Zinc deficiency induced by the chelating agent DTPA and its regulatory interpretation for developmental toxicity classification.

Aminocarboxylic acid (ethylenediamine-based) chelating agents such as DTPA are widely used in a variety of products and processes. Recently, DTPA was classified in the European Union as a developmental toxicant CLP Category 1B. However, according to the CLP regulation (CLP, 2008) classification as a developmental toxicant requires a chemical to possess an intrinsic, specific property to do so. This paper provides overwhelming evidence that shows the developmental toxicity only seen at a sustained high dose of 1000 mg DTPA/kg bw/day in rats during pregnancy is mediated by zinc depletion which leads to non-specific secondary effects associated with zinc deficiency. Therefore, based on the CLP regulation itself, viz. the lack of a specific, intrinsic property, supported by significant differences in zinc kinetics and physiology between pregnant rats and pregnant women, DTPA should not be classified as a developmental toxicant. Moreover, classification for developmental toxicity resulting from zinc deficiency, and only observed at high doses, would not increase protection of human health; instead, it will only lead to onerous and disproportionate restrictions being placed on the use of this substance.

Should DTPA, an Aminocarboxylic acid (ethylenediamine-based) chelating agent, be considered a developmental toxicant?

Aminocarboxylic acid (ethylenediamine-based) chelating agents, such as DTPA and EDTA, are widely used in a variety of products and processes. Recently the European RAC proposed to classify DTPA as a developmental toxicant Category 1B according to CLP. This paper provides unequivocal and significant evidence that developmental effects cannot be considered an intrinsic property of the chelating substances themselves since: (1) animals fed a zinc deficient diet during gestation exhibit developmental toxicity of a similar nature and severity to that observed in studies involving such chelates, (2) sufficient supplementation of zinc in the diet, or administration of zinc bound chelates, completely negates the developmental effects. Moreover, the bioavailability of DTPA is very low with >95% of oral doses excreted unchanged via the feces within 24 h. If DTPA would possess the intrinsic property to be developmentally toxic, simple zinc supplementation should not be sufficient to negate these effects. Furthermore, the relevance of classification is highly questionable since worker or consumer exposure could not lead to a scenario whereby sufficient zinc deficiency would manifest itself. Therefore classification of DTPA for such effects is not protective of human health; instead it leads to onerous and disproportionate restrictions being placed on this substance.

Reaction of gadolinium chelates with ozone and hydroxyl radicals.

Gadolinium chelates are used in increasing amounts as contrast agents in magnetic resonance imaging, and their fate in wastewater treatment has recently become the focus of research. Oxidative processes, in particular the application of ozone, are currently discussed or even implemented for advanced wastewater treatment. However, reactions of the gadolinium chelates with ozone are not yet characterized. In this study, therefore, rate constants with ozone were determined for the three commonly used chelates Gd-DTPA, Gd-DTPA-BMA, and Gd-BT-DO3A, which were found to be 4.8 ± 0.88, 46 ± 2.5, and 24 ± 1.5 M(-1) s(-1), respectively. These low rate constants indicate that a direct reaction with ozone in wastewater is negligible. However, application of ozone in wastewater leads to substantial yields of (•)OH. Different methods have been applied and compared for determination of k((•)OH+Gd chelate). From rate constants determined by pulse radiolysis experiments (k((•)OH+Gd-DTPA) = 2.6 ± 0.2 × 10(9) M(-1) s(-1), k((•)OH+Gd-DTPA-BMA) = 1.9 ± 0.7 × 10(9) M(-1) s(-1), k((•)OH+Gd-BT-DO3A) = 4.3 ± 0.2 × 10(9) M(-1) s(-1)), it is concluded that a reaction in wastewater via (•)OH radicals is feasible. Toxicity has been tested for educt and product mixtures of both reactions. Cytotoxicity (MTT test) and genotoxicity (micronuclei assay) were not detectable.

Evidence for a differential translocation of actinides across human lung epithelial cell monolayer in vitro according to their physicochemical properties and the presence of a chelating agent.

The epithelial cell plays a key role in the transfer of radionuclides from lungs to blood following pulmonary exposure. The present study was designed to evaluate the transfer across human lung epithelial cells of various actinides (plutonium, americium and uranium), the influence of the physicochemical properties of plutonium compounds and of the chelating agent diethylene triamine pentaacetic acid (DTPA). To address this question, Calu-3 cells grown in a bicameral culture system were used. The integrity of the epithelial barrier was evaluated by measuring transepithelial electrical resistance (TEER) and the passage of a fluorescent marker, lucifer yellow. Activity measurement in basal compartment following periodic collection of culture medium was made from 2 h to seven days. To facilitate data handling and analysis, the statistical tool STATBIODIS was used. The results indicate differences in transfer for the different elements, and according to Pu physicochemical properties. Though to various extents, the chelating agent DTPA always increased the transfer of Pu and Am across the epithelial cells, without altering the integrity of the epithelial barrier. This in vitro cell culture model, by mimicking translocation of actinides from lungs to blood, can represent a valuable tool to further understand the underlying mechanisms and properties controlling this process.

Final report on the safety assessment of pentasodium pentetate and pentetic acid as used in cosmetics.

Pentasodium Pentetate and Pentetic Acid function as chelating agents in cosmetics. Pentasodium Pentetate is readily soluble in water, but the corresponding free acid is not. Pentasodium Pentetate is used in almost 400 cosmetic products over a wide range of product categories, although it is mostly used in hair dyes and colors at use concentrations of 0.1% to 1.0%. Pentetic Acid is used in 150 cosmetic products, mostly in hair dyes and colors. Chelating agents are used in cosmetics to remove calcium and magnesium cations, which impede foaming and cleansing performance and which can cause a haze in clear liquids. The acute oral LD(50) of Pentasodium Pentetate in rats was > 5 g/kg. The acute dermal LD(50) of Pentapotassium Pentetate using rats was reported to be > 2 g/kg. The intraperitonal LD(50) of Pentetic Acid was reported to be 585 mg/kg. Short-term studies of the calcium and sodium salts of Pentetic Acid in male mice demonstrated no dose-related toxicity over the dose range of 10, 100, and 250 mg/kg. In a 4-week dermal toxicity study, daily topical application of 0.05% Pentasodium Pentetate to shaved and abraded rabbit skin produced moderate erythema after the first week and throughout the study, but no systemic toxicity. Pentasodium Pentetate or Pentapotassium Pentetate applied to intact albino rabbit skin were not irritating. A 40% solution of Pentapotassium Pentetate was not sensitizing in a guinea pig maximization test. The no observed adverse effect level (NOAEL) for rats given 40% Pentapotassium Pentetate by oral gavage was reported to be 83 mg/kg day(-1). Subchronic inhalation evaluation of a bath freshener containing 0.05% or 0.09% Pentasodium Pentetate using albino rats determined that there was no cumulative systemic toxicity attributable to the ingredient at either concentration. The no observed effect level (NOEL) for maternal toxicity in pregnant rats was 400 mg/kg body weight and for fetal toxicity was 100 mg/kg body weight. Another reproductive toxicity study evaluated Pentetic Acid-Zn with and without sodium chloride in pregnant C57/B1 Dougherty mice. No toxicity was found without added sodium chloride. Pentapotassium Pentetate was not mutagenic in an Ames test, with or without metabolic activation. The same material tested in Chinese hamster ovary cells was not clastogenic. Calcium Pentetate at 1.351 microg/ml produced a statistically significant increase in the number of sister-chromatid exchanges. Pentasodium Pentetate is nonirritating to moderately irritating, but not a sensitizer in clinical tests. A human comedogenicity (acne promotion) test using Pentasodium Pentetate found no effect. Although data are lacking on the dermal penetration of these two ingredients, other chelating agents such as EDTA do not penetrate the skin, so it is likely that Pentasodium Pentetate and Pentetic Acid also would not penetrate. The high water solubility of Pentasodium Pentetate and the low water solubility of Pentetic Acid also support that their dermal penetration will be low. Other chelating agents, including EDTA and its salts, have been determined to be safe in the current practices of use in cosmetics. Meta-, Tri-, and Hexametaphosphate salts are chelating agents determined to be safe in the current practices of use in cosmetics. Metasilicate salts were found to be safe as chelating agents in cosmetics when formulated to avoid irritation. Overall, these data were considered sufficient to support the safety of Pentesodium Pentetate and Pentetic Acid as used in cosmetics.

[Preclinical investigation of Mn(II)-diethylenetriaminepentaacetate (Mangapentetate) as paramagnetic contrast agent for magnetic resonance tomography].

The preclinical evaluation of 0.5 M solution of a manganese(II)-DTPA complex (Mangapentetate, Pentamang) has been carried out in order to test the ability of manganese to be used as substitute for potentially toxic gadolinium in paramagnetic contrast agents in the MRI clinical routines. The toxicologic tests of the Mn(II) - DTPA were carried out in mice, rats, and rabbits. Liquid phantoms served for direct comparison of the ability of Mn(II) - DTPA to increase the intensity of T1-weighted SE-images to the contrast properties of the Gd(III) - DTPA (Magnevist). Normal healthy rabbits (n = 12) were used for quantification of the imaging ability of Mn(II) - DTPA. The value of LD50 in rabbits was above 10 ml/kg, rather close to that one of Gd(III) - DTPA. An increase in intensity of the T1-weighted images induced by addition of Mn(II) - DTPA in phantom tests did not differ significantly from the values obtained with Gadopentetate. Mn(II) - DTPA delivered prominent enhancement of normal kidneys in healthy rabbits as well as chest tumors in dogs.

[Preclinical toxicological evaluation of Pentamang and Mangascan].

We have carried out a preclinical toxicological investigation (acute toxicity evaluation) of Mangascan (0.5 M solution of manganese(II) - EDTA complex) and Pentamang (0.5 M solution of manganese(II) - DTPA complex), a new paramagnetic contrast agents for MRI procedures. In 14 days after single intravenous introduction of Mangascan (10.0 ml/kg) or Pentamang (5.0 ml/kg) to rats, no any toxic influence of the studied agents was detected in the general condition, bone marrow, cardiovascular and central nervous systems, and liver and kidney functions of experimental animals. No pathological changes were observed in the functional activity and morphology of the internal organs and systems. The results showed that both Mangascan and Pentamang belong to the class of low toxicity substances.

Imaging of non-small cell lung cancers with a monoclonal antibody, KC-4G3, which recognizes a human milk fat globule antigen.

To determine the role of lung cancer tumor imaging with monoclonal antibodies directed against high molecular weight human milk fat globule antigens, we administered i.v. 111In-KC-4G3 to 24 patients with advanced non-small cell lung cancer. One mg of 111In-KC-4G3 was mixed with 0, 9, 49, 99, or 499 mg of unlabeled KC-4G3 and infused i.v. over 1 to 5 h. The mean 111In-KC-4G3 radiochemical purity was greater than 97% and the resultant immunoreactivity averaged 62%. Successful imaging of cancer sites was accomplished in 92% of 24 patients, and 57% of 91 total lesions were visualized. Successful localization of tumor sites related to size (P less than 0.001), with 81% of lesions greater than 3.0 cm in diameter, 50% of lesions 1.5 to 3 cm, and 6% of lesions less than 1.5 cm successfully imaging, and to location (P less than 0.05), with 69% of pulmonary lesions, 80% of soft tissue lesions, and only 32% of bone metastases being visualized. Nonspecific reticulo-endothelial uptake of radioactivity was a major problem. Approximately 35% of 111In was chelated to serum transferrin by 24 and 48 h after infusion. The mean t 1/2 beta for plasma radioisotope and immunoreactive KC-4G3 was 29 and 27 h, respectively. There was no correlation between total infused antibody dose and imaging success or between total dose and effect on 111In and KC-4G3 kinetics. Circulating free KC-4 antigen was measurable in all but one patient before study. Tumor biopsy following infusion could demonstrate antibody presence but not saturable antigen binding. We conclude that (a) 111In-KC-4G3 demonstrates successful tumor localization in non-small cell lung cancers bearing generally high expression of its antigen and (b) further investigations to diminish nonspecific radioactivity for imaging and utilization of high dose radiolabeled antibody for therapeutic intent are warranted.

Establishing principal soil quality parameters influencing earthworms in urban soils using bioassays.

Potential contamination at ex-industrial sites means that, prior to change of use, it will be necessary to quantify the extent of risks to potential receptors. To assess ecological hazards, it is often suggested to use biological assessment to augment chemical analyses. Here we investigate the potential of a commonly recommended bioassay, the earthworm reproduction test, to assess the status of urban contaminated soils. Sample points at all study sites had contaminant concentrations above the Dutch soil criteria Target Values. In some cases, the relevant Intervention Values were exceeded. Earthworm survival at most points was high, but reproduction differed significantly in soil from separate patches on the same site. When the interrelationships between soil parameters and reproduction were studied, it was not possible to create a good model of site soil toxicity based on single or even multiple chemical measurements of the soils. We thus conclude that chemical analysis alone is not sufficient to characterize soil quality and confirms the value of biological assays for risk assessment of potentially contaminated soils.

Alpha-emitting bismuth cyclohexylbenzyl DTPA constructs of recombinant humanized anti-CD33 antibodies: pharmacokinetics, bioactivity, toxicity and chemistry.

UNLABELLED: The alpha-particle-emitting radionuclides have several physical characteristics that make them attractive candidates for radioimmunotherapy: (a) high linear energy transfer; (b) short path lengths (50-80 microm); and (c) limited ability of cells to repair damage to DNA. This article describes the pharmacokinetic, bioactivity, toxicity and chemical characteristics of alpha-particle-emitting, 213Bi and 212Bi radiometal conjugated HuM195 (anti-CD33) constructs. Conjugation of HuM195 to SCN-CHX-A-DTPA resulted in the attachment of up to 10 chelating ligand molecules per antibody. RESULTS: Radiolabeling efficiency of the CHX-A-DTPA-HuM195 construct with 213Bi was 78%+/-10% (n = 46) after 10 min at specific activities of up to 1110 MBq/mg. The immunoreactivity of the 213Bi-labeled CHX-A-DTPA-HuM195 construct was 84%+/-10% (n = 28) and was independent of the specific activity. The bismuth-labeled CHX-A-DTPA-HuM195 construct was rapidly internalized into the cell in a time-dependent manner ranging from 50% at 1 h to 65% at 24 h. 205Bi/206Bi-labeled constructs were stable for at least 2 d in vitro in the presence of human serum at 37 degrees C. After injection into mice, there was no uptake or loss of bismuth to mouse tissues, which do not express CD33, or to the kidney, which has avidity for free bismuth. Mice injected intraperitoneally with doses of (213Bi)CHX-A-DTPA-HuM1 95 ranging from 18.5 to 740 MBq/kg showed no toxicity, but at 2590 MBq/kg, two of the three mice died within 2 wk and a third mouse showed significant reductions in white blood cell counts. Mice injected intravenously with doses of (213Bi)CHX-A-DTPA-HuM195 up to 370 MBq/kg exhibited little toxicity, but 666 MBq/kg was above the MTD for mice. Leukemia cell killing in vitro with bismuth-labeled HuM1 95 showed dose- and specific activity-dependent killing of CD33+ HL60 cells; approximately 50% killing was observed when two bismuth atoms (50 fM radiolabeled antibody) were initially bound onto the target cell surface. CONCLUSION: Alpha-emitting antibodies are among the most potent cytotoxic agents known, yet are specific and appear safe in vivo. The physical and biochemical characteristics of the 213Bi isotope and its generation, as well as the biochemistry of the 213Bi-labeled CHX-A-DTPA-HuM195 construct, make it possible to use the constructs safely and feasibly in humans at therapeutic levels.

Use of the magnetic resonance contrast agent gadodiamide in the central nervous system. Results of a multicenter trial.

To investigate the safety and efficacy of the low-osmolar, nonionic contrast agent, gadodiamide injection (Omniscan, Sanofi Winthrop Pharmaceuticals, New York, NY), for magnetic resonance imaging (MRI) of the head and spine, a multicenter study involving 439 patients was done at 15 centers as part of a Phase II/III clinical trial. Unenhanced MRI scans were obtained after which the patients were injected with 0.1 mmol/kg gadodiamide, and the MRI was repeated. The patients' vital signs were monitored, and laboratory studies were conducted. Neurologic status was examined before and after the study. The images were evaluated for contrast enhancement. No patient had any significant adverse event or serious change in clinical status. Abnormalities were found in 80% (351) of all patients studied, and it was found that, in 75% (266) of these, the postgadodiamide injection images were improved or facilitated visualization of lesions compared with preinjection images. The investigators believe that, based on the results of this study, gadodiamide injection is safe and effective for imaging the head and spine. They suggest that future studies further assess and compare the safety parameters of gadodiamide injection with those of other nonionic and ionic gadolinium ligands.

Gadodiamide injection. First human experience with the nonionic magnetic resonance imaging enhancement agent.

The safety, tolerance, and pharmacokinetics of gadodiamide injection (Omniscan, Sanofi Winthrop Pharmaceuticals, New York, NY) were evaluated in an open, ascending-dose study in 20 healthy male volunteers. Gadodiamide injection was administered intravenously at doses of 0.05, 0.1, 0.2, and 0.3 mmol/kg. Mild adverse events were experienced by nine subjects. These events included, but were not limited to, light-headedness, dizziness, and perversion of taste or smell. There was one occurrence of injection-associated discomfort that resolved within seconds. Vital sign and electrocardiogram measurements did not show any clinically relevant changes. There were no clinically significant changes in laboratory parameters, but minor transient elevations in serum iron were detected. These elevations typically occurred 8 and 48 hours after administration of gadodiamide injection and were not dose related. The pharmacokinetics of gadodiamide injection were evaluated in the 0.1-mmol/kg and 0.3-mmol/kg dose groups with the serum time-concentration data fitted to an open two-compartment model and the urine time-concentration data fitted to a one-compartment model. The serum elimination half-life was approximately 70 minutes, and urinary recovery was greater than 95% by 72 hours after administration.

Detailed toxicity studies of liposomal gadolinium-DTPA.

Acute, subacute, and delayed toxicity testing was assessed in mice for liposomal gadolinium-DTPA (Gd-DTPA), blank liposomes, and nonliposomal Gd-DTPA. In the subacute experiments mice were injected intravenously (IV) with 0.3 mmol/kg Gd-DTPA per day for 30 days in the form of either free Gd-DTPA, liposomal Gd-DTPA, or an equivalent amount of lipid in blank liposomes without Gd-DTPA. The interpolated acute LD50 of liposomal and nonliposomal Gd-DTPA, estimated as a means of identifying the approximate level, was similar (LD50 = 5.7 mmol/kg Gd-DTPA). In subacute toxicity testing, prolonged high doses of liposomal Gd-DTPA caused splenomegaly, cardiomegaly, lymphocytopenia and hypergammaglobulinemia (P less than .05). Nonliposomal Gd-DTPA caused mild cardiomegaly and altered liver enzymes (P less than .05). Blank liposomes caused relatively mild splenomegaly (P less than .05) but few other changes. Delayed testing three months after the subacute testing showed that most of the changes caused by the liposomal Gd-DTPA were reversible.

Extravascular toxicity of two magnetic resonance contrast agents. Preliminary experience in the rat.

We compared the relative toxicities of standard concentrations of two magnetic resonance imaging (MRI) contrast agents, ionic gadolinium diethylenetriaminepentacetic acid (DTPA) and low-osmolar gadolinium-1, 4, 7 tris (carboxymethyl)-10-(2'-hydroxypropyl)-1, 4, 7, 10 tetra-azacyclododecane (HP-DO3A) with that of the conventional radiographic contrast medium meglumine diatrizoate, when extravasated into the deep dermal tissues of laboratory rats. Gadolinium-DTPA caused moderate necrosis, hemorrhage, and edema which was not statistically different than meglumine diatrizoate. In contrast, gadolinium HP-DO3A was significantly less toxic than meglumine diatrizoate. Additional experience will be needed in order to determine whether these laboratory results will be clinically relevant in humans.

Ytterbium-DTPA. A potential intravascular contrast agent.

Ytterbium-DTPA was evaluated as a potential intravascular contrast agent. Ytterbium-DTPA was synthesized from ytterbium oxide and diethylene triamine penta-acetic acid (DTPA). CT scans of increasing concentrations of ytterbium and iodine showed that at 125 kVp, ytterbium was denser than an equal concentration of iodine. The LD50 of intravenous ytterbium-DTPA was 10 mM/kg (1.73 g ytterbium/kg) in rats. In enhanced CT scans and pulmonary angiography in dogs, ytterbium was visibly denser than iodine, and CT Hounsfield units showed greater enhancement of the aorta and inferior vena cava with ytterbium. The animals showed no sign of acute or delayed toxicity. Ytterbium-DTPA deserves further evaluation as a contrast agent for high kVp techniques.

The tissue proton T1 and T2 response to gadolinium DTPA injection in rabbits. A potential renal contrast agent for NMR imaging.

Three different doses of gadolinium (Gd) DTPA were administered intravenously to rabbits. Cardiovascular responses and changes in blood T1 and T2 were serially followed for 15 minutes when the animals were sacrificed for in vitro measures of tissue T1 and T2. Gd-DTPA was distributed and excreted like water soluble iodinated contrast agents with large changes in blood, urine, and kidney proton relaxation. An imaging experiment confirmed the efficacy as an NMR contrast agent for renal excretion. At effective doses, no adverse effects were observed and the agent appeared to be much safer than x-ray contrast agents, but with a similar potential for clinical utility.

The synthesis and evaluation of macrocyclic gadolinium-DTPA-bis(amide) complexes as magnetic resonance imaging contrast agents.

The authors found that DTPA bis(amide) macrocycles can be prepared in reasonable yields using simple methods and readily available starting materials. Gadolinium complexation is facile and gives rise to monomeric and dimeric species. The "pocket size" influences the solid state structure of the final complex, with Gd-DTPA-EAM existing as a dimer wherein the macrocycle bridges between two metal centers. Increasing the size of the bridging diamide moiety yields a macrocycle with a sufficiently large pocket to allow for the formation of nine-coordinant monomeric complexes. The solution behavior of all the complexes studied is consistent with the complex being present as monomers. All complexes display kinetic lability comparable to Gd-DTPA-BMA. The measured KTherm and KSel values of the complexes vary with the size of the pocket. Values similar to those observed for Gd-DTPA-BMA have been obtained with Gd-DTPA-OAM. There appears to be a good correlation between log K(Gd/Zn) and the acute toxicity for the complexes studied, with Gd-DTPA-OAM showing a toxicity value similar to that of Gd-DTPA-BMA. Although many of these complexes are chemically interesting, they do not offer any unique advantages as new magnetic resonance imaging contrast agents compared with the DOTA- and DTPA-based products currently used clinically.

Preclinical safety assessment and pharmacokinetics of gadodiamide injection, a new magnetic resonance imaging contrast agent.

In a wide range of preclinical studies of gadodiamide injection (Omniscan, Sanofi Winthrop, New York, NY, and Nycomed AS, Oslo, Norway), the pharmacokinetics of the compound have been delineated and its safety demonstrated. The pharmacokinetic behavior of gadodiamide was consistent with its extracellular distribution. Its half-life in rats, rabbits, and monkeys was short, 18, 38, and 75 minutes, respectively. Gadodiamide was shown to be excreted rapidly, primarily through the kidneys. In rats, 94% of the administered dose was excreted in the urine within the first 24 hours after administration. Approximately 1% to 4% appeared in the feces during the same period. Gadodiamide injection has been shown to have a remarkably low acute lethal toxicity, superior to that of gadopentetate dimeglumine injection (Magnevist, Berlex Laboratories, Wayne, NJ, and Schering AG, Berlin, Germany) or gadoterate meglumine (Dotarem, Laboratoire Guerbet, Aulnay-Sous-Bois, France). In comparison with gadopentetate dimeglumine injection, gadodiamide injection had fewer effects on cardiovascular and hemodynamic function after rapid intravenous injection in anesthetized dogs and, in vitro at high concentrations, on erythrocyte fragility and arterial wall tension. The lesser effects might be attributable, at least in part, to the lower osmolality of gadodiamide injection, although it remains to be seen whether this will translate into any advantage for gadodiamide injection at the lower doses used for imaging procedures in patients. Similar to all known intravenously administered diagnostic imaging agents, gadodiamide injection produces vacuolization of the proximal tubular cells in the kidney, without any change in renal function. However, the single-dose threshold for this effect is greater than 0.5 mmol/kg in the rat; even after a dose of 10 mmol/kg, the vacuolization was only "moderate" in degree and was shown to have regressed partially during the 7 days after administration. In monkeys, administration of 0.25 mmol/kg daily for 28 days had no effect on the kidney, thus providing reassurance of the wide margin of safety for any effect of this compound on the kidney. Although intended for single administration in patients, gadodiamide injection has been studied extensively in a range of subchronic studies in rats and monkeys. The compound was well tolerated in monkeys even when administered at doses up to 1.25 mmol/kg daily for 28 consecutive days. In rats, significant toxicity occurred only at high doses, particularly in male animals, and the pattern of toxicity (involving the stomach, testes, and skin) suggested a disturbance of zinc metabolism. Gadodiamide injection produced no significant irritation when administered by a variety of intravascular and extravascular routes.

Contrast media-induced renal tubular vacuolization. A light and electron microscopic study on rat kidneys.

The morphologic changes in healthy rat kidneys (n = 102) were studied 2 or 48 hours after intravenous injection of 1 or 3 g iodine (I)/kg of high-osmolality diatrizoate, low-osmolality iopromide and iohexol, or iso-osmolality iotrolan, as well as after 0.2 or 0.6 g/kg of the high-osmolality magnetic resonance contrast medium gadolinium DTPA. Physiologic saline was injected in controls. The kidneys were fixed by perfusion and the specimens were analyzed semiquantitatively by two independent observers blinded to the treatment. A statistically significant (P less than .01) cytoplasmic vacuolization was noticed in the proximal convoluted tubule cells 2 hours after injection of 3 g I/kg of diatrizoate or iopromide. Iohexol and iotrolan induced an even more significant (P less than .01) and longer-lasting vacuolization, but gadolinium DTPA did not produce lysosomal alterations. Although the vital cell organelles remained intact, reversible lysosomal alterations may represent the first structural signs of a threatening cellular injury.

Early effect of gadopentetate and iodinated contrast media on rabbit kidneys.

RATIONALE AND OBJECTIVES: The authors compared the physiologic and nephrotoxic effects of the magnetic resonance imaging contrast medium gadopentetate with two conventional radiographic contrast media. METHODS: Rabbits were injected intravenously with one of the following solutions: 1) gadopentetate (0.1 M); 2) iohexol (300 mg I/mL); 3) metrizoate (300 mg I/mL); and 4) NaCl (0.9%). Blood samples were taken before and 5, 15, 45, 90, and 180 minutes after injection of the solutions and were analyzed for creatinine, aldosterone, and contrast media levels. Urine was sampled before and 1, 2.5, and 5 hours after injection of the solutions, and creatinine, leucine amino peptidase (LAP), alkaline phosphatase (ALP), gamma glutaryl transferase (GGT), and N-acetyl beta-D-glucosaminidase (NAG) activities were quantified. RESULTS: Contrast media clearance was similar for gadopentetate, iohexol, and metrizoate. Plasma aldosterone was significantly higher in the two groups injected with iodinated contrast agents compared with the gadopentetate and saline groups in the 3-hour samples. During the 5 hours after injection, the excretion of brushborder enzymes LAP, ALP, and gamma GT was significantly higher for all contrast media compared with pre-contrast values and 0.9% NaCl controls. NAG, a lysosomal enzyme from tubular cells, showed a significant increase compared with pre-contrast values for all contrast media. CONCLUSIONS: Intravenous injection of gadopentetate in rabbits showed nephrotoxicity of the same order as that of conventional iodinated contrast media.