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The applicability of the ADI (Acceptable Daily Intake) for food additives to infants and children.

Children are not little adults. Children may respond differently from adults because they are in a state of growth and development; or because of differences in toxicokinetics or toxicodynamics. Infants and children are often assumed to be more susceptible to toxic effects, but this generalization is founded on assumptions rather than on facts. Available data are mostly concerned with toxicity and therapeutic effects of pharmaceuticals, while the effects in children of industrial chemicals are less well documented. Childhood is characterized by growth and development. Toxicants may interfere with these processes, and therefore toxic exposure may have more serious consequences for children than for adults, irrespective of sensitivity. Immature physiological functions of the foetus and young child theoretically make these age groups more vulnerable to toxicants, at least up to 1 year of age. The existing data on effects of chemical exposure in children point in the direction that susceptibility depends on the substance and on the exposure situation. For a particular compound children may be more sensitive than adults, or they may be less sensitive. Further, the sensitivity of children to a particular substance varies greatly with age. It is necessary to view premature neonates, neonates, infants, and children of different ages as separate risk groups. The long-term studies used as the basis for establishing ADIs cover lifetime for laboratory animals. Methods which have special emphasis on reproductive cells, on the foetus, and on the immature organism are used. Taken together, these studies cover exposure during all life stages. However, some specific types of effects, and delayed effects of perinatal exposure are not always included in standard toxicity test protocols. Exposure may also differ between children and adults. The food intake of children is qualitatively and quantitatively different form that of adults, and the EU Scientific Committee for Food has recommended that intake assessment of children be considered separately from that of adults because patterns of consumption are different. The ADI should cover the entire population including children. Special considerations regarding the use of food additives do apply to infants below the age of 12 weeks, who depend entirely on infant formula for nutrition.

Adult↗

Glucuronidation as a mechanism of intrinsic drug resistance in human colon cancer: reversal of resistance by food additives.

Colon cancer exhibits inherent insensitivity to chemotherapy by mechanisms that are poorly characterized. We have shown that human colon cancer cells are efficient in drug conjugation catalyzed by UDP-glucuronosyltransferases (UGTs) and now report on the role of glucuronidation in de novo resistance to two topoisomerase I inhibitors. Identification of the UGT responsible for glucuronidation of SN-38 and the anthraquinone NU/ICRF 505 was achieved by first using a panel of human cDNA-expressed isozymes to measure conjugating activity. HT29 colon cancer cells were then probed by reverse transcriptase-PCR, Western Blot analysis, and liquid chromatography with mass spectrometry for their profile and activity of UGT isozymes and screened for effective inhibitors of glucuronidation. Expression analysis was also conducted in colon cancer biopsies and paired adjacent normal colon specimens. UGT1A9 was identified as the isozyme catalyzing biotransformation of the two compounds in HT29 cells and propofol as an effective competitive inhibitor of this metabolism. Inhibition of glucuronidation resulted in up to a 5-fold enhancement in drug activity. The majority of colon cancer biopsies studies expressed UGT protein at levels greater than in HT29 cells but with marked interpatient variations and proficiently glucuronidated the two anticancer drugs. A range of UGT aglycones were capable of modulating glucuronidation in the biopies with octylgallate being 10-fold more potent (ID(50) 24 microM) than propofol. In a subset of tumors (33%), UGT protein levels and activity exceeded that of paired normal colon. Glucuronidation may represent a mechanism of intrinsic drug resistance in colon cancer open to modulation by a range of food additives and proprietary medicines.

Anthraquinones↗

A square-wave adsorptive stripping voltammetric method for the determination of Amaranth, a food additive dye.

Square-wave adsorptive stripping voltammetric (AdSV) determinations of trace concentrations of the azo coloring agent Amaranth are described. The analytical methodology used was based on the adsorptive preconcentration of the dye on the hanging mercury drop electrode, followed by initiation of a negative sweep. In a pH 10 carbonate supporting electrolyte, Amaranth gave a well-defined and sensitive AdSV peak at -518 mV. The electroanalytical determination of this azo dye was found to be optimal in carbonate buffer (pH 10) under the following experimental conditions: accumulation time, 120 s; accumulation potential, 0.0 V; scan rate, 600 mV/s; pulse amplitude, 90 mV; and frequency, 50 Hz. Under these optimized conditions the AdSV peak current was proportional over the concentration range 1 x 10(-8)-1.1 x 10(-7) mol/L (r = 0.999) with a detection limit of 1.7 x 10(-9) mol/L (1.03 ppb). This analytical approach possessed enhanced sensitivity, compared with conventional liquid chromatography or spectrophotometry and it was simple and fast. The precision of the method, expressed as the relative standard deviation, was 0.23%, whereas the accuracy, expressed as the mean recovery, was 104%. Possible interferences by several substances usually present as food additive azo dyes (E110, E102), gelatin, natural and artificial sweeteners, preservatives, and antioxidants were also investigated. The developed electroanalyticals method was applied to the determination of Amaranth in soft drink samples, and the results were compared with those obtained by a reference spectrophotometric method. Statistical analysis (paired t-test) of these data showed that the results of the 2 methods compared favorably.

Adsorption↗

A procedure for the safety evaluation of flavouring substances. Joint FAO/WHO Expert Committee on Food Additives.

This review describes a procedure for the safety evaluation of flavouring substances. Over 2500 flavouring substances are currently in use in food. While toxicity data do not exist on all flavouring substances currently in use, within structurally related groups of flavouring substances many do have toxicity data and this information along with knowledge of structure-activity relationships and data on the daily intake provides a framework for safety evaluation. The safety evaluation procedure provides a scientifically based practical method of integrating data on intake, structure-activity relationships, metabolism and toxicity to evaluate flavouring substances in a timely manner. The procedure has been used recently by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) to evaluate a total of 263 flavouring substances.

Flavoring Agents↗

Additional food folate derived exclusively from natural sources improves folate status in young women with the MTHFR 677 CC or TT genotype.

The effectiveness of additional food folate in improving folate status in humans is uncertain particularly in people with the common genetic variant (677 C-->T) in the methylenetetrahydrofolate reductase (MTHFR) gene. To examine the effect of a doubling of food folate consumption on folate status response variables, women (n=32; 18-46 years) with the MTHFR 677 CC or TT genotype consumed either 400 (n=15; 7 CC and 8 TT) or 800 (n=17; 8 CC and 9 TT) microg/day of dietary folate equivalents (DFE) derived exclusively from naturally occurring food folate for 12 weeks. A repeated measures two-factor ANOVA was used to examine the effect of the dietary treatment, the MTHFR C677T genotype and their interactions on serum folate, RBC folate and plasma total homocysteine (tHcy) during the last 3 weeks of the study. Consumption of 800 microg DFE/day resulted in serum folate concentrations that were 67% (P=.005) higher than consumption of 400 microg DFE/day (18.6+/-2.9 vs. 31.0+/-2.7 nmol/L, respectively) and RBC folate concentrations that were 33% (P=.001) higher (1172+/-75 vs. 1559+/-70 nmol/L, respectively). Serum folate (P=.065) and RBC folate (P=.022) concentrations were lower and plasma tHcy was higher (P=.039) in women with the MTHFR 677 TT genotype relative to the CC genotype. However, no genotype by dietary treatment interaction was detected. These data suggest that a doubling of food folate intake will lead to marked improvements in folate status in women with the MTHFR 677 CC or TT genotype.

Adolescent↗