Bioaccumulation and elimination rate of cobalt in Capoeta fusca under controlled conditions

Abstract

The objective of the present study was to investigate the pattern of accumulation and elimination of cobalt in selected organs of Capoeta fusca, after chronic exposure. Samples of C. fusca were obtained from a qanat in Birjand between July and September 2010. Cobalt accumulation was studied in fish exposed to 6.8 mg L^-1 of cobalt for 15 days and the elimination was investigated in the contaminated fish samples placed in tap water for another 15 days. Using atomic absorption spectrophotometry it was found that the accumulation of cobalt in tissues was in the following order: liver>muscle>gill>skin. The elimination of cobalt was in the following order: skin>gill>muscle>liver. The bioaccumulation and elimination of cobalt were significant in the organs of C. fusca (P<0.01). The accumulation of cobalt in C. fusca was rapid and increased with an increase in metal concentration in water and the duration of exposure. The results of the present study showed that the accumulation and elimination of cobalt in C. fusca depend on the type of organs and the duration of exposure.     

Kinetics of micronucleus induction and cytotoxic activity of colchicine in murine erythroblast in vivo.

In previous studies, we inferred some pharmacokinetic and pharmacodynamic parameters of alkylating agents and antimetabolites by comparing their kinetics of micronucleated polychromatic erythrocyte (MN-PCE) induction with the one obtained after the exposure to gamma rays in peripheral blood of mice, assuming that radiation acts immediately because it does not require absorption and distribution in the organism. According to our earlier studies, the kinetics of MN-PCE induction depends mainly on the following: (i) the cytotoxic effects that in turn could affect the duration of cell division; (ii) the pharmacokinetics including the metabolic activation requirement; and (iii) the mechanism of MN induction. The aim of the present study was to analyze the kinetics of MN-PCE induction by an aneuploidogen that induces micronuclei by acting on the achromatic spindle. The kinetics of MN-PCE induction by colchicine, as well as the reduction in the PCE frequency over time was determined in peripheral blood of mice treated with different doses of the aneuploidogen. The genotoxic effect, established as the area beneath the curve (ABC) of MN-PCE versus time-response, indicates an almost directly proportional relationship with respect to dose. Similarly, the relationship between dose and cytotoxic effect determined as the ABC of PCE versus time was inversely proportional, suggesting a relationship between both endpoints and doses administered. However, the number of cells affected by these two phenomena indicates that cytotoxicity is not necessarily caused, or at least not only by genotoxicity. The analysis of the kinetics of MN-PCE induction after the treatment with non-cytotoxic dose of colchicine, indicates that the MN-PCE appear in the blood stream at almost the same time, as occurs after the exposure to gamma rays; in spite of the differences in the cell cycle stage in which they can cause micronucleus (MN). Perhaps the fact that cells are not synchronized does not permit one to observe some difference in the time they appear in the blood. These results suggest that colchicine acts rapidly after exposure. The elimination half-life of colchicine is 17h, suggesting that colchicne is disposable for long time. With high doses of colchicine the pharmacokinetic parameters increases substantially. These data imply that low doses of colchicine are slightly cytotoxic, and that under this circumstances colchicines arrives rapidly to hemopoyetic tissues and acts for several hours.     

Factors in the accumulation of dieldrin in broiler organs: doses administered with feed; dose-organ-dieldrin accumulated relationship; toxicological consequences

The quantity of dieldrin accumulated in liver, kidney, heart, gizzard, lung, muscle, and intestine with contents, of broiler chickens fed with feed contaminated by this insecticide, was determined by gas chromatography analysis. The doses used were 60, 90, 120, 200 and 240 ppm. The influence of the doses used in the quantity of dieldrin accumulated in the different organs, the relationship between the doses administered, organs and quantity accumulated, and the toxicological consequences of the contamination were studied. The results show that the doses used did not significantly affect the quantity of dieldrin accumulated by the different organs. The relationship doses-organ-quantity accumulated shows that the muscle accumulates equal dieldrin at all the doses used. The differences in the dieldrin accumulated at different doses increases with the metabolic function of the organs. The principal symptoms of intoxication were anorexia, convulsions and tremors, which indicated that the nervous system is a major site of activity.     

Pharmacokinetics of the enantiomers of terbutaline after repeated oral dosing with racemic terbutaline

Terbutaline is a beta 2-agonist and administered as the racemic mixture. The pharmacokinetics of the separate enantiomers differ with respect to degree of absorption and clearance. In the present study, repeated doses of racemic terbutaline were given to six healthy volunteers. Plasma was analyzed for the concentrations of the two enantiomers. The observed plasma concentrations at steady state differed from those predicted from the values observed after single dose administration of the separate enantiomers. The difference between the observed and predicted values can be tentatively explained by a combined influence of (-)-terbutaline on the absorption of (+)-terbutaline and the influence of (+)-terbutaline on the elimination of (-)-terbutaline. The results have implications for the interpretation of effect/concentration studies with terbutaline, but do not affect the doses used in clinical practice.     

Pharmacokinetics of 125I-GST-TatdMt, a recombinant fusion protein possessing potent anti-obesity activity, after intravenous, nasal, oral, and subcutaneous administration

This study first reports the absorption kinetics of GST-TatdMt, a recombinant Tat protein possessing potent anti-obesity activity, in rats after nasal, s.c., and p.o. administration. GST-TatdMt was over-expressed in E. coli, purified, and radioiodinated using the IODO-GEN method. The radioiodinated 125I-GST-TatdMt was administered to rats by nasal, s.c., and oral routes at doses of 7.3 microg (420.7 nCi), 146.5 microg (8413.8 nCi), and 146.5 microg (8413.8 nCi), respectively. For the determination of absolute bioavailability, 125I-GST-TatdMt was also given to rats by i.v. injection (73.2 microg, 4206.9 nCi). Following administration by extravascular routes, the systemic absorption of radioactivity was prolonged, with Cmax being attained within 4.2-8.0 h. The absolute bioavailability calculated as dose-normalized AUC(extravascular)/AUC(i.v.) was 98.0, 75.8, and 87.1% after nasal, s.c., and oral administration, respectively. The majority of administered radioactivity was excreted in urine (57.5-64.7%), with fecal excretion being less (2.5-12.7%). The distribution of 125I-GST-TatdMt to various tissues was also determined at 4 and 72 h after s.c. injection. The findings of this study suggest that this protein may be absorbed into the systemic circulation when given by extravascular administration.     

Pharmacokinetics of Sulfaphenazole in Sheep

Proprietary formulations of sulfaphenazole were administered intravenously and orally to sheep. After intravenous injection the disposition of sulfaphenazole was described by an open two compartment model, and the elimination half-time was on average 5.58 h. The apparent volume of distribution was 0.273 1/kg and total body clearance 34.1 ml/kg/h. Judged from the area under the curves, the oral dose was completely absorbed, Drug plasma concentrations versus time fitted an open one compartment model, the half-time of absorption and elimination being 2.66 and 7.12 h, respectively. The binding to plasma proteins was high i.e. 93–96 % at therapeutic concentrations, and concentration dependent. The results demonstrate that the doses indicated by the manufacturer appear to be low and more appropriate for drugs with a longer elimination half-time. Consequently, considerable adjustments in the dosage regimen are recommended.     

The role of Na K ATPase in thiamine and lipoic acid interrelations during their absorption in the gastrointestinal tract of mice

35S-lipoic acid (20 mumol/kg) with different doses of thiamine or 35S-thiamine (50 mumol/kg) with unlabelled lipoic acid where administrated to the white mice stomach. It was established that absorption and entrance of both lipoic acid and thiamine when they were in 1:5 quantities in organs and tissues were maximal. The activity of Na+, K-ATPase determined in stomach, duodenum and small intestine was the maximal too.     

Disposition of 14C-flumequine in eel Anguilla anguilla, turbot Scophthalmus maximus and halibut Hippoglossus hippoglossus after oral and intravenous administration.

The absorption, distribution and elimination of 14C-labelled flumequine were studied using whole body autoradiography and liquid scintillation counting. Flumequine was administered to eel Anguilla anguilla, turbot Scophthalmus maximus and halibut Hippoglossus hippoglossus intravenously and orally as a single dose of 5 mg kg(-1), corresponding to 0.1 mCi kg(-1). The turbot and halibut studies were performed in salt water (salinity of 32%) at temperatures of 16 +/- 1 degrees C (turbot) and 9.5 +/- 0.5 degrees C (halibut). The eel study was conducted in fresh water at 23 +/- 1 degrees C. In the intravenously administered groups flumequine was rapidly distributed to all major tissues and organs. After oral administration flumequine also appeared to have rapid and extensive absorption and distribution in all 3 species. After the distribution phase, the level of flumequine was higher in most organs and tissues than in the blood, except in muscle and brain. The most noticeable difference between the species was the slow elimination of flumequine from eel compared to turbot and halibut. In orally administered eels, substantial amounts of flumequine remained in all major organs/tissues for 7 d. At 28 d significant levels of flumequine were present in liver, kidney and skin (with traces in muscle), and at the last sampling point (56 d) in eye, bone, bile and posterior intestine. In orally administered turbot significant levels of flumequine were observed over 96 h in bile, urine, bone, skin, intestine and eye, and traces were detected over 28 d in bone and eye in addition to a significant level in bile. In orally administered halibut, significant levels of flumequine were observed in bile, skin, intestine and eye over 96 h. Traces were present in skin and eye over 7 d. The maximal flumequine concentrations in blood were calculated to be 2.5 mg equivalents l(-1) (eel at 12 h), 0.8 mg l(-1) (turbot at 6 h) and 0.6 mg l(-1) (halibut at 6 h) after oral administration.     

Acute toxicology and pharmacokinetic assessment of a ribozyme (ANGIOZYME) targeting vascular endothelial growth factor receptor mRNA in the cynomolgus monkey

The potential acute toxicity of a ribozyme (ANGIOZYME) targeting the flt-1 vascular endothelial growth factor (VEGF) receptor mRNA was evaluated in cynomolgus monkeys following i.v. infusion or s.c. injection. ANGIOZYME was administered as a 4-hour i.v. infusion at doses of 10, 30, or 100 mg/kg or a s.c. bolus at 100 mg/kg. End points included blood pressure, electrocardiogram (ECG), clinical chemistry, hematology, complement factors, coagulation parameters, and ribozyme plasma concentrations. ANGIOZYME was well tolerated, with no drug-associated morbidity or mortality. There was no clear evidence of ANGIOZYME-related adverse effects in this study. Slight increases in spleen weight and lymphoid hyperplasia were observed in several animals. However, these changes were not dose dependent. Steady-state concentrations of ANGIOZYME were achieved during the 4-hour infusion of 10, 30, or 100 mg/kg. Dose-dependent elimination of ANGIOZYME was observed, with faster clearance at the two highest doses. ANGIOZYME was slowly absorbed after s.c. administration, resulting in steady-state concentrations for the 9-hour sampling period. Monkeys in this toxicology study received significant plasma ANGIOZYME exposure by both the s.c. and i.v. routes.     

Pharmacodynamics and pharmacokinetics of recombinant hirudin via four non-parenteral routes

One of recombinant hirudin variants, rHV2, a polypeptide used as an anticoagulant agent in clinic, was administered to anesthetized rats via intratracheal, buccal, nasal and rectal routes. Prolongation in clotting time and thrombin time was measured to calculate pharmacological bioavailability. Plasma concentration of rHV2 was determined using a chromogenic thrombin substrate assay and pharmacokinetic parameters were obtained on the basis of a non-compartmental model. Intravenous administration was also performed as the gold standard by which the other routes were compared. Difference in pharmacological bioavailability (P.A.), bioavailability (F) and absorption rate of rHV2 was found for the four non-parenteral routes. The rank order for both P.A. and F was intratracheal>nasal>buccal>rectal. Absorption was more rapid after both intratracheal and rectal administration (tmax approximately 20-40 min), compared with that after nasal and rectal administration. It is evident that the pulmonary route is preferable to other three routes for successful systemic delivery of rHV2.     

Doses from radon progeny as a source of external beta and gamma radiation

Great deal of work has been devoted to determine doses from alpha particles emitted by ²²²Rn and its progeny. In contrast, contribution of beta particles and following gamma radiation to total dose has mostly been neglected so far. The present work describes a study of the detriment of ²²²Rn progeny for humans due to external exposure. Doses and dose conversion factors (DCFs) were determined for beta and gamma radiation in main organs and remainder tissue of the Oak Ridge National Laboratory phantom, taking into account ²²²Rn progeny ²¹⁴Pb and ²¹⁴Bi distributed in the middle of a standard or typical room with dimensions 4?m?×?5?m?×?2.8?m. The DCF was found to be 7.37?μSv/WLM. Skin and muscle tissue from remainder tissue receives largest dose. Beta and gamma radiation doses from external exposure were compared with alpha, beta, and gamma doses from internal exposure where the source of radioactivity was the lungs. Total doses received in all main organs and remainder tissues were obtained by summing up the doses from external and internal exposure and the corresponding DCF was found to be 20.67?μSv/WLM.     

Aryl hydrocarbon hydroxylase activity in F-344 rats subchronically exposed to benzo(a)pyrene and fluoranthene through diet

In order to investigate the relationship between aryl hydrocarbon hydroxylase (AHH) activity and exposure to benzo[a]pyrene [B(a)p] and fluoranthene (FLA), AHH activities in liver tissues of male and female F-344 rats were determined. Based on a range-finding study, doses of 0, 5, 50, and 100 mg/kg B(a)p or 0, 150, 750, and 1500 mg/kg FLA were administered in the animal diet over a 90-day period. After dosing, animals were sacrificed, liver tissues were removed, and microsomes were isolated. AHH activities were determined by reverse-phase HPLC coupled with fluorescence detection using 3-hydroxy B(a)p, and trans-2,3-dihydroxy-1,10-epoxy-1,2,3,10b tetrahydrofluoranthene as the standards. A dose-dependent increase in enzyme activity was observed with increased B(a)p or FLA exposure in both males and females. Our results also demonstrate that B(a)p-exposed females possess a higher AHH activity than males, but there is no significant sex difference with regard to enzyme activity in the case of FLA at higher doses. Overall, our findings suggest that long-term exposure to the parent compound results in elevated levels of AHH activity, which may contribute to the formation of toxic reactive metabolites and subsequent symptoms in target organs.     

The effect of exposure to nicotine, carbon monoxide, cigarette smoke or cigarette smoke condensate on the mutagenicity of rat urine

Cigarette smokers have been reported to void urine which is more mutagenic than that voided by non-smokers, but the specific urinary mutagen(s) have not been identified. Since mechanistic studies are best performed in animal models, the objective of this study was to determine if a model to study the role of cigarette smoke and its components in urinary mutagenicity could be developed in rats. XAD-2 resin was used to concentrate the urine and the microsuspension modification of the Ames test used to quantify mutagenicity. Nicotine administered by intraperitoneal injection at 0.8 mg/kg (the maximum tolerated dose) or inhalation of carbon monoxide for 14 days at the maximum tolerated dose (1800 ppm, resulting in 68% carboxyhemoglobin) did not increase urinary mutagenicity. Cigarette smoke condensate (CSC) prepared by electrostatic precipitation of mainstream smoke increased urinary mutagenicity at doses of 100 and 200 mg/kg when administered acutely by either i.p. injection or gavage, verifying that the assay system was capable of detecting cigarette smoke-related mutagens in the urine. However, cigarette smoke administered by the appropriate route of exposure, nose-only inhalation, for 1, 7, 14 or 90 days (1 h per day) did not increase urinary mutagenicity. The smoke concentration administered was at or near the maximum tolerated dose as evidenced by carboxyhemoglobin concentrations of approximately 50%, and of 10% or more weight loss in exposed animals. Thus, although cigarette smoke condensate is mutagenic in vitro and mutagenic urine was observed when rats were given high doses of CSC by inappropriate routes of administration, acute or subchronic inhalation exposure to the maximum tolerated dose of whole cigarette smoke did not increase urinary mutagenicity in rats. These results indicate that the rat may be an inappropriate model to study urinary mutagenicity following the inhalation of tobacco smoke.     

Lipidemic effect of methanol

The effect of methanol on some of the lipid components in serum was studied in rats. Methanol was administered by stomach tube in doses of 2 and 6 ml/kg b.wt daily for 21 and 6 days, respectively. Methanol was found to accumulate lipids; thus, cholesterol, phospholipids and triglycerides increased significantly. Concurrently, modification of the lipoid content of organs has been considered. It was concluded that methanol and not only formate, is toxic to rats, inspite of the alleged difference in routes of its metabolism in primates and rodents.     

Measurement of HPRT mutations in splenic lymphocytes and haemoglobin adducts in erythrocytes of Lewis rats exposed to ethylene oxide

Young adult male Lewis rats were exposed to ethylene oxide (EO) via single intraperitoneal (i.p.) injections (10-80 mg kg-1) or drinking water (4 weeks at concentrations of 2, 5, and 10 mM) or inhalation (50, 100 or 200 ppm for 4 weeks, 5 days week-1, 6 h day-1) to measure induction of HPRT mutations in lymphocytes from spleen by means of a cloning assay. N-ethyl-N-nitrosourea (ENU) and N-(2-hydroxyethyl)-N-nitrosourea (HOENU) were used as positive controls. Levels of N-(2-hydroxyethyl)valine (HOEtVal) adducts in haemoglobin (expressed in nmol g-1 globin) were measured to determine blood doses of EO (mmol kg-1 h, mM h). Blood doses were used as a common denominator for comparison of mutagenic effects of EO administered via the three routes. The mean HPRT mutant frequency (MF) of the historical control was 4.3 x 10(-6). Maximal mean MFs for ENU (100 mg kg-1) and HOENU (75 mg kg-1) were 243 x 10(-6) and 93 x 10(-6), respectively. In two independent experiments, EO injections led to a statistically significant dose-dependent induction of mutations, with a maximal increase in MF by 2.3-fold over the background. Administration of EO via drinking water gave statistically significant increases of MFs in two independent experiments. Effects were, at most, 2.5-fold above the concurrent control. Finally, inhalation exposure also caused a statistically significant maximal increase in MF by 1.4-fold over the background. Plotting of mutagenicity data (i.e., selected data pertaining to expression times where maximal mutagenic effects were found) for the three exposure routes against blood dose as common denominator indicated that, at equal blood doses, acute i.p. exposure led to higher observed MFs than drinking water treatment, which was more mutagenic than exposure via inhalation. In the injection experiments, there was evidence for a saturation of detoxification processes at the highest doses. This was not seen after subchronic administration of EO. The resulting HPRT mutagenicity data suggest that EO is a relatively weak mutagen in T-lymphocytes of rats following exposure(s) by i.p. injection, in drinking water or by inhalation.     

The effect of circadian rhythm on pharmacokinetics and metabolism of the Cdk inhibitor,roscovitine, in tumor mice model

Roscovitine is a selective Cdk-inhibitor that is under investigation in phase II clinical trials under several conditions, including chemotherapy. Tumor growth inhibition has been previously shown to be affected by the dosing time of roscovitine in a Glasgow osteosarcoma xenograft mouse model. In the current study, we examined the effect of dose timing on the pharmacokinetics, biodistribution and metabolism of this drug in different organs in B6D2F1 mice. The drug was orally administered at resting (ZT3) or activity time of the mice (ZT19) at a dose of 300?mg/kg. Plasma and organs were removed at serial time points (10, 20 and 30?min; 1, 2, 4, 6, 8, 12 and 24?h) after the administration. Roscovitine and its carboxylic metabolite concentrations were analyzed using HPLC-UV, and pharmacokinetic parameters were calculated in different organs. We found that systemic exposure to roscovitine was 38% higher when dosing at ZT3, and elimination half-life was double compared to when dosing at ZT19. Higher organ concentrations expressed as (organ/plasma) ratio were observed when dosing at ZT3 in the kidney (180%), adipose tissue (188%), testis (132%) and lungs (112%), while the liver exposure to roscovitine was 120% higher after dosing at ZT19. The metabolic ratio was approximately 23% higher at ZT19, while the intrinsic clearance (CL_int) was approximately 67% higher at ZT19, indicating faster and more efficient metabolism. These differences may be caused by circadian differences in the absorption, distribution, metabolism and excretion processes governing roscovitine disposition in the mice. In this article, we describe for the first time the chronobiodistribution of roscovitine in the mouse and the contribution of the dosing time to the variability of its metabolism. Our results may help in designing better dosing schedules of roscovitine in clinical trials.     

Endogenous excretion and true absorption of cobalt as affected by the oral supply of cobalt

At the end of a 49-d experiment with 32 growing male rats, a period of 8 d was used to determine endogenous excretion and true absorption as well as apparent absorption and retention of cobalt with the aid of the isotope dilution technique. For this purpose, a single im dose of⁵⁸Co was applied at d 35 of the experiment. After that, urine and feces were collected separately from d 8 to 15 after injection of the isotope. The specific cobalt activity of the liver was used as an endogenous reference source. The basal diet provided 5.9 ppb cobalt, the different treatment groups were obtained by supplementing the diet with 0, 10, 50, 250, or 1250 ppb cobalt. The different diets were offered from the beginning of the experiment. In the balance period, apparent and true absorption as well as fecal excretion behaved similar to cobalt intake, whereas urinary excretion increased more rapidly with increasing cobalt supply. Endogenous fecal excretion accounted for 3.5 ng Co/d in the groups fed the diets without and with 10 ppb cobalt. An increase was not observed until supplementing the diet with 50 ppb cobalt. This increase between 250 and 1250 ppb cobalt was higher than the corresponding increase in the dietary cobalt supply. This indicates that endogenous fecal excretion might be more important for homeostatic regulation at a higher dietary cobalt concentration. Endogenous renal excretion as calculated from the results of the isotope dilution technique showed a similar kind of response to increasing cobalt supply as endogenous fecal loss. Nevertheless, the elimination of excessive cobalt mainly took place by adjusting urinary excretion, whereas the variations in true absorption and endogenous fecal excretion had no quantitative importance. Apparent and true absorption were on average 28.0 and 29.8%, respectively, of the cobalt intake. In the case of retention, a marked decline was observed from 19% in the depletion group to 3% with 1250 ppb cobalt, again demonstrating the importance of urinary excretion for controlling the cobalt content of the organism.     

Activity of urethane and N,N-dimethylurethane in the mouse bone-marrow micronucleus assay: equivalence of oral and intraperitoneal routes of exposure

Urethane is shown to be active in the mouse bone-marrow micronucleus assay when administered as a single dose by either gavage or intraperitoneal injection. The magnitude of the response using the two routes was not statistically significantly different. N,N-Dimethylurethane (DMU) is shown to be mutagenic to Salmonella and active in the bone-marrow micronucleus assay by both routes of administration. The activity of DMU in the bone marrow precludes elimination of ethanol, yielding cyanate ion, as an explanation for the micronucleus-inducing activity of urethane.     

Comparative dose levels between CT-scanner and slot-scanning device (EOS system) in pregnant women pelvimetry

PurposeTo estimate fetal absorbed doses for pregnant women pelvimetry, a comparative study between EOS imaging system and low-dose spiral CT-scanner was carried out. For this purpose three different studies were investigated: in vivo, in vitro and Monte Carlo calculations.MethodsIn vivo dosimetry was performed, using OSL NanoDot dosimeters, to determine the dose to the skin of twenty pregnant women. In vitro studies were established by using a cubic phantom of water, in order to estimate the out of field doses. In the latter study, OSLDs were placed at depths corresponding to the lowest, average and highest position of the uterus. Monte Carlo calculations of effective doses to high radio-sensitive organs were established, using PCXMC and CTExpo software suites for EOS imaging system and CT-scanner, respectively.ResultsThe EOS imaging system reduces radiation exposure 4 to 8 times compared to the CT-scanner. The entrance skin doses were 74% (p-values <0.01) higher with the CT-scanner than with the EOS system. In the out of field region, the measured doses of the EOS system were reduced by 80% (p-values <0.02).Monte Carlo calculations confirmed that effective doses to organs are less accentuated for EOS than for CT pelvimetry.ConclusionsThe EOS system is less irradiating than the CT exam. The out-of-field dose which is significant, is lower in the EOS than in the CT-scanner and could be reduced even further by optimizing the time used for image acquisition.     

Caffeine,quercetin and alizarin stimulate the exhalation of metabolic products of [14C]-N-nitrosodiethylamine in mice

Naturally occurring plant products belonging to different chemical classes namely alizarin, an anthraquinone, caffeine, a methylxanthine derivative and quercetin, a flavonol were studied for their effect on elimination of metabolites of [14C]-N-nitrosodiethylamine (14C-NDEA) through respiration in mice. Treatment with caffeine, quercetin and alizarin at doses of 200, 9 and 9 microg/ml respectively, in drinking water enhanced the exhalation of 14CO2, one of the major end products of NDEA metabolism. Radioactive CO2 exhaled in 60 min increased by 2, 1.61 and 1.4-folds in animals treated with caffeine, quercetin and alizarin for 8 weeks respectively. This increase in exhalation in caffeine-treated animals was achieved even in 2 weeks. These compounds had no adverse effects on the absorption of radioactive NDEA from the gut of the animals as shape and time of 14CO2 peak was similar in i.p. and orally administered [14C-NDEA]. Increased detoxification/elimination of the carcinogen could be one of the mechanisms for the anticarcinogenic properties of these phytochemicals in lung tumorigenesis induced by orally administered NDEA.