Application of the threshold of toxicological concern approach to ingredients in personal and household care products.

In the absence of chemical-specific data, the threshold of toxicological concern (TTC) provides a method to determine a conservative estimate of a chronic oral exposure below which there is a very low probability of risk. The TTC approach was originally developed to support exposures to indirect food additives and was based on linear low-dose risk estimates to assure protection in the event that the chemical was later determined to be a carcinogen. Subsequently, TTC values based on noncancer endpoints were proposed for chemicals without structural alerts for genotoxicity. The original database supporting the TTC values for noncancer endpoints includes >600 structurally diverse chemicals. The objectives of this work were to evaluate the applicability of the TTC database to ingredients used in consumer products based on a comparison of the diversity of chemical structures with those in the original TTC database and to confirm that the range of NOELs for these ingredients is consistent with the range of NOELs in the original database. The results show good coverage of the product ingredient structures and confirm that the NOELs for the ingredient chemicals are similar in range to the original dataset, supporting the use of the TTC for ingredients in consumer products.

Radioimmunotherapy of human colon carcinoma xenografts using a 213Bi-labeled domain-deleted humanized monoclonal antibody.

The data presented within this paper is the first report of a humanized domain-deleted monoclonal antibody (HuCC49DeltaCH2) to be utilized in a radioimmunotherapeutic (RIT) application with 213Bi. An initial study indicated that 111In-HuCC49DeltaCH2 targets the subcutaneously implanted human colon carcinoma xenograft, LS-174T, when injected via a peritoneal route. The HuCC49DeltaCH2 was then radiolabeled with 213Bi, an alpha-emitting radionuclide with a half-life of 45.6 minutes, and evaluated for therapeutic efficacy. Dose titration studies indicated that a single dose of 500-1000 microCi, when injected by an intraperitoneal route, resulted in the growth inhibition or regression of the tumor xenograft. The radioimmunotherapeutic effect was found to be dose-dependent. Specificity of the therapeutic efficacy was confirmed in a subsequent experiment with athymic mice bearing TAG-72 negative MIP (human colorectal) xenografts. A preliminary study was also performed to assess a multiple-dose administration of 213Bi-HuCC49DeltaCH2. Doses (500 microCi) were administered at 14-day intervals after tumor implantation. A reduction in volume and/or delay in tumor growth was evident following the second and third injections of 213Bi-HuCC49DeltaCH2. As further validation of the use of 213Bi-HuCC49DeltaCH2 for RIT, a study using 131I was conducted. The overall survival of mice receiving 213Bi-HuCC49DeltaCH2 was greater than those that received 131I-HuCC49DeltaCH2.

In vivo comparison of macrocyclic and acyclic ligands for radiolabeling of monoclonal antibodies with 177Lu for radioimmunotherapeutic applications.

The studies reported herein present the first in vitro and in vivo comparison of radioimmunoconjugates (RIC) radiolabeled with 177Lu using the acyclic CHX-A"-DTPA ligand and the macrocyclic ligands, C-DOTA and PA-DOTA. The in vivo studies include pharmacokinetics and biodistribution of the formed 177Lu-labeled immunoconjugates in a tumor bearing murine model with engineered monoclonal antibody HuCC49DeltaCH2. The in vitro analysis indicated that the CHX-A" RIC was superior with respect to immunoreactivity, radiolabeling with 177Lu, and specific activity. The in vivo pharmacokinetic data by itself indicated that the Lu(III)-PA-DOTA complex may not be as stable as Lu(III) complexes with CHX-A" or C-DOTA. All three RICs demonstrated tumor targeting of human colon carcinoma xenografts in athymic mice. In these biodistribution studies, there appears to be no overall pattern or trend of one RIC over the other two. Based on these in vitro and in vivo studies, the CHX-A" DTPA ligand should be considered a suitable bifunctional chelate for the radiolabeling of monoclonal antibodies with 177Lu for radioimmunotherapy applications.

Effect of Mixed Pendent Groups on the Solution and Catalytic Properties of Europium(III) Macrocyclic Complexes: Bifunctional and Monofunctional Amide and Alcohol Pendents in Septadentate or Octadentate Ligands.

Five new Eu(III) macrocyclic complexes have been prepared and their solution and catalytic properties studied. The Eu(III) complexes with septadentate ligands TRED and NB-TRED dissociate rapidly at pH 7.4, 37 degrees C (TRED = 1,4,7-tris(hydroxyethyl)-1,4,7,10-tetraazacyclododecane, NB-TRED = 1-(nitrobenzyl)-4,7,10-tris(hydroxyethyl)-1,4,7,10-tetraazacyclododecane). Dissociation rates as determined in the presence and absence of strongly binding competing ligands suggest that under most conditions the Eu(III) complexes of ATHC, ABHC, and CNPHC are more kinetically inert to dissociation than is the Eu(III) complex containing all hydroxyethyl groups (ATHC = 1-(carbamoylmethyl)-4,7,10-tris(hydroxyethyl)-1,4,7,10-tetraazacyclododecane, ABHC = 1,7-bis(carbamoylmethyl)-4,10-bis(hydroxyethyl)-1,4,7,10-tetraazacyclododecane, CNPHC = 1-(1-carboxamido-3-(4-nitrophenyl)propyl)-4,7,10-tris(2-hydroxyethyl)-1,4,7,10-tetraazacyclododecane). Laser-induced luminescence excitation spectra of Eu(III) complexes of ABHC, ATHC, CNPHC, THED, and S-THP suggest that there is a single major species in solution at pH 6.3 and a second species that appears at more basic pH values (THED = 1,4,7,10-tetrakis(hydroxyethyl)-1,4,7,10-tetraazacyclododecane, S-THP = 1S,4S,7S,10S-tetrakis(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane). The species present at basic pH is proposed to be an alkoxide or hydroxide complex; pK(a) values as determined by potentiometric titrations are 7.5 and 8.1 for Eu(CNPHC)(3+) and Eu(ABHC)(3+), respectively. Eu(CNPHC)(3+), Eu(ATHC)(3+), and Eu(ABHC)(3+) promote transesterification of the hydroxypropyl ester of 4-nitrophenyl phosphate with pseudo-first-order rate constants at pH 7.3, 37 degrees C, and 1.00 mM complex of 1.4 x 10(-)(5), 9.3 x 10(-)(6), and 1.0 x 10(-)(6) s(-)(1), respectively. Both Eu(CNPHC)(3+)and Eu(ABHC)(3+) promote attack of an hydroxyethyl group of the macrocycle on bis(4-nitrophenyl) phosphate with pseudo-first-order rate constants at pH 7.3, 37 degrees C, and 1.00 mM complex of 1.5 x 10(-)(4) and 3.5 x 10(-)(5) s(-)(1), respectively. In general, an increase in the number of amide groups on the macrocycle of the Eu(III) complex decreases the rate of both intramolecular or intermolecular phosphate diester transesterification reactions.