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1.
J Dairy Sci ; 91(1): 11-9, 2008 Jan.
Article in English | MEDLINE | ID: mdl-18096920

ABSTRACT

Antioxidant active packaging consisting of coextruded films made of low density polyethylene (LDPE) added with 0, 8, and 14 mg/g of butylated hydroxytoluene (BHT) and polyamide 6/66 were fabricated. The release of BHT from the films to Asadero cheese was determined. Most of the BHT was diffused from the LDPE layer to the cheese during the first 20 d of storage at 5 degrees C. Diffusion coefficient for the diffusion of BHT from the films 8 and 14 to the cheese was calculated as 6.24E-12 and 6.26E-12 cm2/s, respectively. The release of BHT from the film added with 8 mg/g of the antioxidant in the LDPE layer complied with the legal limit established for food products. However, the film added with 14 mg/g of the antioxidant exceeded that limit. The film added with 8 mg/g of BHT maintained the same levels of oxidized odor from 20 to 100 d of storage.


Subject(s)
Antioxidants/chemistry , Butylated Hydroxytoluene/chemistry , Cheese/analysis , Food Packaging/methods , Odorants/analysis , Polyethylene/chemistry , Food Packaging/standards , Humans , Oxidation-Reduction , Random Allocation
2.
Toxicology ; 173(3): 229-47, 2002 May 01.
Article in English | MEDLINE | ID: mdl-11960676

ABSTRACT

Dichloroacetate (DCA) is a rodent carcinogen commonly found in municipal drinking water supplies. Toxicokinetic studies have established that elimination of DCA is controlled by liver metabolism, which occurs by the cytosolic enzyme glutathione-S-transferase-zeta (GST-zeta). DCA is also a mechanism based inhibitor of GST-zeta, and a loss in GST-zeta enzyme activity occurs following repeated doses or prolonged drinking water exposures. GST-zeta is identical to an enzyme that is part of the tyrosine catabolism pathway known as maleylacetoacetate isomerase (MAAI). In this pathway, GST-zeta plays a critical role in catalyzing the isomerization of maleylacetoacetate to fumarylacetoacetate. Disruption of tyrosine catabolism has been linked to increased cancer risk in humans. We studied the elimination of i.v. doses of DCA to young (10 week) and aged (60 week) mice previously treated with DCA in their drinking water for 2 and 56 weeks, respectively. The diurnal change in blood concentrations of DCA was also monitored in mice exposed to three different drinking water concentrations of DCA (2.0, 0.5 and 0.05 g/l). Additional experiments measured the in vitro metabolism of DCA in liver homogenates prepared from treated mice given various recovery times following treatment. The MAAI activity was also measured in liver cytosol obtained from treated mice. Results indicated young mice were the most sensitive to changes in DCA elimination after drinking water treatment. The in vitro metabolism of DCA was decreased at all treatment rates. Partial restoration ( approximately 65% of controls) of DCA elimination capacity and hepatic GST-zeta activity occurred after 48 h recovery from 14 d 2.0 g/l DCA drinking water treatments. Recovery from treatments could be blocked by interruption of protein synthesis with actinomycin D. MAAI activity was reduced over 80% in liver cytosol from 10-week-old mice. However, MAAI was unaffected in 60-week-old mice. These results indicate that in young mice, inactivation and re-synthesis of GST-zeta is a highly dynamic process and that exogenous factors that deplete or reduce GST-zeta levels will decrease DCA elimination and may increase the carcinogenic potency of DCA. As mice age, the elimination capacity for DCA is less affected by reduced liver metabolism and mice appear to develop some toxicokinetic adaptation(s) to allow elimination of DCA at rates comparable to naive animals. Reduced MAAI activity alone is unlikely to be the carcinogenic mode of action for DCA and may in fact, only be important during the early stages of DCA exposure.


Subject(s)
Dichloroacetic Acid/pharmacokinetics , Dichloroacetic Acid/toxicity , Tyrosine/metabolism , Administration, Oral , Age Factors , Animals , Body Weight , Circadian Rhythm/drug effects , Cytosol/drug effects , Cytosol/enzymology , Cytosol/metabolism , Dichloroacetic Acid/administration & dosage , Dichloroacetic Acid/blood , Dose-Response Relationship, Drug , Drinking , Fresh Water , Glutathione Transferase/drug effects , Glutathione Transferase/metabolism , Injections, Intravenous , Kinetics , Liver/drug effects , Liver/enzymology , Liver/metabolism , Male , Mice , Mice, Inbred Strains , Time Factors , Tyrosine/drug effects , cis-trans-Isomerases/analysis
3.
Toxicol Appl Pharmacol ; 158(2): 103-14, 1999 Jul 15.
Article in English | MEDLINE | ID: mdl-10406925

ABSTRACT

Chloro, bromo, and mixed bromochloro haloacetates (HAs) are by-products of drinking water disinfection and are hepatocarcinogenic in rodents. We compared the toxicokinetics of a series of di-HAs, dichloro (DCA), bromochloro (BCA), dibromo (DBA) and tri-HAs: trichloro (TCA), bromodichloro (BDCA), chlorodibromo (CDBA), and tribromo (TBA) after iv and oral dosing (500 micrometer/kg) in male F344 rats. The blood concentrations of the HAs after iv injection declined in a bi-exponential manner with a short but pronounced distributive phase. The structural features that had the greatest influence on the disposition of HAs were substitution of a halogen for a hydrogen and the degree of bromine substitution. All di-HAs had blood elimination half-lives of less than 4 h (DCA > DBA, BCA) compared to the tri-HAs, which had half-lives that varied from 0.6 to 8.0 h (TCA > BDCA > CDBA > TBA). The urinary excretion of all di-HAs was low and accounted for less than 3% of the dose in contrast to the tri-HAs, where urinary excretion accounted for at least 30% of the dose. Toxicokinetic analysis indicated the steady-state apparent volume of distribution varied between 301 and 881 ml/kg among the HAs, but the variation was not statistically significant (P > 0.17). The blood concentration-time profiles for all di-HAs after oral dosing was complex and exhibited multiple peaks. This did not appear to be due to enterohepatic recirculation, as bile duct cannulated animals also displayed similar profiles. In contrast, the profiles for the tri-HAs did not exhibit multiple peaking after oral dosing and could be described using a one-compartment pharmacokinetic model. The oral bioavailability of the HAs varied between 30% (DBA) and 116% (TCA), depending on the number of halogen substituents and the degree of bromine substitution. In general, three patterns of elimination for the HAs can be broadly described: low metabolism with moderate renal clearance (TCA), high metabolism and renal clearance (BDCA, CDBA, TBA), and high metabolism, low renal clearance (DCA, BCA, DBA).


Subject(s)
Acetates/pharmacokinetics , Acids/pharmacokinetics , Hydrocarbons, Brominated/pharmacokinetics , Hydrocarbons, Chlorinated/pharmacokinetics , Acetates/blood , Acetates/urine , Acids/blood , Acids/urine , Administration, Oral , Animals , Biological Availability , Half-Life , Hydrocarbons, Brominated/blood , Hydrocarbons, Brominated/urine , Hydrocarbons, Chlorinated/blood , Hydrocarbons, Chlorinated/urine , Infusions, Intravenous , Male , Protein Binding , Rats , Rats, Inbred F344 , Structure-Activity Relationship , Tissue Distribution
4.
Chem Biol Interact ; 123(3): 239-53, 1999 Dec 15.
Article in English | MEDLINE | ID: mdl-10654841

ABSTRACT

Dichloroacetate (DCA) and trichloroacetate (TCA) are prominent by-products of chlorination of drinking water. Both chemicals have been shown to be hepatic carcinogens in mice. Prior work has demonstrated that DCA inhibits its own metabolism in rats and humans. This study focuses on the effect of prior administration of DCA or TCA in drinking water on the pharmacokinetics of a subsequent challenge dose of DCA or TCA in male B6C3F1 mice. Mice were provided with DCA or TCA in their drinking water at 2 g/l for 14 days and then challenged with a 100 mg/kg i.v. (non-labeled) or gavage (14C-labeled) dose of DCA or TCA. The challenge dose was administered after 16 h fasting and removal of the haloacetate pre-treatment. The haloacetate blood concentration-time profile and the disposition of 14C were characterized and compared with controls. The effect of pre-treatment on the in vitro metabolism of DCA in hepatic S9 was also evaluated. Pre-treatment with DCA caused a significant increase in the blood concentration-time profiles of the challenge dose of DCA. No effect on the blood concentration-time profile of DCA was observed after pre-treatment with TCA. Pre-treatment with TCA had no effect on subsequent doses of DCA. Pre-treatment with DCA did not have a significant effect on the formation of 14CO2 from radiolabeled DCA. In vitro experiments with liver S9 from DCA-pre-treated mice demonstrated that DCA inhibits it own metabolism. These results indicate that DCA metabolism in mice is also susceptible to inhibition by prior treatment with DCA, however the impact on clearance is less marked in mice than in F344 rats. In contrast, the metabolism and pharmacokinetics of TCA is not affected by pre-treatment with either DCA or TCA.


Subject(s)
Dichloroacetic Acid/administration & dosage , Trichloroacetic Acid/administration & dosage , Water Supply , Animals , Carbon Radioisotopes , Chromatography, Gas , Dichloroacetic Acid/pharmacokinetics , Male , Mice , Rats , Trichloroacetic Acid/pharmacokinetics
5.
Toxicol Sci ; 45(1): 33-41, 1998 Sep.
Article in English | MEDLINE | ID: mdl-9848108

ABSTRACT

Conflicting data have been published related to the formation of dichloroacetate (DCA) from trichloroethylene (TRI), chloral hydrate (CH), or trichloroacetic acid (TCA) in B6C3F1 mice. TCA is usually indicated as the primary metabolic precursor to DCA. Model simulations based on the known pharmacokinetics of TCA and DCA predicted blood concentrations of DCA that were 10- to 100-fold lower than previously published reports. Because DCA has also been shown to form as an artifact during sample processing, we reevaluated the source of the reported DCA, i.e., whether it was metabolically derived or formed as an artifact. Male B6C3F1 mice were dosed with TRI, CH, trichloroethanol (TCE), or TCA and metabolic profiles of each were determined. DCA was not detected in any of these samples above the assay LOQ of 1.9 microM of whole blood. In order to slow the clearance of DCA, mice were pretreated for 2 weeks with 2 g/liter of DCA in their drinking water. Even under this pretreatment condition, no DCA was detected from a 100 mg/kg i.v. dose of TCA. Although there is significant uncertainty in the amount of DCA that could be generated from TRI or its metabolites, our experimental data and pharmacokinetic model simulations suggest that DCA is likely formed as a short-lived intermediate metabolite. However, its rapid elimination relative to its formation from TCA prevents the accumulation of measurable amounts of DCA in the blood.


Subject(s)
Chloral Hydrate/pharmacokinetics , Dichloroacetic Acid/metabolism , Ethylene Chlorohydrin/analogs & derivatives , Trichloroacetic Acid/pharmacokinetics , Trichloroethylene/pharmacokinetics , Animals , Biological Availability , Dichloroacetic Acid/blood , Ethylene Chlorohydrin/pharmacokinetics , Half-Life , Male , Metabolic Clearance Rate , Mice , Models, Biological
6.
Toxicol Appl Pharmacol ; 146(2): 189-95, 1997 Oct.
Article in English | MEDLINE | ID: mdl-9344886

ABSTRACT

The effect of prior administration of dichloroacetate (DCA) in drinking water on the pharmacokinetics of DCA in male F344 rats was studied. Rats were provided with DCA in their drinking water at 0.2 and 2.0 g/liter for 14 days and then challenged with iv bolus iv or gavage doses of [14C1,2]DCA, 16 hr after pretreatment withdrawal. The blood concentration-time profiles of DCA and the disposition of 14C was characterized and compared with controls. The effect of pretreatment on the in vitro metabolism of DCA in hepatic cytosol was also evaluated. Pretreatment caused a significant increase in the blood concentration and AUC0-->infinity of DCA (433.3 versus 2406 microg ml-1 hr). Pharmacokinetic analysis indicated that pretreatment significantly decreased total body clearance (267.4 versus 42.7 ml hr-1 kg-1), which was largely due to decreased metabolism since only modest differences in the urinary clearance of DCA were observed. Pretreatment significantly decreased the formation of 14CO2 after both iv and oral doses of [14C]DCA. The decrease in CO2 formation was also observed after pretreatment with DCA at 0.2 g/liter. Pretreatment also increased the urinary elimination of DCA and several metabolites, particularly glycolate. The in vitro experiments demonstrated that DCA pretreatment inhibited the conversion of DCA to glyoxylate, oxalate, and glycolate in hepatic cytosol. These results indicate that DCA has an auto-inhibitory effect on its metabolism and that pharmacokinetic studies using single doses in naïve rats will underestimate the concentration of DCA at the target tissue during chronic or repeated exposures.


Subject(s)
Dichloroacetic Acid/pharmacokinetics , Liver/drug effects , Administration, Oral , Animals , Carbon Dioxide/metabolism , Carbon Radioisotopes , Chromatography, Gas , Cytosol/drug effects , Cytosol/metabolism , Dichloroacetic Acid/administration & dosage , Dichloroacetic Acid/blood , Dichloroacetic Acid/urine , Dose-Response Relationship, Drug , Drinking , Fresh Water/chemistry , Glycolates/urine , Glyoxylates/urine , In Vitro Techniques , Injections, Intravenous , Liver/metabolism , Male , Oxalates/urine , Rats , Rats, Inbred F344
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