors in the females. This is the first report that oximes, which are fairly widely used in industry, are tumorigenic.