Biomedical subjects
M W Pariza
Publications and source records attributed to M W Pariza.
Safety assessment of polylactide (PLA) for use as a food-contact polymer.
This report constitutes a safety assessment of polylactide (PLA), a polymer of lactic acid intended for use in fabricating various food-contact articles. Migration studies were conducted on samples of the polymer following guidelines issued by the Food and Drug Administration. Potential migrants from PLA include lactic acid, lactide (the monomer), and lactoyllactic acid (the linear dimer of lactic acid). The studies were designed to model reasonable 'worst' case extraction situations when the polymer is used (a) in houseware articles for short and intermediate time periods at various temperatures and (b) in food-packaging materials. The limited migration observed during the trials represents no significant risk since migrating species are expected to convert to lactic acid, a safe food substance. It is concluded that PLA is safe and 'Generally Recognized As Safe' for its intended uses as a polymer for fabricating articles that will hold and/or package food.
Protection of conjugated linoleic acids against 2-amino-3- methylimidazo[4,5-f]quinoline-induced colon carcinogenesis in the F344 rat: a study of inhibitory mechanisms.
Grilled ground beef contains a number of heterocyclic amine carcinogens, such as 2-amino-3-methylimidazo[4,5-f] quinoline (IQ), as well as anticarcinogenic conjugated linoleic acids (CLA). In the present study, CLA was administered to male F344 rats by gavage on alternating days in weeks 1-4, while IQ was given by gavage every other day in weeks 3 and 4 (100 mg/kg body wt). Rats were killed 6 h after the final carcinogen dose 16 in order to score colonic aberrant crypt foci (ACF). In the ACF study, CLA had no effect on the size of the foci, but inhibited significantly (P < 0.05) the number of ACF/colon, from 4.3 +/- 2.4 in controls to 1.1 +/- 1.3 in CLA-treated rats (mean +/- SD, n = 10). Rats given CLA also had significantly lower IQ-DNA adducts in the colon as determined by 32P-postlabeling analysis; relative adduct labeling levels (RAL x 10(7) for the major adduct were 9.13 +/- 2.6 in controls versus 5.42 +/- 1.8 in CLA-treated animals (P < 0.05). Mechanism studies indicated that CLA and other fatty acids interact with certain heterocyclic amines in a manner consistent with substrate-ligand binding. However, no such interaction occurred with IQ, and CLA failed to inhibit significantly the mutagenicity of N-hydroxy-IQ in the Salmonella assay. Liver microsomes from CLA-treated rats exhibited lower activities for dealkylation of 7-ethoxyresorufin and methoxyresorufin and activated IQ to DNA binding species less effectively than microsomes from control animals. Direct addition of CLA to the in vitro incubation inhibited IQ-DNA binding and was associated with increased recovery of unmetabolized parent compound. In the Salmonella assay, CLA inhibited the mutagenic activity of IQ in the presence of S9 or ram seminal vesicle microsomes. Collectively, these results support a mechanism involving inhibition of carcinogen activation by CLA, as opposed to direct interaction with the procarcinogen, scavenging of electrophiles or selective induction of phase I detoxification pathways.
Feeding conjugated linoleic acid to animals partially overcomes catabolic responses due to endotoxin injection.
The ability of conjugated linoleic acid to prevent endotoxin-induced growth suppression was examined. Mice fed a basal diet or diet with 0.5% fish oil lost twice as much body weight after endotoxin injection than mice fed conjugated linoleic acid. By 72 hours post injection, mice fed conjugated linoleic acid had body weights similar to vehicle injected controls; however, body weights of basal and fish oil fed mice injected with endotoxin were reduced. Conjugated linoleic acid prevented anorexia from endotoxin injection. Splenocyte blastogenesis was increased by conjugated linoleic acid.
Conjugated linoleic acid and atherosclerosis in rabbits.
Conjugated linoleic acid (CLA) consists of a series of positional and geometric dienoic isomers of linoleic acid that occur naturally in foods. CLA exhibits antioxidant activity in vitro and in vivo. To assess the effect of CLA on atherosclerosis, 12 rabbits were fed a semi-synthetic diet containing 14% fat and 0.1% cholesterol for 22 weeks. For 6 of these rabbits, the diet was augmented with CLA (0.5 g CLA/rabbit per day). Blood samples were taken monthly for lipid analysis. By 12 weeks total and LDL cholesterol and triglycerides were markedly lower in the CLA-fed group. Interestingly, the LDL cholesterol to HDL cholesterol ratio and total cholesterol to HDL cholesterol ratio were significantly reduced in CLA-fed rabbits. Examination of the aortas of CLA-fed rabbits showed less atherosclerosis.
Conjugated linoleic acid (9,11- and 10,12-octadecadienoic acid) is produced in conventional but not germ-free rats fed linoleic acid.
Conjugated linoleic acid (CLA) is an anticarcinogen in several model animal systems. Conjugated linoleic acid occurs naturally in food and is present at higher concentrations in products from ruminant animals. Given that certain rumen microorganisms produce CLA from free linoleic acid, we studied the effect of feeding free or esterified linoleic acid on tissue CLA concentrations using conventional and germ-free rats. Conventional rats were fed a 5% (wt/wt) corn oil control diet alone or supplemented with 5% free linoleic acid or 8.63% corn oil (equivalent to 5% linoleic acid in triglyceride). Germ-free rats were fed autoclavable nonpurified diet alone or supplemented with 5% free linoleic acid. Analyses of CLA concentrations were performed on lipids extracted from liver, lung, kidney, skeletal muscle and abdominal adipose tissue, and on liver phospholipid and neutral lipid fractions. Tissue CLA concentrations were higher in conventional rats fed free linoleic acid (the major isomers were cis-9, trans-11 and trans-9, cis-11) than in control animals. Conjugated linoleic acid concentrations in free linoleic acid-fed rats were maximal at 4 wk, and levels were 5-10 times higher than those of controls. Elevated CLA concentrations were also observed in liver phospholipid and neutral lipid fractions. In contrast, CLA concentrations in the tissues of germ-free rats were not affected by diet. Feeding the corn oil-fortified diet to conventional rats did not increase CLA concentration in the tissues.(ABSTRACT TRUNCATED AT 250 WORDS)
Inhibition of benzo[a]pyrene-induced mouse forestomach neoplasia by a principal flavor component of Japanese-style fermented soy sauce.
A refined diet supplemented with Japanese-style fermented soy sauce (shoyu) inhibits benzo[a]pyrene-induced forestomach neoplasia in mice (Cancer Res., 51:2940-2942, 1991). In the present study, soy sauce was extracted with ethyl acetate. The soluble fraction contained flavor/aroma compounds and antioxidants, whereas amino-carbonyl compounds that impart color were concentrated in the ethyl acetate insoluble fraction. Both fractions inhibited benzo[a]pyrene-induced forestomach neoplasia in a protocol in which the test material was fed following exposure to the carcinogen. A principal flavor/aroma component of soy sauce, 4-hydroxy-2(or 5)-ethyl-5(or 2)-methyl-3(2H)-furanone, was fed to mice following benzo[a]pyrene administration and found to inhibit the subsequent development of forestomach neoplasia. 4-Hydroxy-2(or 5)-ethyl-5(or 2)-methyl-3(2H)-furanone was effective when fed at 4 mg/kg body weight/day, indicating that it is a potent anticarcinogen.
A new approach to evaluating carcinogenic risk.
Carcinogenic risk assessments are based on extrapolating from high-dose chronic rodent-feeding studies to human-exposure levels. A serious problem is that about half of all substances tested at their respective maximum tolerated dose (MTD) are found to induce cancer. The MTD as currently defined has been criticized because it may stimulate cell proliferation in susceptible tissues. Such chemically induced mitogenesis is postulated to increase the probability that neoplasia will develop at the affected site. It is proposed that, in the development of an MTD for a given substance, chemically induced mitogenesis be considered an undesirable toxic manifestation. Hence, mitogenesis should not be induced by a substance fed at its true MTD. Since MTDs determined in this fashion are likely to be lower than those developed using current criteria, an added level of protection is introduced by employing a safety factor similar to that used now in determining acceptable daily intakes for noncarcinogenic food additives. In calculating acceptable daily intakes, the usual safety factor is 100; i.e., the acceptable daily intake is set at 1% of the no-observed-effect level. Hence it is proposed that the acceptable daily level of exposure to a substance that does not induce cancer at its MTD as defined herein be set at 1% of that MTD. On the other hand, a chemical that induces cancer at its MTD as defined herein would continue to be regulated as is customary now.
Designer foods: effects on development of cancer.
There are numerous anticarcinogens in the diet. An important question is how to use such substances in an effective, directed way to reduce cancer risk in humans. The "designer foods" concept is one approach for accomplishing this goal. Foods would be engineered to contain effective levels of anticarcinogens. This idea will work only to the extent that there is sufficient scientific knowledge on which to base such food design. Obviously, it is not sufficient simply to extrapolate from animal data to humans. A hypothetical example of the possible "designer fat substitute" is presented and discussed.
Mammary cancer prevention by conjugated dienoic derivative of linoleic acid.
Conjugated dienoic derivative of linoleic acid (CLA) is a collective term which refers to a mixture of positional and geometric isomers of linoleic acid. It is a naturally occurring substance in food and is present at higher concentrations in products from animal sources. The present study reports that synthetically prepared CLA is an effective agent in inhibiting the development of mammary tumors induced by dimethylbenz(a)anthracene. Rats were fed either the AIN-76A basal diet or the same diet supplemented with 0.5, 1, or 1.5% CLA by weight. These diets were started 2 weeks before carcinogen administration and continued until the end of the experiment. The total number of mammary adenocarcinomas in the 0.5, 1, and 1.5% CLA groups was reduced by 32, 56, and 60%, respectively. The final tumor incidence and cumulative tumor weight were similarly diminished in rats fed the CLA-containing diets. In general, there appeared to be a dose-dependent protection at levels of 1% CLA and below, but no further beneficial effect was evident at levels above 1%. Chronic feeding of up to 1.5% CLA produced no adverse consequences in the animals. Analysis of the phospholipid fraction from liver and mammary tumor extracts showed that only the c9,t11 isomer of CLA was incorporated and that the level of incorporation increased with dietary intake. An interesting property of CLA is its ability to suppress peroxide formation from unsaturated fatty acid in a test-tube model (Cancer Res., Ha et al. 50: 1097-1101, 1990). In view of this information, the amount of thiobarbituric acid-reactive substances (lipid peroxidation products) present endogenously in liver and mammary gland was quantitated. The feeding of CLA (for either 1 or 6 months) resulted in a decrease in the extent of lipid peroxidation in the mammary gland, but such a suppressive effect was not detected in the liver. It should be noted that maximal antioxidant activity was observed with only 0.25% CLA in the diet, whereas maximal tumor inhibition was achieved at about 1% CLA. Hence there is a discrepancy between the antioxidant efficacy of CLA and its anticarcinogenic potency, suggesting that some other mechanisms might be involved in cancer protection. Unlike the stimulatory effect of linoleic acid in carcinogenesis (Cancer Res., Ip et al., 45: 1997-2001, 1985), the reaction of CLA in cancer prevention is specific, and CLA is more powerful than any other fatty acid in modulating tumor development.
Inhibition of benzo(a)pyrene-induced mouse forestomach neoplasia by dietary soy sauce.
We show that Japanese-style fermented soy sauce (shoyu) contains anticarcinogenic activity. Female ICR mice were fed a semipurified diet containing soy sauce (0-30%). Two weeks later a regimen consisting of 4 doses of benzo(a)pyrene (1 dose/week p.o. for 4 weeks) was begun to initiate forestomach neoplasia. Twenty-three weeks after the first intubation the animals were sacrificed, and forestomach neoplasms were counted and histologically confirmed. Soy sauce produced a significant dose-dependent reduction in forestomach neoplasms, which appeared to be maximal when soy sauce constituted 20% of the diet. Exposure to nitrite (0-500 ppm through drinking water) neither enhanced nor diminished the anticarcinogenic effect of the dietary soy sauce. Soy sauce was found to contain antioxidant activity which may be related to the observed anticarcinogenic effect. Contrary to expectations, mouse forestomach ornithine decarboxylase activity was induced by soy sauce. This appeared to be due at least in part to the relatively high sodium chloride content of soy sauce.
Formation and action of anticarcinogenic fatty acids.
Conjugated dienoic derivatives of linoleic acid (referred to by the acronym CLA) constitute a newly recognized class of anticarcinogenic fatty acids. Of the eight major CLA isomers, the cis-9, trans-11 isomer alone is incorporated into phospholipid and may be the most biologically relevant isomer. CLA exhibits potent antioxidant activity; evidence is presented indicating that CLA acts both as an in vitro and in vivo antioxidant. The formation of CLA in foods, and its possible biological significance in cell membranes, is discussed.
Inhibition of benzo(a)pyrene-induced mouse forestomach neoplasia by conjugated dienoic derivatives of linoleic acid.
Grilled ground beef contains factors that inhibit the initiation of mouse epidermal carcinogenesis by 7,12-dimethylbenz(a)anthracene. Previously we isolated an active principal and characterized it as an isomeric mixture of conjugated dienoic derivatives of linoleic acid (CLA). We now show that synthetic CLA inhibits the initiation of mouse forestomach tumorigenesis by benzo(a)pyrene. Four and 2 days prior to p.o. treatment with benzo(a)pyrene, female ICR mice were given (a) CLA in olive oil, (b) linoleic acid in olive oil, or (c) olive oil alone or plus 0.85% saline (control groups). Three days later the cycle was repeated for a total of 4 times. At 30 wk of age, the mice were sacrificed. In three independent experiments, mice treated with CLA developed only about half as many neoplasms/animal as mice in the control groups (P less than 0.025); in two of the experiments tumor incidence was also reduced (P less than 0.05). There were no significant differences in food intake or body weight among the groups. High-performance liquid chromatography/gas chromatography analysis established that, following intubation, only the c-9, t-11 CLA isomer was incorporated into forestomach phospholipids. In studies aimed at elucidating the mechanism of action, we found that CLA is an effective antioxidant. Under the conditions of the test CLA was more potent than alpha-tocopherol and almost as effective as butylated hydroxytoluene. These observations indicate that CLA might serve as an in situ defense mechanism against membrane attack by free radicals and may, at least in part, explain the anticarcinogenic properties of CLA.
Newly recognized anticarcinogenic fatty acids.
Evidence leading to the recognition of the anticarcinogenic activity of the conjugated dienoic derivatives of linoleic acid (CLA) is reviewed. New data indicate that CLA has potent antioxidant activity. Because the c-9, t-11 CLA isomer is esterified in phospholipid, it may represent a heretofore unrecognized in situ defense mechanism against membrane attack by oxygen radicals.
Conjugated dienoic derivatives of linoleic acid: a new class of anticarcinogens.
Evidence establishing the anticarcinogenic activity of the conjugated dienoic derivatives of linoleic acid (CLA) is reviewed. Our findings demonstrate that CLA is a potent antioxidant and that the c-9,t-11 CLA isomer is selectively incorporated into cellular phospholipid, which may at least in part explain the anticarcinogenic activity of CLA. Dietary sources of CLA include grilled beef, cheese, and related foods. Another source of CLA is its endogenous generation via the carbon centered free radical oxidation of linoleic acid. We propose that the formation and action of CLA represents a previously unrecognized in situ defense mechanism against membrane attack by oxygen radicals.
Conjugated dienoic derivatives of linoleic acid: mechanism of anticarcinogenic effect.
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Reduction of benzo[a]pyrene-induced forestomach neoplasms in mice given nitrite and dietary soy sauce.
This study was conducted to determine the effects of nitrite (0.05% in drinking-water) and soy sauce (20% in a refined diet) on the initiation and promotion of benzo[a]pyrene-induced forestomach neoplasia in ICR mice. In two experiments nitrite and soy sauce together significantly reduced the number of neoplasms per animal. Soy sauce (without nitrite) produced a smaller apparent (non-significant) reduction whereas nitrite (without soy sauce) had no effect. Evidence suggested that soy sauce might contain factors that reduce calorie absorption or utilization, but this observation was independent of the inclusion of nitrite in the drinking-water and therefore could not by itself explain the significant reduction in neoplasms in mice given soy sauce plus nitrite. Protection appeared to primarily involve the tumour promotion stage.