Diet and colon cancer: assessment of risk by fiber type and food source.

How fiber in the diet is related to the development of colon cancer was assessed in a population-based study conducted on 231 cases and 391 controls in Utah between 1979 and 1983. Crude fiber consistently decreased risk associated with colon cancer in both males [odds ratio (OR) = 0.4] and females (OR = 0.5). Dietary fiber, as analyzed by the method of A. S. Bitner, and neutral detergent fiber were not consistently related to colon cancer risk. Of the noncellulose polysaccharides examined, mannose and galactose were protective against cancers in the ascending colon in males (ORs = 0.5 and 0.3, respectively), whereas galactose and uronic acid were protective against cancers in the ascending colon in females (ORs = 0.5). Highest quartiles of intake of fruits and vegetables were also associated with a decreased risk of colon cancer in males (ORs = 0.3 and 0.6, respectively) and in females (ORs = 0.6 and 0.3, respectively) compared with lowest quartile of intake, whereas high intake of grains was not protective.

The need for comprehensive diet studies to assess the relation of lipids to cancer.

Dietary lipids have been linked by both basic research and epidemiological evidence to the etiology of some cancers. It is yet unclear which lipid(s) may be active in the carcinogenic process, but one promising hypothesis concerns the interaction of cholesterol metabolites, considered a risk factor for colon cancer, and dietary fiber which may have a protective role. A multidisciplinary case control study currently underway is investigating the relationship and possible mode of action of fiber and bile acids on colon cancer. The study has epidemiological, biochemical, and pharmacological components that have been designed to integrate data on the intake and fate of lipids, dietary fiber, and other nutritional parameters in colon cancer cases and matched controls and in animal models. Subcomponents of the study deal specifically with the characterization of dietary fiber constituents and their in vivo effect on lipid metabolism.

Quantitation of metabolic and radiobiological effects of 6-aminonicotinamide in RIF-1 tumor cells in vitro.

6-Aminonicotinamide (6AN) can be metabolized to 6-amino-NAD(P+), a competitive inhibitor of NAD(P+)-requiring processes, especially the pentose phosphate pathway (PPP) enzyme, 6-phosphogluconate dehydrogenase. The effect of 6AN on the flux of 1 and 6 13C-labeled glucose to lactate, via glycolysis and the PPP, was investigated using 1H-nuclear magnetic resonance. These studies showed that 6AN as a single agent caused a significant 89% (P < 0.0001) inhibition of glycolytic flux but had no detectable effect on the PPP. 31P-nuclear magnetic resonance studies of perifused RIF-1 cells indicated that 4 h of exposure to 6AN were sufficient to cause significant accumulation of 6-phosphogluconate, the substrate for this enzyme (P < 0.0001). A significant reduction in the phosphocreatine: inorganic phosphate ratio was observed under conditions that led to accumulation of 6-phosphogluconate (P < 0.006). Accumulation of 6-phosphogluconate and subsequent reduction in phosphocreatine correlated with significant potentiation of 6 Gy of irradiation by 6AN. These results suggest that the radiation enhancement effect of 6AN may be due to inhibition of glycolysis (mediated by 6-phosphogluconate) and the associated reduction in high-energy phosphates. Additional studies analyzing the metabolic effects of 6AN in combination with radiation are necessary to determine the role of inhibition of the PPP in 6AN enhancement of radiation.

Cadmium uptake from feed and its distribution to food products of livestock.

Distribution of cadmium (Cd) into the edible products of three species of food-producing animals was investigated during long-term dietary administration of supplemental cadmium chloride. Cows were exposed to 0.2 (control), 2.4, and 11.3 ppm Cd on whole ration basis for a period of three months followed by a three-month period on control ration. No accumulation of Cd occurred in milk, muscle, or bone at any of the time periods. A dose-related increase of Cd was observed in liver and kidney. The Cd concentration in these organs showed a gradual rise even when the animals were given control ration for three months after an initial three-month exposure to Cd; this observation suggests a mobilization and redistribution of this metal from other tissues. Dietary Cd levels in swine rations were 0.2, 2.4, and 10.1 ppm. The highest level of Cd produced a slightly reduced growth rate in swine. No accumulation of Cd was observed in muscle, bone, or brain. Liver and kidney showed a treatment and time-related increase in cadmium values at 6 and 12 weeks on experiment. During a three-month depletion phase after an initial three months of Cd administration, no further change in liver and kidney Cd levels was observed. White Leghorn chickens were treated by administering 0.3, 1.9, and 13.1 ppm Cd in their diets for up to 6 months. No accumulation of Cd occurred in eggs or bones. A slight increase of Cd level was observed in chicken muscle after six months of exposure. Liver and kidney had the highest levels of Cd, which showed a dose and time-related increase in these organs. No depletion of liver and kidney Cd was seen during seven weeks following a six-week treatment period. In all three species, the kidney Cd levels were severalfold higher than those of liver at all dietary levels. In swine, the renal cortex and medulla had similar Cd concentration in control animals but in all animals exposed to supplemental Cd, a dramatic rise in Cd levels in renal cortex was observed. Medullary Cd did not show a proportional time and dose-related increase in Cd levels, although the levels showed some increase. In kidney and liver of all three species the Cd levels showed a positive correlation with the amount of Cd-binding protein in these tissues. Induced levels of this metal-binding protein may explain accumulation and persistence of Cd-residues in these organs. In all three species, the concentrations of renal Cd-binding protein increased at a rate greater than those in liver. Although the food-producing animals may act as an effective filter of Cd in the case of an environmental increase of this metal, consumption of visceral organs from such animals may pose a hazard. This is particularly critical since the daily intake of Cd in human diet is already estimated to exceed the tolerance limits suggested by WHO/FAO.

Ascorbic acid requirements and metabolism in relation to organochlorine pesticides.

Those organochlorine pesticides which possess both high lipoid solubility and high resistance to biodegradation are prone to accumulation in animal tissues and produce relatively long-term effects as toxicants. Such compounds, typified by DDT, Dieldrin, and Lindane, are profound inducers of hepatic microsomal enzymes, including parts of the glucuronic acid and ascorbic acid biosynthetic pathways. Consequently, administering such pesticides to rats in accompanied by enhanced formation and excretion of D-glucuronic acid and L-ascorbic acid, or D-glucaric acid in the case of guinea pigs. Secondarily, the efficiency in biodegrading the pesticides is reduced in ascorbic-acid-deficient guinea pigs with correspondingly greater residue accumulation in tissue. This would aggravate chronic toxic effects of the compounds. Finally, the capacity of the liver to adapt to the presence of such toxicants through enhanced microsomal enzymatic levels appears to be sensitive to its ascorbate status. Impaired enzyme induction is apparent quite early during ascorbic acid depletion in guinea pigs. The enhanced turnover of ascorbate produced by such pesticides, the poor enzymatic adaptation to them during ascorbate depletion and the dependency of the oxidase system upon adequate ascorbate, all point to the central significance of ascorbate status in the liver, and possibly other tissues, as a determinant of their chronic toxicity.

In vivo and ex vivo study of metabolic and cellular effects of 5-fluorouracil chemotherapy in a mouse mammary carcinoma.

The effect of 5-fluorouracil (5FU) on the 31P nuclear magnetic resonance (NMR) profile of a mouse mammary carcinoma, implanted on the foot of CH3/He mice, was studied both in vivo and in perchloric acid extracts. In vivo, significant increases in the ratios, nucleotide triphosphate:inorganic phosphate (Pi) (p < 0.02) and phosphocreatine:Pi (p < 0.005), were observed 48 h after 5FU, relative to control. Two readily resolvable peaks were observed in the phosphomonoester region of the in vivo NMR spectrum, phosphocholine (PC) and a peak (denoted PME') comprised of mainly phosphoethanolamine (PE). PME':PC was significantly elevated relative to control from 24 h to 168 h (p < 0.0001 at 48 h). Perchloric acid extract data indicate that the change in this ratio was due to an increase in the PE concentration rather than a decrease in PC. PE increased from 0.56 +/- 0.11 micromol/g tissue in controls to 0.95 +/- 0.29 micromol/g tissue 48 h after 5FU (p < 0.006). Perchloric acid extracts also revealed a significant increase in phosphodiesters. Glycerophosphocholine increased from 0.82 +/- 0.24 micromol/g tissue in controls to 1.82 +/- 0.61 micromol/g tissue in 5FU treated tumors after 48 h (p < 0.002), and glycerophosphoethanolamine increased from 0.25 +/- 0.06 micromol/g tissue in controls to 0.36 +/- 0.10 micromol/g tissue in treated tumors (p < 0.004). These changes suggest that ethanolamine and choline containing metabolites in this tumor may be metabolized via different pathways. Cell cycle analysis showed only relatively small changes in cell cycle distribution and apoptotic fraction following 5FU.

Effect of radiotherapy and chemotherapy on composition of tumor membrane phospholipids.

Phospholipid extracts were made of a murine mammary adenocarcinoma implanted in the dorsum of the foot of C3H/He mice before and 96 h after 17 Gy irradiation or 150 mg/kg cyclophosphamide. Extracts of untreated tumors, which had grown for a further 96 h, were also studied. Although previous studies have shown significant changes in the precursors and catabolites of phosphatidylcholine and phosphatidylethanolamine following therapy, 31P nuclear magnetic resonance analysis of extracts showed no changes in these membrane constituents and other observed phospholipid species. A significant decrease in 1-alkyl-2-acyl-sn-glycero-3-phosphocholine, however, was observed 96 h following cyclophosphamide treatment.

A specific gas chromatographic analysis for cysteinyl-S-sulfonate residues in physiologically significant proteins treated with sulfite.

It has been shown in previous studies that when sulfite is absorbed by rabbits via either inhalation of SO2 or oral exposure to sulfite, the hydrated form, bisulfite, interacts with plasma disulfides where it is suspected to be in the form, cysteine-S-sulfonate. A rapid and specific gas chromatographic analysis procedure for cysteine-S-sulfonate has been developed to better study the distribution of sulfite in biological systems. Sulfonated proteins are enzymatically hydrolyzed to ensure stability of the acid labile S-sulfonate disulfide. The hydrolysate is then applied to a 6 cm cation-exchange column and eluted with 0.1 N HCl, which elutes the acidic cysteine-S-sulfonate with the void volume of the column, leaving behind any remaining cysteine. The silylated derivatives of the column effluent are prepared using Tri-Sil/BSA. These derivatives are injected into a gas chromatograph equipped with a flame-photometric detector operating in the sulfur mode, 2% OV-101 on Chromosorb W/HP 1/4 inch glass column, oven temperature 140 degrees C, and carrier flow rate of 86 mL/min. The presence of cysteine-S-sulfonate in sulfite-treated rabbits has been directly determined by the described method.

Hepatic and renal metallothionein concentrations in cows, swine, and chickens given cadmium and lead in feed.

Dairy cows, growing swine, and laying chickens were given supplemental cadmium (Cd) at concentrations of approximately 2 and 10 ppm in feed as cadmium chloride and were given lead at concentrations of 5 and 25 ppm in feed as lead acetate for 12 to 24 weeks. Metallothionein (MT) and Cd concentrations increased more in renal than in hepatic tissues of the Cd-treated animals. The hepatic MT values in pigs and chickens and the renal MT values in all species continued to increase for several weeks after Cd feeding was stopped. A significant correlation between Cd and MT concentrations of the hepatic and the renal tissues was observed, except in bovine liver. The feeding of lead did not have any effect on the hepatic or the renal MT concentrations in cows, pigs, and chickens. Dietary Cd and possibly some other metals, but not lead, may be determinants of concentration of metal binding protein in tissues.

Public health aspects of toxic heavy metals in animal feeds.

Studies involving animals of three species (dairy cattle, growing swine, and laying chickens) indicated that residues of lead and cadmium do not increase appreciably in major food products obtained from the animals during long-term exposure to subtoxic dietary concentrations of these heavy metals. Human risk would not be expected by the consumption of milk, meat, or eggs from animals similarly exposed. Both metals accumulate in liver and kidney, and lead accumulates in bone. A moderate intake of liver and kidney from lead-exposed animals appears to present little or no health hazard. Utilization of these organs from cadmium-exposed animals, however, should be avoided.