Vegetables, Fruit, and Cancer Prevention: A Review

In this review of the scientific literature on the relationship between vegetable and fruit consumption and risk of cancer, results from 206 human epidemiologic studies and 22 animal studies are summarized. The evidence for a protective effect of greater vegetable and fruit consumption is consistent for cancers of the stomach, esophagus, lung, oral cavity and pharynx, endometrium, pancreas, and colon. The types of vegetables or fruit that most often appear to be protective against cancer are raw vegetables, followed by allium vegetables, carrots, green vegetables, cruciferous vegetables, and tomatoes. Substances present in vegetables and fruit that may help protect against cancer, and their mechanisms, are also briefly reviewed; these include dithiolthiones, isothiocyanates, indole-3-carbinol, allium compounds, isoflavones, protease inhibitors, saponins, phytosterols, inositol hexaphosphate, vitamin C, D-limonene, lutein, folic acid, beta carotene, lycopene, selenium, vitamin E, flavonoids, and dietary fiber. Current US vegetable and fruit intake, which averages about 3.4 servings per day, is discussed, as are possible noncancer-related effects of increased vegetable and fruit consumption, including benefits against cardiovascular disease, diabetes, stroke, obesity, diverticulosis, and cataracts. Suggestions for dietitians to use in counseling persons toward increasing vegetable and fruit intake are presented. J Am Diet Assoc. 1996; 96:1027-1039.     

A New Low Threshold Platinized Epicardial Pacing Electrode: Comparative Evaluation in Immature Canines

A prospective comparison of pacing and sensing capabilities between the conventional Medtronic Model 4951 platinum-iridium epicardial pacing electrode and a new modified "platinized" version of the same electrode was performed in immature canines to determine if the new electrode design improves pacing in the immature myocardium. The conventional electrode was modified by electroplating platinum black particles onto the surface to increase the effective or true microscopic surface area, yet essentially maintain the same overall geometric electrode size. Both epicardial electrodes were inserted into the right ventricular myocardium with the lead pad sutured to the epicardium, and externalized to the scruff in five puppies (age 3 months). An additional left ventricular lead was implanted to permit chronic pacing following epicardially-induced atrioventricular block. Acute and chronic sensing and pacing capabilities of each externalized electrode were performed at implant and weekly up to 4 months. Histologic examination of each electrode implant site was performed at the end of the study period. At implant, both electrodes exhibited comparable values for sensed R waves, lead impedances, and pacing thresholds. During the study, the platinized electrode exhibited lower pacing thresholds. Analysis of all postimplant data demonstrated this threshold difference to be significantly lower (P less than .01) for the platinized version. Lead impedance and sensing capabilities remained comparable between the two designs. Histologic study demonstrated less fibrotic infiltration at the platinized electrode site. This preliminary evaluation indicates that for the duration of the postimplant study period, the platinized epicardial electrode design was associated with significantly lower thresholds and less fibrosis as a function of time compared to the conventional smooth electrode surface design. The new platinized electrode limits exit block in the developing immature myocardium and permits safe pacing at lower pulse widths and voltages to increase battery life.     

Effects of Glycerol on Lung and Liver Tumor Development

Mice of several strains(A/J, SWR, MaMyJ, BALB/cByJ, 129J, andC57BL/6J) were treated with the carcinogens 3-methylcholanthrene,urethane, and 4-nitroquinoline 1 -oxide and then given 1 or5% glycerol in the drinking water for up to 4 months. Effectsof glycerol on lung tumor multiplicity and incidence were evaluated.The effects of glycerol were variable, and in the majority ofexperiments glycerol failed to enhance tumor development inmouse lung. Analysis of cell kinetics did not show a proliferativeresponse of alveolar or bronchiolar cells to glycerol. In rats,glycerol did not enhance the appearance of putative preneoplasticliver foci, and in C3H mice it did not increase the incidenceof spontaneously occurring liver tumors. It is concluded thatglycerol does not increase number or incidence of lung tumorsin the mouse strains used, whether the animals are pretreatedwith a carcinogen or not. Glycerol does not affect liver tumordevelopment.     

Acute, Distribution, and Subchronic Toxicological Studies of Succinate Tartrates

The estimated single-dose oral toxicity (50% lethality) of succinatetartrates (ST) was 2–3 g/kg in rats. ST produced minimalto moderate dermal irritation but no evidence of systemic toxicityin a standard acute percutaneous toxicity test in rabbits. STwas not an eye irritant in a standard rabbit low-volume eyeirritation test ST was not genotoxic in a series of six genotoxicitytests. A 14-day oral gavage study in rats at a dose range of0.05–1.0 g ST/kg/day produced only gastric irritation.The no-observed-effect level (NOEL) for gastric irritation was0.1 g/kg for males and 0.05 g/kg for females. A 28-day percutaneoustoxicity study in rabbits produced minimal to moderate dermalirritation and no adverse systemic effects at a high dose of450 mg ST/kg/day. Single-dose absorption, distribution, andelimination (ADE) studies in male rats showed that 10–15%of an oral dose and 1–3% of a dermal dose were absorbed.Approximately 98% of the orally administered ST was eliminatedas ¹⁴C in urine, feces, or expired CO₂ after 72 hr. Approximately80% of the dermally absorbed ¹⁴C dose was eliminated in urine,feces, or expired CO₂ after 72 hr. In conclusion, no adverseeffects were noted in acute toxicity, genotoxicity, or subchronictoxicity studies conducted with ST.     

Distribution of matrix metalloproteinases and their inhibitor, TIMP-1, in developing human osteophytic bone

Connective tissues synthesise and secrete a family of matrix metalloproteinases (MMPs) which are capable of degrading most components of the extracellular matrix. Animal studies suggest that the MMPs play a role in bone turnover. Using specific polyclonal antisera, immunohistochemistry was used to determine the patterns of synthesis and distribution of collagenase (MMP-1), stromelysin (MMP-3), gelatinase A (MMP-2) and gelatinase B (MMP-9) and of the tissue inhibitor of metalloproteinases-1 (TIMP-1) within developing human osteophytic bone. The different MMPs and TIMP showed distinct patterns of localisation. Collagenase expression was seen at sites of vascular invasion, in osteoblasts synthesising new matrix and in some osteoclasts at sites of resorption. Chondrocytes demonstrated variable levels of collagenase and stromelysin expression throughout the proliferative and hypertrophic regions, stromelysin showing both cell-associated and strong matrix staining. Intense gelatinase B expression was observed at sites of bone resorption in osteoclasts and mononuclear cells. Gelatinase A was only weakly expressed in the fibrocartilage adjacent to areas of endochondral ossification. There was widespread but variable expression of TIMP-1 throughout the fibrous tissue, cartilage and bone. These results indicate that MMPs play a role in the development of human bone from cartilage and fibrous tissue and are likely to have multiple functions.     

Transplantation Antigens and Malignant Lymphomas in Man: Follicular Lymphoma, Reticulum Cell Sarcoma and Lymphosarcoma

134 patients with malignant lymphoma (follicular lymphoma, 56 patients; lymphosarcoma, 50 patients; reticulum cell sarcoma, 28 patients) have been typed for eight well-defined antigens of the HL—A system, the major histocompatibility system in man. A significant association exists between HL—A12 and this disease group. This is most marked for the patients with follicular lymphoma. The significance of this finding is discussed.     

Acute Inhalation Toxicity of Aliphatic (C1-C5) Nitrites in Rats

Acute Inhalation Toxicity of Aliphatic (C₁–C₅) Nitritesin Rats. KLONNE, D. R., ULRICH, C. E., WEISSMANN, J., and MORGAN,A. K. (1987). Fundam. Appl. Toxicol. 8, 101–106. The 4-hrinhalation LC50 was determined for methyl-, ethyl-, n-propyl-,n-butyl-, isobutyl-, and isopentyl nitrite in Sprague-Dawleyrats. LC50 values were 176, 160, 300, 420, 777, and 716 ppm,respectively. The dose-mortality curves were characterized byextremely steep slopes. Toxic signs observed during exposureincluded cyanosis, prostration, and rarely, convulsions. Therewere no effects of exposure on body weight gain during a 14-daypostexposure observation period. Signs of pulmonary hemorrhagewere apparent in rats which died during exposure but were muchless prominent in rats sacrificed at study termination. No animalsdied after cessation of exposure, and rapid recovery was apparentafter exposure. Concentration x Time (CT) relationships suggestedthat the actual concentration was more important than the "dose"in determining the lethal effects of inhalation exposure tonitrites. Because of the extremely steep dose-mortality curves,the aliphatic nitrites are more hazardous than the LC50 valueswould indicate.     

The Effects of Magnetic Resonance Imaging on Implantable Pulse Generators

The effects of magnetic resonance imaging were assessed on four dual chamber and two single chamber pulse generators. The tests were performed with a resistive, water-cooled magnet operating at 0.15 T. The 6.4-MHz radiofrequency (RF) field was operated at a maximum power of 1,000 watts with a period adjusted from 130 to 500 ms. Reed switch closure occurred in all six pulse generators tested when placed near the entrance of the magnetic resonance imaging scanner, and the generators reverted to asynchronous operation unless programmed to the "magnet off" mode. None of the pulse generators exhibited any alterations in programmed parameters or in the ability to be reprogrammed after RF pulsing. When the RF field was turned on, there was no change in the asynchronous paced cycle length in four pulse generators; however, during RF scanning there was rapid cardiac stimulation at the RF pulse period in one single chamber and one dual chamber pulse generator.     

Developmental Toxicity Evaluation of Ethylene Glycol by Gavage in New Zealand White Rabbits

Artificially inseminated New Zealand white (NZW) rabbits wereadministered ethylene glycol (EG) by gavage on Gestational Days(GD) 6 through 19 at doses of 0, 100, 500, 1000, or 2000 mg/kg/day,with 23–24 inseminated animals per group. Clinical signswere recorded and water consumption was measured daily; doeswere weighed on GD 0, 6–19, 25, and 30. At necropsy (GD30), maternal liver, kidney, and gravid uterine weights wererecorded. Histopathologic examination was performed on kidneysfrom 10 does/dose and for all unscheduled deaths. Ovarian corporalutea were counted and uterine implantation sites (total sites,resorptions, dead and live fetuses) were recorded. All livefetuses were weighed, sexed, and examined for external, visceral,and skeletal malformations and variations. EG resulted in profoundmaternal toxicity at 2000 mg/kg/day (42% mortality; three earlydeliveries and one spontaneous abortion) associated with renalpathology and unaccompanied by any other indicators of maternaltoxicity. Renal lesions at 2000 mg/kg/day involved the corticalrenal tubules and included intraluminal oxalate crystals, epithelialnecrosis, and tubular dilatation and degeneration. No dose-relatedmaternal toxicity occurred at 100–1000 mg/kg/day. Therewas no indication of developmental toxicity at any dose tested,including no effects on pre- or postimplantation loss, numberof fetuses, fetal body weight, or sex ratio (% male fetuses)per litter, and no evidence of teratogenicity. The "no observableadverse effect level" (NOAEL) for maternal toxicity was therefore1000 mg/kg/day and the NOAEL for developmental toxicity wasat least 2000 mg/kg/day in this study. The sensitivity of NZWrabbits relative to that of Sprague—Dawley rats and Swissmice for maternal and developmental toxicity from gavage administrationof EG during organogenesis can be determined for maternal toxicity:rabbits>mice>rats, and for developmental toxicity, mice>>rats >> rabbits.     

Subchronic Toxicity of Cupric Sulfate Administered in Drinking Water and Feed to Rats and Mice

Subchronic Toxicity of Cupric Sulfate Administered in DrinkingWater and Feed to Rats and Mice. HÉBERT, C. D., ELWELL,M. R., TRAVLOS, G. S., FITZ, C. J., AND BUCHER, J. R. (1993).Fundam. Appl. Toxicol. 21, 461–475. The effects of acute poisoning by cupric sulfate in a numberof species are well known; however, the effects of chronic low-levelingestion of cupric sulfate are less well characterized. Becauseexposure of humans to cupric sulfate may occur through drinkingwater, food, soil, or ambient air, subchronic toxicity studieswere conducted in male and female F344/N rats and B6C3F₁ miceby the drinking water (2-week exposure) and dosed feed (2-and13-week exposure) routes. Animals were evaluated for histopathology,clinical pathology, reproductive toxicity, and tissue metalaccumulation, and target organs were examined by a variety ofspecial stains and by electron microscopy to characterize theobserved lesions. In drinking water, cupric sulfate concentrationsof 300 to 100 ppm produced no ill effects, whereas concentrationsof 3000 to 30,000 ppm were lethal to rats and mice within 2weeks. In feed, cupric sulfate concentrations of 4000 to 16,000ppm caused significant reductions in body weight gain in bothspecies in the 2- and 13-week studies. Hyperplasia and hyperkeratosisof the limiting ridge of the forestomach were present in bothspecies in the 2- and 13-week studies. Rats in the dosed feedstudies had a dose-related increase in inflammation in the liverand changes in clinical chemistry parameters which were indicativeof hepatocellular damage and cholestasis. Histologic changesin the kidneys of rats consisted of a dose-related increasein the number and size of eosinophilic protein droplets in theepithelial cytoplasm and the lumina of the proximal convolutedtubules. Droplets were larger and more numerous in males thanin females. Urinalysis results were suggestive of renal tubularepithelial damage. Iron staining of spleens from treated animalsindicated a marked depletion of iron stores in both male andfemale rats, but not in mice, while hematologic and clinicalchemistry alterations in rats in the 13-week study, along withhistologic changes in bone in the 2-week dosed feed study, wereindicative of a microcytic anemia. Cupric sulfate produced noadverse effects on any of the reproductive parameters measuredin rats or mice of either sex. These results indicate that cupricsulfate at high exposure levels is a hepatic and renal toxicant,as well as an inducer of anemia in rodents, with rats more sensitivethan mice following subchronic exposure.