In vitro genotoxicity and cytotoxicity of benzalkonium chloride

Benzalkonium chloride (BAC) acts as a preservative in numerous nasal preparations. Possible genotoxic and cytotoxic effects of BAC in human respiratory epithelial BEAS-2B cells should be investigated in vitro.

Cell cultures were exposed for 2 h to BAC in concentrations ranging from 0.002% to 0.05%. Methyl methanesulfonate served as positive control, PBS as negative control. The tail moment of single-cell gel-electrophoresis (SCGE) was used to assess BAC-induced DNA damage. Cell viability was measured by trypan blue dye exclusion staining. Additionally, the critical micellar concentration (CMC) of BAC in PBS was detected.

The tail moment increased dose dependently with the maximum value at 0.02%, and declined for higher concentrations. Nearly all cells died at low BAC concentrations up to 0.01%. Above this concentration cell viability increased. The CMC of BAC in PBS was estimated to be 0.02%.

BAC caused relevant DNA changes in respiratory epithelial cells in vitro at concentrations commonly employed in commercially available nasal preparations. Some of the exposed cells survived. In further studies it could be considered to look whether these cells would still be able to proliferate and possibly fix the damage that they have possibly accumulated into an actual mutation using for example the induction of micronuclei.     

In vitro and in vivo evaluation of the genotoxicity of N-nitrosooxprenolol.

N-nitrosooxprenolol (NO-oxprenolol) might be formed in the stomach of patients taking the beta-adrenergic blocking drug, oxprenolol. This nitroso derivative has previously been shown to induce DNA damage and repair in both rat and human cultured hepatocytes. The results of the present study show that in the presence of co-cultured rat hepatocytes, 0.03 mM NO-oxprenolol produced a significant increase in the frequency of 6-thioguanine-resistant but not of ouabain-resistant mutants. No mutagenic activity was detected in the absence of metabolic activation. In mice, NO-oxprenolol (1 g/kg) increased the incidence of micronucleated cells in the liver but not in the bone marrow and the spleen. These results suggest that NO-oxprenolol, consistent with its chemical nature of nitrosamine, is biotransformed into short-lived reactive species.     

Pluchea lanceolata attenuates cadmium chloride induced oxidative stress and genotoxicity in Swiss albino mice

Cadmium intoxication induces lipid peroxidation and causes oxidative damage to various tissues by altering antioxidant defence system enzymes. At 24 h after treatment with a single intraperitoneal dose of cadmium chloride (5 mg kg-1), Swiss albino mice showed a significant increase in the levels of malanodialdehyde and xanthine oxidase (P<0.001), and a concomitant depletion of renal glutathione, catalase (P<0.001) and other antioxidant enzymes. CdCl2 also led to a simultaneous increase in micronuclei formation (P<0.001) and chromosomal aberrations (P<0.05) in mouse bone marrow cells. Oral pre-treatment with Pluchea lanceolata extract at doses of 100 and 200 mg kg-1 for 7 consecutive days before CdCl2 intoxication caused a significant reduction in malanodialdehyde formation and xanthine oxidase activity (P<0.001). A significant restoration of the activity of antioxidant defence system enzymes such as catalase, glutathione peroxidase (P<0.05), glutathione-S-transferase and glutathione reductase (P<0.001) was observed. A significant dose-dependent decrease in chromosomal aberrations and micronuclei formation was also observed (P<0.05). The results indicate that pre-treatment with P. lanceolata attenuates cadmium chloride induced oxidative stress and genotoxicity by altering antioxidant enzymes and reducing chromatid breaks and micronuclei formation.     

In vivo and in vitro studies of the hepatotoxic effects of 4-chlorophenol in mice

4-Chlorophenol (4-CP) was studied for its toxicological effect on liver by using both in vivo and in vitro approaches. Male mice were administered 4-CP, 1.5 mmol/kg body weight, i.p., and were killed at 10, 20, 30 and 50 min after drug injection. Either i.p. or oral 4-CP administration significantly lowered total liver thiol levels by 20-30% after 30 min and 3 hr respectively. This time-dependent effect of 4-CP after i.p. treatment was enhanced when mice were pretreated with hepatic microsomal enzyme inducers (phenobarbital, 40 mg/kg body weight, b.i.d., 7 days; and beta-naphthoflavone, 80 mg/kg body weight once daily, 4 days). Further, the microsomal cytochrome P-450 inhibitor, SKF 525-A, 75 mg/kg body weight injected i.p. to mice 30 min prior to 4-CP administration, blocked the reduction of liver thiol content produced by 4-CP. The results suggest that a chemically reactive intermediate of 4-CP may be formed in liver which is responsible for the observed decrease in liver thiol content. Other investigations were done to characterize the in vitro irreversible binding of [14C]4-CP. [14C]4-CP was bound irreversibly to mouse liver microsomal proteins in a concentration-dependent manner. Binding was NADPH dependent and gave a maximal binding of 12.0 nmol/mg protein/20 min and an apparent binding constant of 0.222 mM. [14C]-Binding of 4-CP was increased by 155 and 127% in liver microsomes of phenobarbital- and beta-naphthoflavone. SKF 525-A, and CO:O2 (4:1, v/v)] and selected nucleophilic compounds (glutathione, L-cysteine or L-lysine) significantly reduced [14C]4-CP binding to mouse liver microsomes. An epoxide hydrolase inhibitor, cyclohexene oxide, did not alter the extent of irreversible binding, whereas scavengers of superoxide anions or agents that are reported to reduce accumulation of active semiquinone and quinone species (L-ascorbic acid, superoxide dismutase or epinephrine) decreased the binding of [14C]4-CP to mouse liver microsomal proteins by 56, 31 and 92% respectively. The data suggest that semiquinone and quinone species of 4-CP may be the chemically reactive intermediates leading to the in vivo reduction of liver thiol levels. Since 4-CP is a minor contaminant and possible metabolite of clofibrate and chemically related hypolipidemic agents, 4-CP and its metabolites may be partly responsible for some of the hepatotoxic effects seen after long-term administration of this therapeutic class of drugs.     

In vitro and in vivo studies on chelation of manganese

This work deals with new chelating agents of manganese (Mn). Out of 24 compounds chosen for their chemical structure supposed to be favorable for Mn complexation, six polyaminopolycarboxylic acids proved to be efficient for displacing Mn bound to serum bovine proteins in vitro: TTHA, DTPA, DPTA, DPTA-OH, HBED, EDTA (mobilization > or =50%). The first five compounds were then tested in vivo on rats pretreated with MnCl2. They exhibited only slight to moderate efficacy to diminish Mn in tissues and were ineffective on increased Mn concentration in whole blood; in addition, they had different and specific mobilizing effects on other essential elements (Fe, Zn, Cu). Their limited efficacy in vivo could be due to the formation of very stable complexes between Mn2+ and different molecules such as hemoglobin and certain cytochromes, instead of Fe2+. This could disturb the functioning of the cellular respiratory chain, leading to an incomplete reduction of O2 with formation of free oxygenated radicals, reduction in the energy supply, and disturbance of the cytochromes renewal mechanism. All of these phenomena could accelerate cellular aging and explain the lack of efficacy of the chelating agents towards Mn neurotoxicity (Parkinson's syndrome).     

In vitro and in vivo studies on the metabolism of tirofiban.

Tirofiban hydrochloride [L-tyrosine-N-(butylsulfonyl)-O-[4-(4-piperidinebutyl)] monohydrochloride, is a potent and specific fibrinogen receptor antagonist. Radiolabeled tirofiban was synthesized with either (3)H-label incorporated into the phenyl ring of the tyrosinyl residue or (14)C-label in the butane sulfonyl moiety. Neither human liver microsomes nor liver slices metabolized [(14)C]tirofiban. However, male rat liver microsomes converted a limited amount of the substrate to a more polar metabolite (I) and a relatively less polar metabolite (II). The formation of I was sex dependent and resulted from an O-dealkylation reaction catalyzed by CYP3A2. Metabolite II was identified as a 2-piperidone analog of tirofiban. There was no evidence for Phase II biotransformation of tirofiban by microsomes fortified with uridine-5'-diphospho-alpha-D-glucuronic acid. After a 1 mg/kg i.v. dose of [(14)C]tirofiban, recoveries of radioactivity in rat urine and bile were 23 and 73%, respectively. Metabolite I and unchanged tirofiban represented 70 and 30% of the urinary radioactivity, respectively. Tirofiban represented >90% of the biliary radioactivity. At least three minor biliary metabolites represented the remainder of the radioactivity. One of them was identified as I. Another was identified as II. When dogs received 1 mg/kg i.v. of [(3)H]tirofiban, most of the radioactivity was recovered in the feces as unchanged tirofiban. The plasma half-life of tirofiban was short in both rats and dogs, and tirofiban was not concentrated in tissues other than those of the vasculature and excretory organs.     

Tolerance to cadmium hepatotoxicity by metallothionein and zinc: in vivo and in vitro studies with MT-null mice

The protective role of metallothionein (MT) in Cd-mediated hepatotoxicity was investigated in vivo and in vitro. Following injection of Cd (2 mg/kg, intraperitoneal or subcutaneous) hepatoxicity was significantly greater at 20 h in metallothionein-null (MT−/−) mice, compared with controls (MT+/+). The decrease in the blood and liver glucose concentrations correlated with the extent of hepatotoxicity, with blood glucose 43% lower in MT−/− mice. Zinc (50 μM) and/or Dex (1 μM) were used in hepatocyte cultures to raise MT 2–5-fold. When Cd at 10 μM was co-treated with Zn and/or Dex, lactate dehydrogenase (LD) leakage in the MT+/+ and MT−/− hepatocytes was reduced only when Zn was present. Cellular glutathione (GSH) was the same in control MT+/+ and MT−/− cultures and was uninfluenced by Zn and Dex. After treatment with 5 and 10 μM Cd, GSH levels were lower in MT−/− than MT+/+ hepatocytes in the control and Dex groups. Higher GSH concentrations were maintained in Zn co-treated cultures from both genotypes, indicating that the superior protective effect of Zn may in part derive from its influence on cellular GSH. Pre-treatment with Zn and/or Dex provided no further protection than co-treatment. Tolerance to brief (15 min) Cd exposure was also investigated in the presence of MT inducers including progesterone (100 μM). Zn, Dex and progesterone treated hepatocytes had less LD leakage than controls with Zn giving the greatest protection (LD leakage 18% of controls at 100 μM Cd). Zn pre-treated cells had higher cytosolic/particulate ratios of Cd. These findings demonstrate that MT protects primary cultures of mouse hepatocytes from short-term exposure to Cd. Zn enhances the protection through MT and non-MT mechanisms.     

Jejunal transfer rates of 109cadmium chloride increase in rats in vitro and in vivo after oral pretreatment with cadmium or zinc chloride

An increased body retention of Cd in rats orally pretreated with Cd or Zn is explained by induction of hepatic and renal metallothionein. Whether intestinal absorption of Cd increases after such treatments is not clear yet. To approach this problem we measured jejunal transfer rates of 109Cd in vitro and in vivo in pretreated rats (0.44 mmol Cd/l or 4.6 mmol Zn/l in the drinking water for 10 days) and compared them with those of untreated controls. Isolated jejunal segments were used for in vitro perfusion. In vivo perfusion was performed in anaesthetized rats with blood collected from mesenteric venules substituting corresponding losses by reinfusion of rat blood. Water and glucose transfer did not differ between controls and pretreated rats. At a luminal concentration of 5 micromol 109CdCl2/l, Cd and Zn pretreatment significantly increased the transfer rate of 109Cd in vitro and in vivo similarly. The 109Cd transfer rates in controls in the final perfusion intervals (80-120 min) were 0.06 (pmol/cm/min) in vivo and 0.05 in vitro; the corresponding rates in Cd or Zn pretreated rats were significantly higher (P<0.05) and amounted to 0.11 and 0.18 or 0.15 and 0.23, respectively. Mucosal concentrations of 109Cd measured at the end of the perfusion period tended to be lower in the pretreated animals than in the controls. This suggests that pretreatment with Cd or Zn reduces the amount of 109Cd bound to the tissue leaving more 109Cd for the transfer step. As compared to a level of mucosal metallothionein of 8 microg/g wet weight in controls, increased amounts of 67 or 52 microg/g wet weight in the Cd or Zn pretreated rats, respectively, thus did not decrease but increased transfer rates of 109Cd. Therefore, increased small intestinal transfer rates of Cd can contribute to increase the body retention of Cd seen after oral pretreatment with Cd or Zn.     

In vivo genotoxicity assessment of nerolidol

Nerolidol is a sesquiterpenoid component of essential oil used as a flavor and aroma enhancer. It has also been studied as a topical skin penetration enhancer, and has inhibitory activities against S. aureus and E. coli, among other activities. The objective of this study was to evaluate the ability of a single nerolidol treatment to induce DNA damage in peripheral blood and liver cells of mice and micronuclei in polychromatic erythrocytes of bone marrow cells of the same animals. In the dose range‐finding assays, the maximum tolerated dose was higher than 2000 mg kg^?1. The doses used in the experiments were 250, 500 and 2000 mg kg^?1, administered by gavage in a single dose. Peripheral blood cells were collected 4 and 24 h after the treatments and liver cells 24 h after. At least 100 nucleoids per cell type/animal were analyzed to determine the DNA damage scores and 2000 PCEs per animal for micronuclei in PCEs. The positive control was N‐nitroso‐N‐ethylurea 50 mg kg^?1. Cytotoxicity was assessed by scoring 200 consecutive total polychromatic (PCE) and normochromatic (NCE) erythrocytes (PCE:NCE ratio). The results showed that nerolidol induced weak levels of dose‐related DNA damage in both types of cells analyzed, and enhanced the average number of micronucleated cells in the two high doses tested. The PCE:NCE ratio showed no cytotoxicity for the three doses of the compound. The data obtained support the view that nerolidol induces clastogenicity and very weak genotoxicity in the mouse cells tested. Copyright © 2010 John Wiley & Sons, Ltd.     

In vivo and in vitro hyperbaric studies in mice suggest novel sites of action for ethanol

 The present study uses increased atmospheric pressure as an ethanol antagonist to test the hypothesis that allosteric coupling pathways in the GABA_A receptor complex represent initial sites of action for ethanol. This was accomplished using behavioral and in vitro measures to determine the effects of pressure on ethanol and other GABAergic drugs in C57BL/6 and LS mice. Behaviorally, exposure to 12 times normal atmospheric pressure (ATA) of a helium-oxygen gas mixture (heliox) antagonized loss of righting reflex (LORR) induced by the allosteric modulators ethanol and pentobarbital, but did not antagonize LORR induced by the direct GABA agonist 4,5,6,7-tetrahydroisoxazolo-pyridin-3-ol (THIP). Similarly, exposure to 12 ATA heliox antagonized the anticonvulsant effects verses isoniazid of ethanol, diazepam and pentobarbital. Biochemically, exposure to 12 ATA heliox antagonized potentiation of GABA-activated ³⁶Cl^– uptake by ethanol, flunitrazepam and pentobarbital in LS mouse brain preparations, but did not alter GABA-activated ³⁶Cl^– uptake per se. In contrast to its antagonist effect versus other allosteric modulators, pressure did not antagonize these behavioral or in vitro effects induced by the neuroactive steroid, 3α-hydroxy-5β-pregnan-20-one (3α,5β-P). These findings add to evidence that pressure directly and selectively antagonizes drug effects mediated through allosteric coupling pathways. The results fit predictions, and thus support the hypothesis that allosteric coupling pathways in GABA_A receptors represent initial sites of action for ethanol. Collectively, the results suggest that there may be common physicochemical and underlying structural characteristics that define ethanol sensitive regions of receptor proteins and/or their associated membranes that can be identified by pressure within (e.g., GABA_A) and possibly across (e.g., GABA_A, NMDA, 5HT₃) receptors. Received: 15 December 1997 / Final version: 23 July 1998     

In vitro and in vivo studies of the non-sedating antihistamine epinastine

Epinastine (3-amino-9,13b-dihydro-1H-dibenz [c,f]imidazo[1,5-a]azepine hydrochloride, WAL 801 CL) was tested in vitro and in vivo in comparison with other H1-receptor antagonists. In the guinea pig ileum and in receptor binding studies the test substance showed a high affinity to H1-receptors. The following rank order was determined: WAL 801 CL greater than astemizole greater than terfenadine. These results were confirmed in vivo. The studies were carried out with oral and intravenous administration of WAL 801 CL to assess the inhibition of histamine-induced reactions in the skin or the lung of rats, dogs and guinea pigs. 10- to 100fold antihistaminic doses of WAL 801 CL showed no effect on the sleeping-waking behaviour of cats. From this and other results it is suggested that the compound does not penetrate in the central nervous system. The action pattern of WAL 801 CL as a non-sedating antihistamine corresponds more to that of terfenadine than that of ketotifen.     

In vitro and in vivo studies of the Interferon-alpha action on distinct Orthobunyavirus

Oropouche, Caraparu, Guama, Guaroa and Tacaiuma viruses (Orthobunyavirus genus) cause human febrile illnesses and/or encephalitis. To achieve a therapeutical agent to prevent and/or treat these diseases we evaluated the antiviral action of Interferon-alpha (IFN-alpha) on these orthobunyaviruses. In vitro results showed that all the studied orthobunyaviruses are susceptible to antiviral action of IFN-alpha, but this susceptibility is limited and dependent on both concentration of drug and treatment period. In vivo results demonstrated that IFN-alpha present antiviral action on Oropouche and Guaroa viruses when used as a prophylactic treatment. Moreover, a treatment initiated 3h after infection prevented the death of Guaroa virus infected-mice. Additionally, mortality of mice was related to the migration and replication of viruses in their brains. Our results suggest that IFN-alpha could be potentially useful in the prevention of diseases caused by Oropouche virus and in the prevention and/or treatment of diseases caused by Guaroa virus.     

Evaluation of salidroside in vitro and in vivo genotoxicity

It is reported that salidroside, the main component of a traditional Chinese medicine, Rhodiola rosea, has the efficacy of protecting Coxsackie virus impairment. As part of a safety evaluation on salidroside for use in the treatment of viral myocarditis, the present study evaluated potential genotoxicity of salidroside by using the standard battery of tests (i.e., bacterial reverse mutation assay, chromosomal aberrations assay, and mouse micronucleus assay) recommended by the State Food and Drug Administration of China. The results showed that salidroside was not genotoxic under the conditions of the reverse mutation assay, chromosomal aberrations assay, and mouse micronucleus assay conditions. The anticipated clinical dose seems to be smaller than the doses administered in the genotoxicity assays. With confirmation from further toxicity studies, salidroside would hopefully prove to be a safe anti-Coxsackie virus agent.     

Review of the in vitro and in vivo genotoxicity of dichlorvos

Dichlorvos has been in widespread use as an insecticide for over 40 years, during which time its carcinogenicity and genotoxicity have been evaluated extensively. In vitro genotoxicity assays--have shown dichlorvos to be a direct acting genotoxicant at high concentrations, consistent with its known chemical reactivity. This activity is greatly reduced in the presence of S9-mix providing auxiliary metabolic activation, again consistent with its known chemistry and metabolism. Dichlorvos has been examined in a number of in vivo genotoxicity assays using a range of cell types and endpoints, and whilst there are some reports of activity, a critical evaluation has shown that there is no convincing evidence that dichlorvos has significant genotoxic activity in vivo under exposure conditions relevant to potential human exposures. In combination with the extensive carcinogenicity database for dichlorvos, the weight of evidence indicates that dichlorvos is not genotoxic under exposure conditions relevant to those that might occur in humans.     

Mechanisms of genotoxicity. A review of in vitro and in vivo studies with engineered nanoparticles

Engineered nanoparticles (NPs) are widely used in different technologies but their unique properties might also cause adverse health effects. In reviewing recent in vitro and in vivo genotoxicity studies we discuss potential mechanisms of genotoxicity induced by NPs. Various factors that may influence genotoxic response, including physico-chemical properties and experimental conditions, are highlighted. From 4346 articles on NP toxicity, 112 describe genotoxicity studies (94 in vitro, 22 in vivo). The most used assays are the comet assay (58 in vitro, 9 in vivo), the micronucleus assay (31 in vitro, 14 in vivo), the chromosome aberrations test (10 in vitro, 1 in vivo) and the bacterial reverse mutation assay (13 studies). We describe advantages and potential problems with different methods and suggest the need for appropriate methodologies to be used for investigation of genotoxic effects of NPs, in vitro and in vivo.     

In vivo micronucleus assay and GST activity in assessing genotoxicity of plumbagin in Swiss albino mice

Information available on the mutagenicity of a large number of indigenous drugs commonly employed in the Siddha and Ayurveda systems of medicine is scanty. In this context, the current investigation on plumbagin, 5-hydroxy-2methyl-1,4-napthoquinone, an active principle in the roots of Plumbago zeylanica used in Siddha and Ayurveda for various ailments, was carried out; 16 mg/kg b.w. (LD(50)) was fixed as the maximum dose. Subsequent dose levels were fixed as 50% and 25% of LD(50) amounting to 8 mg and 4 mg/kg b.w., respectively, and given orally for 5 consecutive days in 1% Carboxyl Methyl Cellulose (CMC) to Swiss albino mice weighing 25-30 g. The micronucleus assay was done in mouse bone marrow. Plumbagin was found to induce micronuclei at all the doses studied (4 mg/kg, 8 mg/kg, 16 mg/kg b.w.), and it proves to be toxic to bone marrow cells of Swiss albino mice. Animal treated with cyclophosphamide (40 mg/kg b.w.) served as positive control. In addition, glutathione S-transferase (GST) activity was observed in control, plumbagin (4 mg, 8 mg, 16 mg/kg b.w., respectively), and genotoxin-treated experimental group of animals. No significant change in GST activity was observed with plumbagin dose of 4 mg/kg b.w., whereas GST activity was significantly inhibited by higher doses of plumbagin (8 mg and 16 mg/kg b.w.) and cyclophosphamide.     

Coir fibre toxicity: In vivo and in vitro studies

The biological activity of coir fibre, coir ash and their components were investigated in vitro by measuring the haemolytic activity and macrophage cytotoxicity. In vivo studies carried out by injecting guinea pigs intratracheally with coir fibres resulted in resolving granulomas. The observed haemolytic activity and macrophage cytotoxicity was more marked with coir ash compared with coir fibres. Chemical analysis of coir ash revealed the presence of toxic chemical constituents in appreciable amounts.     

In vitro and in vivo studies of diclofenac suppositories in humans

Five different preparations of diclofenac-suppositories (A, B, C, D, E) are investigated for in vitro liberation (modified paddle method) and for in vivo bioavailability in man (8-12 subjects) in a crossover design. In vitro, the time at which 63.2% of the drug are liberated (tL) is 14, 20, 25, 14 and 3.5 min for the preparations A, B, C, D and E, respectively. The steady state concentrations from the preparations B and C are 51 and 11%, respectively, and lower than for the others. In vivo, the time of the concentration maximum (tmax) in min is (mean +/- S mean): A = 68 +/- 18, B = 72 +/- 9, C = 120 +/- 22, D = 42 +/- 3, E = 24 +/- 0.5. The concentration maximum (cmax) in mumol . l-1 at tmax is (mean +/- S mean): A = 5.9 +/- 0.8, B = 3.9 +/- 0.3, C = 3.1 +/- 0.4, D = 5.7 +/- 0.6, and E = 5.5 +/- 0.8. The area under the curve (AUC) for all the preparations has found to be between 8.7 and 10,6 mumol . h . l-1. There is a significant correlation between the in vitro parameter tL and the in vivo data of tmax and cmax, respectively. In consequence, the invasion behaviour in vivo can be derived from in vitro data for drugs with similar good physicochemical properties as diclofenac-Na.     

Effects of diethyldithiocarbamate on the toxicokinetics of cadmium chloride in mice

Diethyldithiocarbamate (DDC) efficiently alleviates the acute toxicity of injected cadmium chloride, but enhances the acute toxicity of orally administered cadmium chloride. Further, DDC induces extensive changes in organ distribution of cadmium, and mobilizes aged cadmium depots. The present study investigates effects of DDC on the toxicokinetics of cadmium at lower doses of cadmium than those used in previous studies. During single exposure to subtoxic oral doses of cadmium chloride DDC enhanced intestinal cadmium absorption, both after intraperitoneal and oral administration of DDC. In such acute exposure experiments orally administered DDC only slightly changed the relative organ distribution of absorbed cadmium, while intraperitoneal administration of DDC induced extensive changes in organ preference of absorbed cadmium. The relative hepatic and testicular deposition was reduced, while the relative deposition in heart, spleen, lungs, brain and carcass was increased. Bi-weekly intraperitoneal injections of DDC enhanced the rate of elimination of aged cadmium depots and changed the organ distribution of retained cadmium, compared to the control group. Chronic exposure to DDC in the feed and cadmium chloride in the drinking water did however not result in increased whole-body retention, and the organ distribution in the DDC-exposed group was similar to that in the control group. This result could be due to both increased rate of absorption and increased published extensive changes in the toxicokinetics of cadmium induced by DDC are mainly due to the high cadmium doses employed and the intraperitoneal administration of DDC. At lower doses and more realistic administration routes for cadmium and DDC, the effect of DDC is less. However, still DDC does not seem to have any potential as an antidote for cadmium or for mobilization of cadmium depots in humans.