Riboflavin and mouse hepatic cell structure and function. II. Division of mitochondria during recovery from simple deficiency.

Mice which had been on a riboflavin-free diet for 6-8 wk were given daily intraperitoneal injections of riboflavin. The hepatic mitochondria, which in the deficient animals were greatly enlarged, were restored to normal dimensions within 3 days. Normalization of the mitochondrial population was brought about by division of the giant organelles. Dividing mitochondria were characterized by a membranous partition separating the inner compartment into two distinct chambers. Such organelles showed varying degrees of pinching at the level of the partition. The most common site of partition formation was at the base of a small mitochondrial bud. During the 1st day of recovery, dividing mitochondria were so common that they could be easily found in mitochondrial pellets. Injection of riboflavin into normally nourished mice also produced an apparent increase in the frequency of dividing mitochondria in the liver cells.

Smoke of cigarettes and little cigars: an analytical comparison.

Chemical data are presented from a comparison study of the smoke of cigarettes and little cigars. The tobacco products and their mainstream smokes were analyzed for a number of toxic constituents in an effort to define "smoke inhalability." This issue has particular public health importance because the difference in the inhalability of cigar and cigarette smoke is generally assumed to account for the differences in the health risk to the individual smoker.

Artificial sweetener use and bladder cancer: a case-control study.

In a case-control study of 302 male and 65 female bladder cancer patients and an equal number of other patients matched to them in age, sex, hospital, and hospital-room status, no association was found between use of artificial sweeteners or diet beverages and bladder cancer. No dose-response was observed with respect to quantity or duration of use of the two combined. No evidence was found to suggest that artificial sweeteners or diet beverages promote the tumorigenic effect of tobacco smoking. Artificial sweetener and diet beverage use strongly reflected socioeconomic status among controls with various diagnoses.

Hydroxyurea: suppression of two-stage carcinogensis in mouse skin.

Hydroxyurea, a selective cytotoxic agent for cells in DNA synthesis, injected intraperitoneally at 24 and 48 hours after the first painting with 1 percent croton oil, significantly reduced the tumor yield in the two-stage chemical carcinlogenesis in mouse skin. A comparable group of mice receiving hydroxyurea only once at 24 hours had a tumor induction similar to that in controls.

Carcinogenicity of methylchrysenes.

Methylchrysenes are present in tobacco smoke and are suspected to contribute to the tumorigenicity of this inhalant. Chrysene and the six isomeric methylchrysenes were obtained in high purity (99.9 percent); they were tested on mouse skin for tumor initiating activity and carcinogenicity. The 3- and 6-methylchrysenes are strong tumor initiators, whereas the other five chrysenes have moderate initiatinig activity. 5-Methylchrysene is a strong carcinogen; the other chrysenes are inactive or weak carcinogens.

Fecal bacterial beta-glucuronidase: control by diet.

The effect of a mixed Western, high meat diet or a nonmeat diet on the intestinal bacterial beta-glucuronidase activity was studied in human volunteers. This enzyme was significantly higher in stools of subjects on a high meat diet as compared to the nonmeat regimen. Thus, intestinal flora of subjects on a high meat diet was more able to hydrolyze glucuronide conjugates than that of individuals on a nonmeat diet. This, in turn, may raise the amount of substances, such as carcinogens, within the colonic lumen.

N'-nitrosonornicotine in tobacco.

N'-Nitrosonornicotine, a potential carcinogen, has been positively identified in unburned tobacco. The amount in commercial U.S. tobacco products is between 1.9 to 88.6 parts per million, one of the highest values of an environmental nitrosamine yet reported. The amount in food and drink rarely exceeds 0.1 part per million. This compound is the first example of a potential organic carcinogen isolated from tobacco.

Impact of long-term filter cigarette usage on lung and larynx cancer risk: a case-control study.

A case-control study was conducted among 1.034 white male and female hospital patients with histologically proved lung cancer (Kreyberg type l) or larynx cancer. After adjustment for duration of the smoking habit, inhalation, and butt length, relative risks of developing lung or larynx cancer were consistently lower among long-term smokers of filter cigarettes than among smokers of nonfilter cigarettes, irrespective of quantity smoked. Relative risks in all groups declined with increased years of smoking cessation. The observed risk reduction among current smokers of filter cigarettes was consistent with that expected, considering that these persons had smoked the older high-tar nonfilter cigarettes for a large proportion of their lives.

Differences in lung cancer risk between men and women: examination of the evidence.

BACKGROUND: Lung cancer incidence is gradually leveling off in U.S. men but is continuing to rise in U.S. women. This increase in U.S. women exceeds that expected from a slower decline of smoking among women. Recent epidemiologic and biochemical studies suggest gender differences in susceptibility to tobacco carcinogens. PURPOSE: We conducted an up-to-date, more in-depth evaluation of our earlier observation of a potential gender difference in relative risk (RR) of lung cancer due to smoking. We added information from several additional case and control subjects and included more precise histologic classification of the cancer type, accurate quantitation of smoke exposure, and adjustments for body size. METHODS: The present investigation was a part of an ongoing hospital-based, case-control study by the American Health Foundation. It included data from 1889 case subjects (1108 males and 781 females) with lung cancer of squamous/epidermoid, small-cell/oat cell, large-cell, and adenocarcinoma types and 2070 control subjects (1122 males and 948 females) with diseases unrelated to smoking. The case and control subjects were admitted to participating hospitals from 1981 to 1994 and were pair-matched by age, sex, hospital, and the time of hospital admission. Ex-smokers and non-Caucasians were excluded from analyses to avoid confounding. The RRs and 95% confidence intervals were estimated from adjusted odds ratios (ORs) by use of unconditional multiple logistic regression analysis, and statistical significance was determined by two-sided tests. The ORs for major histologic types were estimated at increasing levels of exposure to cigarette smoke. RESULTS: Our results indicated that women were more likely to be never-smokers than men, particularly those with the squamous/epidermoid-type cancer (8.3% for women versus 2.9% for men 55 years old or older). Men started smoking earlier, reported inhaling more deeply, and smoked more cigarettes per day than women. In contrast, dose-response ORs over cumulative exposure to cigarette smoking were 1.2-fold to 1.7-fold higher in women than in men for the three major histologic types; these differences were more pronounced for small-cell/oat cell carcinomas and adenocarcinomas than for squamous/epidermoid carcinomas. Adjustments for weight, height, or body mass index did not alter the ORs. CONCLUSIONS: These results confirm our earlier finding that the ORs for major lung cancer types are consistently higher for women than for men at every level of exposure to cigarette smoke. Furthermore, this gender difference cannot be explained by differences in base-line exposure, smoking history, or body size, but it is likely due to the higher susceptibility to tobacco carcinogens in women.

Epidemiology of breast cancer and hair dyes.

In a case-control study of 401 breast cancer cases and 625 age-matched controls, the possible etiologic role of hair dye usage was investigated. No association was found between hair dye use and breast cancer (odds ratio = 1.02; 95% confidence interval = 0.77-1.32) or any factors affecting dosage, frequency, duration, type, or color of hair dye. Important confounders of hair dye use included religion and smoking status. When stratified by 10-year age groups, there was no appreciable trend in risk status between case and referent populations. No dose-response relationship (frequency X duration X shade X type of dye used) was found, even after controlling for factors affecting hair dye use. A multiple logistic regression analysis supported the absence of this relationship.

Association of dietary fat and lung cancer.

An international comparison study of the relationship among dietary predictors, tobacco consumption, income, and truncated age-adjusted lung cancer mortality was conducted with the use of time-lagged data available for 43 countries. A regression analysis weighting each country by the square root of the appropriate population and adjusting for several covariates showed that calories from dietary fat were highly significantly associated (P less than .0001) with lung cancer mortality. This finding was obtained after accounting for disappearance data for tobacco (P less than .0001), the dominant risk factor for lung cancer, and total nonfat calories (P less than .002). Other covariates included per capita gross national product and proportion of calories from fruits, vegetables, roots, tubers, and pulses. Weaknesses of this study, statistical considerations, biologic plausibility, in particular the modulation of tobacco-smoke carcinogens by lipids in the lung, and suggestions for future study are discussed.

Breast cancer risk: effects of estrogen replacement therapy and body mass.

BACKGROUND: Epidemiologic studies have focused on the association between breast cancer risk and a variety of lifestyle and exogenous factors. PURPOSE: The purpose of this study was to clarify the effects of alcohol consumption, cigarette smoking, oral contraceptive (OC) use, estrogen replacement therapy (ERT), and body mass on risk of breast cancer. METHODS: These variables were examined in a case-control study of 604 patients with newly diagnosed breast cancer and 520 control subjects who did not have breast cancer and were frequency matched for age, hospital, and time of diagnosis. These case patients and control subjects were part of an ongoing study of breast cancer by the American Health Foundation and were selected for interview from hospitals in the New York City area from January 1987 through December 1989. The data were analyzed by computation of odds ratios (ORs) for potential risk factors, with adjustment for age at diagnosis and other potential confounding variables and with stratification by menopausal status. RESULTS: We observed positive effects of ERT and high body mass on the risk of postmenopausal breast cancer, particularly when each factor was examined in the absence of the other factor. In lean postmenopausal women, the adjusted summary OR associated with ERT was significantly elevated (OR = 2.0; 95% confidence interval [CI] = 1.1-3.5; P < .01), and there was a statistically significant dose response of breast cancer risk with ERT duration (adjusted ORs = 2.0 for < 5 years and 2.2 for > or = 5 years; positive trend, P < .02). Reciprocally, in women who did not receive ERT, high body mass (Quetelet index > 27) was a significant risk factor for postmenopausal breast cancer (OR = 2.1; 95% CI = 1.3-3.3; P < .02), and the linear trend in risk with increasing body mass was significant (positive trend, P < .02). The strongest effect of body mass occurred in women who were lean at age 18 and gained enough weight to place them in the upper tertile of body mass at the time of diagnosis (OR = 2.6; 95% CI = 1.5-4.6; P < .01). There was no evidence of significant positive associations between breast cancer risk and cigarette smoking, alcohol consumption, or OC use in any subgroup of these women. CONCLUSIONS: Our results support the hypothesis that excess adipose deposition heightens breast cancer risk in the postmenopausal years. Furthermore, they underscore the need for continuing investigation of the effects of exogenous estrogens on the development of this malignancy, particularly in lean postmenopausal women.

Oral cancer and mouthwash use.

The role of mouthwash and other factors was examined in relation to oral cavity cancer by means of a retrospective study. Daily use of mouthwash showed an excess risk in females but no excess risk in males. No dose response was seen in females with increased duration of use. In nonsmoking, nondrinking women as well, daily mouthwash use was associated with excess risk. Multiple logistic regression including all factors of interest showed inconsistent results for duration and frequency of mouthwash use. Due to the absence of a dose-response relationship and the possibility of confounding by tobacco and alcohol use, it was not possible to attribute causal significance to the association between daily mouthwash use and oral cancer in women.

Primary prevention of cancer among children: changes in cigarette smoking and diet after six years of intervention.

A study of the effectiveness of an intervention program designed to favorably modify behaviors hypothesized to be related to the future development of cancer was initiated among 1,105 eligible children in 15 schools in the vicinity of New York City. Schools were assigned to either an intervention or a nonintervention group. Subjects in schools in the intervention group received each year, from fourth through ninth grade, a teacher-delivered curriculum focusing on diet and prevention of cigarette smoking. After 6 years of intervention, the rate of initiation of cigarette smoking was significantly lower among subjects in intervention schools than among those in nonintervention schools. There was a significant net decrease in reported intake of saturated fat and a significant net increase in reported intake of total carbohydrate among subjects in intervention schools compared to those in nonintervention schools. These findings, if replicated, suggest that such programs are feasible and acceptable and may have a favorable effect on diet and prevention of cigarette smoking in children.

Demographic aspects of the low-yield cigarette: considerations in the evaluation of health risk.

Control data from a large-scale case-control study of tobacco-related diseases were analyzed to characterize variables associated with cigarette preference (or type of cigarette smoked). Age, sex, race, education, and religion were found to have a strong influence on the choice of cigarette according to tar and nicotine yield. Data on the amount and duration of cigarette smoking also were evaluated by brand history to determine whether tar yield was associated with these variables. Women smoking cigarettes in the low-tar categories tended to smoke fewer cigarettes per day than women smoking cigarettes in the higher tar categories. A similar trend was not found for men. As might be expected, only 2% of the men and 3% of the women over the age of 40 smoked low-tar cigarettes (less than 10 mg tar) for 10 years or more.

A study of tobacco carcinogenesis. XIV. Effects of N'-nitrosonornicotine and N'-nitrosonanabasine in rats.

N'-Nitrosonornicotine (NNN) and N'-nitrosoanabasine (NAB) were synthesized and administered in drinking water to male Fischer rats for 30 weeks (total dose, 630 mg). 1,4-Dinitrosopiperazine (DNPI) served as the positive control. By 11 months, all surviving rats given NNN developed esophageal tumors (12/20); 1 had a pharyngeal tumor and 3 had invasive carcinomas originating in the nasal cavity. During the same time, only 1 of 20 rats given NAB developed esophageal tumors. Compared to the strong esophageal carcinogen DNPI, NNN was a moderately active and NAB a weak carcinogen. NNN (0.3-90 parts per million) in chewing tobacco was related to the observation that cancer of the oral cavity and esophagus in man was correlated with the chewing of tobacco.

Influence of dietary fat on the induction of mammary tumors by N-nitrosomethylurea: associated hormone changes and differences between Sprague-Dawley and F344 rats.

A single iv dose of N-nitrosomethylurea (NMU, 50 mg/kg) given to 50-day-old F344 and Sprague-Dawley rats was sufficient to induce mammary adenocarcinomas. The Sprague-Dawley rats were more sensitive to the carcinogenic action of NMU than were the F344 rats. Moreover, regardless of strain, tumors developed in greater numbers and with a shorter latent period in animals fed a high-fat (HF) diet compared with animals fed a low-fat (LF) diet. The tumor-enhancing effect of HF diet was not related to body weight, since the mean body weight of the rats on the two diets was similar. In addition, no correlation was found between body weight and tumor incidence in individual rats under either dietary regimen. Since the most pronounced difference in tumor incidence between groups fed HF and LF diets was exhibited by the F344 rats, hormone analyses were performed on this group. At termination of the experiment, prolactin levels in the group fed an HF diet were significantly higher than those in the group fed an LF diet. Total estrogen levels were also significantly higher in the group fed an HF diet, compared with the group fed an LF diet, but this difference was seen only at the metestrus-diestrus stage. Regardless of diet or estrous cycle, when animals with tumors were compared with those without tumors, the former exhibited higher prolactin-estrogen (P/E) ratios. The results suggested a relationship between the ingestion of high levels of dietary fat, a high P/E ratio, and increased mammary tumor incidence.

Promoting effect of sodium deoxycholate on colon adenocarcinomas in germfree rats.

The promoting effect of sodium deoxycholate (DC) on colon carcinogenesis was studied in female F344 germfree rats. Animals received intrarectal (ir) instillations of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) for 4 weeks (total dose, 16 mg/rat), then weekly ir doses of DC (total dose, 3 g/rat); the rats were autopsied 52 weeks after the first injection. DC increased the number of MNNG-induced colon adenocarcinomas. No tumors were in the colons of germfree rats given DC alone. It was concluded that DC (present in high concentrations in human stools) had a promoting effect on colon carcinogenesis in rats.

Breast cancer: weighing the evidence for a promoting role of dietary fat.

It has been hypothesized that a high-fat diet promotes the development of postmenopausal breast cancer. This contention is supported by data showing high international correlations between fat intake and breast cancer rates, modest positive associations with a high-fat diet in case-control studies, and animal model studies that have consistently demonstrated that dietary fat influences mammary cancer development at several stages in the carcinogenic process. A number of plausible biologic mechanisms have been suggested that may explain such promotional effects. In contrast, dietary fat intake is unrelated to the risk of breast cancer in cohort studies. The conflicting findings from cohort studies have created uncertainty regarding nutritional recommendations and breast cancer prevention. After reviewing key scientific findings that are relevant to this issue, the following conclusion is drawn: In the absence of data from dietary intervention trials, the weight of available evidence suggests that the type and amount of fat in the diet is related to postmenopausal breast cancer and that the inability to detect associations within populations (cohort studies) is because of measurement error and the relative homogeneity of diets measured. It is expected that the results from intervention trials will clarify this issue.

The epidemiology of large bowel cancer.

Results from epidemiogical studies have provided clues as to etiological factors involved in the development of large bowel cancer. Overnutrition, especially in terms of dietary fat consumed, appears to be a key etiological variable affecting the rate of colon cancer. Epidemiologists can provide the leads for chemists and bacteriologists to pursue in population groups and for experimentalists to test in laboratory animals. Coordination of and cooperation between many disciplines is necessary in order to contribute to the prevention of this man-made disease.