Hepatic effects of 2-butoxyethanol in rodents.

Chronic inhalation of 2-butoxyethanol resulted in an increase in liver hemangiosarcomas and hepatic carcinomas in male mouse liver. No increase in liver neoplasia was observed in similarly exposed male and female rats or female mice. We proposed that the production of liver neoplasia in the male mouse is the result of oxidative damage secondary to the hemolytic deposition of iron in the liver. This occurs selectively in the male mouse and leads either directly or indirectly to liver neoplasia. To address this proposal, male B6C3F1 mice and male F344 rats were treated with 2-butoxyethanol (via daily gavage; five times per week) at doses of 0, 225, 450, and 900 mg/kg/day (mice) and 0, 225, and 450 mg/kg/day (rats) respectively. Following treatment for 7, 14, 28, and 90 days, DNA synthesis, oxidative damage, hematocrit, and iron deposition were measured in the livers. An increase in hemolysis (measured by a decrease in hematocrit and increase in relative spleen weight) was observed in 2-butoxyethanol-treated rats and mice in a dose-dependent manner. An increase in the percentage of iron-stained Kupffer cells was observed following treatment with 450 and 900 mg/kg of 2-butoxyethanol in mice and 225 and 450 mg/kg of 2-butoxyethanol in rats. A biphasic increase in oxidative damage (8-hydroxydeoxyguanosine and malondialdehyde) was seen in mouse liver after 7 and 90 days of treatment with 2-butoxyethanol, whereas no increases were observed in treated rat liver. Vitamin E levels were reduced by 2-butoxyethanol treatment in both mice and rat liver; however, the basal level of vitamin E was approximately 2.5-fold higher in rat than in mouse liver. A similar biphasic induction of DNA synthesis was seen following 2-butoxyethanol treatment in the mouse. In the mouse liver, increased DNA synthesis was observed in hepatocytes at 90 days and in endothelial cells at 7 and 14 days at all doses. No change in DNA synthesis was seen in 2-butoxyethanol-treated rat liver. No apparent differences in apoptosis and mitosis in the liver were observed in mouse and rat liver between 2-butoxyethanol treatment groups and untreated controls. These results suggest that DNA synthesis, possibly from oxidative stress or Kupffer cell activation, occurs selectively in the mouse liver, primarily in endothelial cells (a target of 2-butoxyethanol neoplasia), following exposure to 2-butoxyethanol.     

Mode of action and pharmacokinetic studies of 2-butoxyethanol in the mouse with an emphasis on forestomach dosimetry.

Chronic inhalation studies with 2-butoxyethanol (BE) conducted by the National Toxicology Program identified the forestomach and liver of B6C3F1 mice as target organs for tumorigenicity (NTP, 2000). Previous studies have shown that the liver tumors likely resulted from chronic hemolysis-induced oxidative stress. For the forestomach lesions seen in mice, chronic contact irritation (cytotoxicity) and regenerative hyperplasia are hypothesized to result in forestomach tumor development. To test this hypothesis, several experiments were conducted to address the sensitivity of the mouse forestomach to BE administered by various routes. Oral administration of undiluted BE was shown to cause irritation and a compensatory proliferative response in the mouse forestomach, confirming that direct contact between the forestomach and BE, which can occur via grooming of BE condensed on the fur during inhalation exposures, can cause irritation. However, only small amounts of BE (<10 mg/kg) were detected on the fur of mice at the end of 6-h, whole-body or nose-only inhalation exposures to the highest concentration used in the NTP chronic inhalation studies (250 ppm). Furthermore, no significant differences were detected in the end-exposure blood concentrations of BE and butoxyacetic acid (BAA) between these types of exposures. In addition, parenteral administration of BE (ip and sc injection) also resulted in forestomach lesions, indicating that there may be sources other than grooming for BE- or BAA-induced forestomach irritation. In the pharmacokinetic study, BE and, to a lesser extent, BAA was eliminated more slowly from the forestomach tissue of mice than from blood or other tissues, following either oral gavage or ip injection. The forestomach was the only tissue with detectable levels of BE at 24 h. BE and BAA were both excreted in the saliva and were present in stomach contents for a prolonged period of time following these routes of exposure, which may further contribute to forestomach tissue dosimetry. Thus, there appear to be multiple mechanisms behind the increased levels of BE and BAA in the forestomach tissue of mice, which together can contribute to a prolonged contact irritation, compensatory hyperplasia, and tumorigenicity in mice. The relevance of these effects in humans, who lack a forestomach, is questionable.     

Galantamine is a novel post-exposure therapeutic against lethal VX challenge

The ability of galantamine hydrobromide (GAL HBr) treatment to antagonize O-ethyl-S-(2-diisopropylaminoethyl) methylphosphonothiolate (VX)-induced lethality, impairment of muscle tension, and electroencephalographic (EEG) changes was assessed in guinea pigs. Guinea pigs were challenged with 16.8 μg/kg VX (2LD50). One min after challenge, animals were administered 0.5 mg/kg atropine sulfate (ATR) and 25 mg/kg pyridine-2-aldoxime methochloride (2-PAM). In addition, guinea pigs were given 0, 1, 2, 4, 8 or 10 mg/kg GAL as a post-exposure treatment immediately prior to ATR and 2-PAM. Animals were either monitored for 24-h survival, scheduled for electroencephalography (EEG) recording, or euthanized 60 min later for measurement of indirectly-elicited muscle tension in the hemidiaphragm. Post-exposure GAL therapy produced a dose-dependent increase in survival from lethal VX challenge. Optimal clinical benefits were observed in the presence of 10 mg/kg GAL, which led to 100% survival of VX-challenged guinea pigs. Based on muscle physiology studies, GAL post-exposure treatment protected the guinea pig diaphragm, the major effector muscle of respiration, from fatigue, tetanic fade, and muscular paralysis. Protection against the paralyzing effects of VX was dose-dependent. In EEG studies, GAL did not alter seizure onset for all doses tested. At the highest dose tested (10 mg/kg), GAL decreased seizure duration when administered as a post-exposure treatment 1 min after VX. GAL also reduced the high correlation associated between seizure activity and lethality after 2LD50 VX challenge. GAL may have additional benefits both centrally and peripherally that are unrelated to its established mechanism as a reversible acetylcholinesterase inhibitor (AChEI).     

Curcumin supplementation protects from genotoxic effects of arsenic and fluoride

The present study was aimed to evaluate curcumin as a potential natural antioxidant to mitigate the genotoxic effects of arsenic (As) and fluoride (F) in human peripheral blood lymphocytes. The study was divided into nine groups consisting of negative control, positive control treated with ethyl methane sulphonate (EMS; 1.93 mM) and curcumin control with only curcumin (1.7 μM) in blood culture. As (1.4 μM) and F (34 μM) were added alone as well as in combination, to the cultures, with and without curcumin. Cultures were analysed for chromosomal aberrations (both structural and numerical) and primary DNA damage via comet assay as the genotoxic parameters after an exposure duration of 24 h. Results revealed that curcumin efficiently ameliorates the toxic effect of As and F by reducing the frequency of structural aberrations (>60%), hypoploidy (>50%) and primary DNA damage. In conclusion, curcumin mitigates the genotoxic effects of the two well known water contaminants (As and F) effectively and efficiently at the given concentration in vitro.     

Development of a source-to-outcome model for dietary exposures to insecticide residues: an example using chlorpyrifos

Probabilistic models of interindividual variation in exposure and response were linked to create a source-to-outcome population model. This model was used to investigate cholinesterase inhibition from dietary exposures to an insecticide (chlorpyrifos) in populations of adults and 3 year old children. A physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model was used to calculate the variation in sensitivity occurring from interindividual variability in physiology, metabolism, and physical activity levels. A dietary intake model characterizes the variation in dietary insecticide exposures and variation in anthropometry in the populations. Published equations were used to describe the necessary physiology for each simulated individual based on the anthropometry from the dietary intake model.The model of the interindividual variation in response to chlorpyrifos was developed by performing a sensitivity analysis on the PBPK/PD model to determine the parameters that drive variation in pharmacodynamics outcomes (brain and red blood cell acetylcholinesterase inhibition). Distributions of interindividual variation were developed for parameters with the largest impact; the probabilistic model sampled from these distributions. The impact of age and interindividual variation on sensitivity at the doses that occur from dietary exposures, typically orders of magnitude lower than exposures assessed in toxicological studies, was assessed using the source-to-outcome model. The resulting simulations demonstrated that metabolic detoxification capacity was sufficient to prevent significant brain and red blood cell acetylcholinesterase inhibition, even in individuals with the lowest detoxification potential. Age-specific pharmacokinetic and pharmacodynamic parameters did not predict differences in susceptibility between adults and children. In the future, the approach of this case study could be used to assess the risks from low level exposures to other chemicals.     

Isochaihulactone protects PC12 cell against H(2)O(2) induced oxidative stress and exerts the potent anti-aging effects in D-galactose aging mouse model

Aim:

To investigate the effect of isochaihulactone (also known as K8), a lignan compound of Bupleurum scorzonerifolium, on H₂O₂-induced cytotoxicity in neuronally differentiated PC12 cells (nPC12).

Methods:

Viability of neuronal PC12 cells was measured using MTT assay. Protein expression was determined by Western blot. Apoptotic cells was determined using TUNEL assay. D-galactose aging mice were used as a model system to study the anti-oxidant effects of isochaihulactone in vivo.

Results:

Pretreatment with isochaihulactone (5–10 μmol/L) increased cell viability and decreased membrane damage, generation of reactive oxygen species and degradation of poly (ADP-ribose) polymerase in H₂O₂-treated nPC12 cells and also decreased the expression of cyclooxygenase-2, via downregulation of NF-kappaB, resulting in a decrease in lipid peroxidation. The results suggest that isochaihulactone is a potential antioxidant agent. In a murine aging model, in which chronic systemic exposure to D-galactose (D-gal) causes the acceleration of senescence, administration of isochaihulactone (10 mg·kg^-1·d^-1, sc) for 7 weeks concomitant with D-gal injection significantly increased superoxide dismutase and glutathione peroxidase activities and decreased the MDA level in plasma. Furthermore, H&E staining to quantify cell death within hippocampus showed that percentage of pyknotic nuclei in the D-gal-treated mice were much higher than in control.

Conclusion:

The results suggest that isochaihulactone exerts potent anti-aging effects against D-gal in mice possibly via antioxidative mechanisms.     

Pharmacokinetics and bioavailability of diisopropanolamine (DIPA) in rats following intravenous or dermal application.

This study was conducted to determine the relative dermal bioavailability (absorption), distribution, metabolism, and excretion (ADME) of diisopropanolamine (DIPA), an alcohol amine used in a number of industrial and personal care products. Groups of 4 female Fischer 344 rats received either a single bolus i.v. dose of 19.0mg/kg (14)C-DIPA in water or a dermal application of 19.5mg/kg (14)C-DIPA in acetone to an area of 1cm(2) on the back and covered with a bandage. Time-course blood and excreta were collected and radioactivity determined. Urine was analyzed for DIPA and monoisopropanolamine (MIPA). Following i.v. administration, DIPA was rapidly cleared from the plasma and excreted into urine in a biexponential manner (t(1/2alpha), 0.4h; t(1/2beta), 2.9h). The levels of radioactivity in plasma dropped below the limit of detection 12h post-dosing. A total of 97+/-4% of the dose was actively excreted in urine by kidney, most ( approximately 71%) within 6h of dosing, virtually all as parent compound; renal clearance exceeded the glomerular filtration rate. Following dermal application, approximately 20% of the dose was absorbed in 48 h with the steady-state penetration rate of approximately 0.2%/h. Most (14.4%) of the applied radioactivity was excreted in urine at a relatively constant rate due to the presence of large amount of the (14)C-DIPA at the application site. Fecal elimination was <0.2% of the dose. The absorbed DIPA did not accumulate in tissues; only approximately 0.1% of the administered dose was found in liver and kidney. The absolute systemic dermal bioavailability (dose corrected AUC(dermal)/AUC(i.v.)) of (14)C-DIPA was 12%. The ADME of DIPA contrasts that of its diethanol analogue, diethanolamine, which displays a broad spectrum of toxicity in rats and mice. Toxicologically significant concentrations of DIPA are unlikely to be achieved in the systemic circulation and/or tissues as a result of repeated dermal application of products containing DIPA due to slow absorption from the skin, rapid unchanged elimination in urine, and majority of the products contain 相似文献   

Efficacy of increasing the therapeutic index of irinotecan, plasma and tissue selenium concentrations is methylselenocysteine dose dependent

This study was designed to understand the basis for the efficacy of methylselenocysteine (MSC) in increasing the therapeutic index of irinotecan against human tumor xenografts. Nude mice bearing human head and neck squamous cells carcinoma xenografts (FaDu and A253) were treated orally with different doses of MSC and irinotecan. Plasma, tumor and normal tissue samples were collected at different times after MSC treatments and were analyzed for selenium (Se) concentration using electrothermal atomic absorption spectrophotometry. MSC is highly effective in modulating the therapeutic index of irinotecan. Enhanced irinotecan efficacy was greater in FaDu tumors (100% CR) than in A253 tumors (60% CR), and depended on MSC dose with a minimum effective dose of 0.01 mg/dx28. The highest plasma Se concentration was achieved 1h after a single dose and 28 d after daily treatments of MSC. The ability of FaDu tumors to retain Se was significantly better than A253 tumors, and the highest Se concentration in normal tissue was achieved in the liver. Peak plasma and tissue Se concentrations were functions of the dose and duration of MSC treatment. The MSC-dependent increase in Se level in normal tissues may contribute to the protective effect against irinotecan toxicity observed in those tissues. Intratumoral total Se concentration was not found to be predictive of the combination therapy response rates. There is a critical need to develop a method to measure the active metabolite of MSC, rather than total Se.     

Diabetic mice are protected from normally lethal nephrotoxicity of S-1,2-dichlorovinyl-L-cysteine (DCVC): role of nephrogenic tissue repair

Streptozotocin (STZ)-induced diabetic (DB) rats are protected from nephrotoxicity of gentamicin, cisplatin and mercuric chloride, although the mechanisms remain unclear. Ninety percent of DB mice receiving a LD90 dose (75 mg/kg, ip) of S-1,2-dichlorovinyl-l-cysteine (DCVC) survived in contrast to only 10% of the nondiabetic (NDB) mice surviving the same dose. We tested the hypothesis that the mechanism of protection is upregulated tissue repair. In the NDB mice, DCVC produced steep temporal increases in blood urea nitrogen (BUN) and plasma creatinine, which were associated with proximal tubular cell (PTC) necrosis, acute renal failure (ARF), and death within 48 h. In contrast, in the DB mice, BUN and creatinine increased less steeply, declining after 36 h to completely resolve by 96 h. HPLC analysis of plasma and urine revealed that DB did not alter the toxicokinetics of DCVC. Furthermore, activity of renal cysteine conjugate beta-lyase, the enzyme that bio-activates DCVC, was unaltered in DB mice, undermining the possibility of lower bioactivation of DCVC leading to lower injury. [3H]-thymidine pulse labeling and PCNA analysis indicated an early onset and sustained nephrogenic tissue repair in DCVC-treated DB mice. BRDU immunohistochemistry revealed a fourfold increase in the number of cells in S-phase in the DB kidneys even without exposure to DCVC. Blocking the entry of cells into S-phase by antimitotic intervention using colchicine abolished stimulated nephrogenic tissue repair and nephro-protection. These findings suggest that pre-placement of S-phase cells in the kidney due to diabetes is critical in mitigating the progression of DCVC-initiated renal injury by upregulation of tissue repair, leading to survival of the DB mice by avoiding acute renal failure.     

Evaluation of ambrein and epicoprostanol for their antioxidant properties: protection against adriamycin-induced free radical toxicity.

Ambrein and epicoprostanol were evaluated for their antioxidant potential in vitro by chemiluminescence (CL), as well as in vivo using lipid peroxides and glutathione levels as indicators in liver tissue of rats treated with adriamycin (doxorubicin) a well known free radicals producing drug. In the in vitro test, the inhibition in CL by ambrein was dose dependent. Both the high concentrations of ambrein (20-40 microg/ml) inhibited CL response significantly (P<0.05 and P<0.01, respectively) when compared to control. Similarly two low concentrations (5-20 microg/ml) of epicoprostanol inhibited CL significantly (P<0.001 and P<0.01, respectively) in comparison of DMSO control. The high concentration (40 microg/ml) of epicoprostanol behaved exceptionally and caused an increase in CL response that was more than control and significantly (P<0.001) higher than both the low concentrations. In the in vivo studies adriamycin treatment significantly (P<0.05) increased malondialdehyde (MDA) and decreased non-protein sulfhydryl (NP-SH) contents in the liver tissue of mice after 5 days treatment. Ambrein (25 and 50 mg/kg) treatment as a solo therapy at both the dose levels significantly (P<0.001) decreased MDA contents in the liver tissue. On the other hand, in the combined treatment the high dose effectively prevented any rise in MDA contents and it remained around the levels of ambrein alone. In the same experiment, adriamycin declined NP-SH contents significantly (P<0.001). Ambrein alone at both the dose levels caused a decline (P<0.01) in NP-SH contents when compared to adriamycin group. But in the combined treatment this decline in NP-SH was significantly (P<0.05) different from adriamycin alone. In the experiments dealing with epicoprostanol, adriamycin treatment increased MDA contents significantly (P<0.05) that declined significantly (P<0.001) with epicoprostanol (10- or 20mg/kg) treatment. In the same experiment co-treatment with adriamycin prevented any rise in MDA contents significantly (P<0.001) as it was observed in adriamycin alone group. Although, this treatment failed to prevent any decline in NP-SH contents either alone or in combination with adriamycin. Epicoprostanol itself had the comparative declining effect on the contents of NP-SH as seen in adriamycin group. From the results of our experiments it seems that ambrein at all concentrations behaves like antioxidant in in vitro studies but the same time it decreased NP-SH contents in vivo accompanied by a decline in MDA contents. Whereas, epicoprostanol at two low concentrations had a decline in CL indicating a possible antioxidant potential but the high concentration increased CL showing a tendency towards oxidant prospective. However, in animal studies it has shown a clear protection against adriamycin induced free radical damage.     

Analytical and pharmacokinetic studies with 5-chloro-2'-deoxycytidine

5-Chloro-2'-deoxycytidine (NSC 371331, CDC) is in development as a possible radiosensitizing agent for cancer treatment. Previous studies have been done to demonstrate the in vivo efficacy of CDC with various modulators of its metabolism. This paper describes our preclinical studies to determine the pharmacokinetic properties of CDC and the disposition of the drug, both alone and in the presence of the metabolic modulator tetrahydrouridine (THU), a cytidine deaminase inhibitor. Detection of the drug in biological fluids was performed by HPLC analysis using a C-18 column, gradient elution with solvents composed of aqueous trifluoroacetic acid and acetonitrile, and ultraviolet absorbance at 290 nm. Samples were processed by treatment with ammonium sulfate prior to injection into the HPLC system. CDC was stable in aqueous solution and in mouse plasma. High doses of CDC (100mg/kg) were given i.v. or i.p. to mice for the determination of CDC plasma half-life (10 min). CDC was not detectable in plasma after oral administration. It was converted rapidly to 5-chloro-2'-deoxyuridine (CDU) by cytidine deaminase, and CDU was readily discernable in plasma and urine samples collected after i.v. and i.p. administration of CDC. When CDC in doses ranging from 5 to 100mg/kg was given with 100mg/kg of THU, increased plasma levels of CDC were seen. CDC was eliminated through the kidneys, as well as by enzymatic deamination, and did not bind to plasma proteins. The initial steps of the CDC metabolic pathway were determined in vitro with isolated enzymes. Cytidine deaminase from mouse kidney converted CDC into CDU; thymidine phosphorylase converted CDU into 5-chlorouracil (5-CU). The conclusions of these studies are: (a) CDC is a drug with a short half-life and (b) it is excreted through the kidney, mainly in metabolite form. Administration of THU substantially increased the concentrations of CDC in mouse plasma, supporting proposals that the combination of THU with CDC should be evaluated in clinical trials.     

Characterization of glycidol-hemoglobin adducts as biomarkers of exposure and in vivo dose

Hemoglobin adducts have been used as biomarkers of exposure to reactive chemicals. Glycidol, an animal carcinogen, has been reported to form N-(2,3-dihydroxy-propyl)valine adducts to hemoglobin (diHOPrVal). To support the use of these adducts as markers of glycidol exposure, we investigated the kinetics of diHOPrVal formation and its elimination in vitro and in vivo.     

Resistance of HepG2 cells against the adverse effects of ethanol related to neutral lipid and phospholipid metabolism

The influence of both short- and long-term ethanol exposure on the lipid metabolism was determined in the human hepatoma cell line HepG2. Ethanol did not cause any cytotoxicity or lipid peroxidation even after 7 days of 100 mM ethanol treatment of HepG2 cells. Incubation of cells in the presence of [1-(14)C]ethanol demonstrated that these cells actively metabolize ethanol to acetyl CoA, incorporating the radioactive label into neutral lipids and phospholipids. [1,2,3-(3)H]glycerol was efficiently used in phospholipid and neutral lipid biosynthesis, showing higher radioactivity in phosphatidylcholine, phosphatidylethanolamine and triacylglycerols. Exposure of HepG2 cells to 100 mM ethanol for 24 hr did not significantly modify the incorporation of glycerol into newly synthesized phospholipids and neutral lipids, nor was lipid degradation affected by the presence of ethanol. When the alcohol treatment was prolonged for 7 days, incorporation of [1,2,3-(3)H]glycerol into triacylglycerols and diacylglycerols showed a slight increase concomitantly with decreased radioactivity in the major phospholipids, phosphatidylcholine and phosphatidylethanolamine. In addition, these changes were associated with a greater release of radiolabeled triacylglycerols into the culture medium. These results indicate that ethanol does not cause in HepG2 cells the marked lipogenic stimulation widely shown in hepatocytes, and demonstrate that HepG2 cells strongly resist the adverse effects of ethanol. Since these cells lack the isoenzymatic form of cytochrome P(450) mainly involved in the ethanol metabolism (namely cytochrome P(450)2E1) and also are devoid of alcohol dehydrogenase activity, we propose that the toxic actions of ethanol on liver must be linked to the activity of one or both of these systems.     

Development of a physiologically-based toxicokinetic model of acrylamide and glycidamide in rats and humans

Physiologically-based toxicokinetic (“pharmacokinetic”) (PBPK or PBTK) modeling can be used as a tool to compare internal doses of acrylamide (AA) and its metabolite glycidamide (GA) in humans and rats. An earlier PBTK model for AA and GA in rats was refined and extended to humans based on new data. With adjustments to the previous parameters, excellent fits to a majority of the data for male Fisher 344 rats were obtained. Kinetic parameters for the human model were estimated based on fit to available human data for urinary metabolites of AA, and levels of hemoglobin adducts of AA and GA measured in studies in which human volunteers ingested known doses of AA. The simulations conducted with the rat and human models predicted that rats and humans ingesting comparable levels of AA (in mg/kg day) would have similar levels of GA in blood and tissues. This finding stands in contrast to the default approach that assumes a 3.2-fold increase in human risk due to pharmacokinetic differences between rats and humans. This model was used in a companion paper to estimate safe levels of ingested AA.     

Using population physiologically based pharmacokinetic modeling to determine optimal sampling times and to interpret biological exposure markers: The example of occupational exposure to styrene

Background

Biomonitoring of chemicals in the workplace provides an integrated characterization of exposure that accounts for uptake through multiple pathways and physiological parameters influencing the toxicokinetics.

Objectives

We used the case of styrene to (i) determine the best times to sample venous blood and end-exhaled air, (ii) characterize the inter-individual variability in biological levels following occupational exposure and (iii) propose biological limit values using a population physiologically based pharmacokinetic (PBPK) model.

Methods

We performed Monte Carlo simulations with various physiological, exposure and workload scenarios. Optimal sampling times were identified through regression analyses between levels in biological samples and 24-h area under the arterial blood concentration vs. time curve. We characterized the variability in levels of styrene in biological samples for exposures to a time weighted average (TWA) of 20 ppm.

Results

Simulations suggest that the best times to sample venous blood are at the end of shift in poorly ventilated workplaces and 15 min after the shift in highly ventilated workplaces. Exhaled air samples are most informative 15 min after the shift. For a light workload, simulated styrene levels have a median (5th–95th percentiles) of 0.4 mg/l (0.2–0.6) in venous blood at the end of shift and 0.5 ppm (0.3–0.8) in exhaled air 15 min after the end of shift.

Conclusion

This study supports the current BEI^® of the ACGIH of 0.2 mg/l of styrene in venous blood at the end of shift and indicates a biological limit value of 0.3 ppm in end-exhaled air 15 min after the end of shift.     

Acrylamide: Consideration of species differences and nonlinear processes in estimating risk and safety for human ingestion

Acrylamide in cooked foods results in wide-spread, low-level human exposure. Potential risks from dietary intake remain unclear due to apparent conflicting results from cancer bioassays conducted in rats that reported tumors and epidemiology studies that are suggestive but provide little or no evidence of increased cancer. Risk estimation often includes two common assumptions: (1) tumor response rates in test species can be extrapolated systematically to estimate human response rates and (2) tumor rates observed following high-dose exposures can be linearly extrapolated to predict response rates following low-dose exposures. The validity of these assumptions was evaluated for acrylamide based upon the examination of relevant toxicokinetic and toxicodynamic differences between humans and rats, including sources of nonlinearity that modify high to low dose extrapolation of cancer incidence. Important species differences and sources of nonlinearity are identified, and recommendations for addressing them within the quantitative framework of a PBTK/TD model are discussed. These differences are likely to estimate risk levels up to several orders of magnitude lower in humans than in rats. Quantitative inclusion of these TK/TD factors will more closely estimate actual human cancer risk derived from high-dose rodent studies, since detoxification processes for acrylamide and glycidamide appear adequately protective against toxicity from human dietary doses.     

The effects of vitamin A supplementation to rats during gestation and lactation upon redox parameters: Increased oxidative stress and redox modulation in mothers and their offspring

Vitamin A is an essential nutrient required in adequate amounts for reproduction and development. Subtle variations in the status of maternal nutrition may affect physiological and metabolic parameters in the fetus. Evidence suggests a key role for oxidative stress in these events. Literature is controversial about the effects of vitamin A supplementation. Here, we studied the effects of vitamin A supplementation on female Wistar rats during gestation and lactation on oxidative stress parameters of maternal and offspring tissues. Rats received daily doses of vitamin A at 2500, 12,500 and 25,000 IU/kg. We observed an increase of oxidative damage markers in the reproductive tissues and plasma of dams. The activity of glutathione-S-transferase was modulated by vitamin A supplementation. It was found to be increased in the liver of dams and decreased in the kidneys of mothers and offspring. In pups, supplementation decreased the total antioxidant potential of the liver along with decreased superoxide dismutase/catalase activity ratio in the kidney. The levels of lipoperoxidation were increased in male offspring, but decreased in female pups. Collectively, the results suggest that excessive vitamin A intake during gestation and lactation might be toxic for mothers with adverse effects for the developing offspring.     

The antioxidant protection of CELLFOOD® against oxidative damage in vitro

CELLFOOD® (CF) is an innovative nutritional supplement containing 78 ionic/colloidal trace elements and minerals combined with 34 enzymes and 17 amino acids, all suspended in a solution of deuterium sulfate. The aim of this study was to investigate, for the first time, the antioxidant properties of CF in vitro in different model systems.Three pathophysiologically relevant oxidants were chosen to evaluate CF protection against oxidative stress: hydrogen peroxide, peroxyl radicals, and hypochlorous acid. Both biomolecules (GSH and plasmid DNA) and circulating cells (erythrocytes and lymphocytes) were used as targets of oxidation.CF protected, in a dose-dependent manner, both GSH and DNA from oxidation by preserving reduced GSH thiol groups and supercoiled DNA integrity, respectively. At the same time, CF protected erythrocytes from oxidative damage by reducing cell lysis and GSH intracellular depletion after exposure to the oxidant agents. In lymphocytes, CF reduced the intracellular oxidative stress induced by the three oxidants in a dose-dependent manner.The overall in vitro protection of biomolecules and cells against free radical attacks suggests that CF might be a valuable coadjuvant in the prevention and treatment of various physiological and pathological conditions related to oxidative stress, from aging to atherosclerosis, from neurodegeneration to cancer.