Dataset Information

Monte Carlo Models for Sub-Chronic Repeated-Dose Toxicity: Systemic and Organ-Specific Toxicity.

ABSTRACT: The risk-characterization of chemicals requires the determination of repeated-dose toxicity (RDT). This depends on two main outcomes: the no-observed-adverse-effect level (NOAEL) and the lowest-observed-adverse-effect level (LOAEL). These endpoints are fundamental requirements in several regulatory frameworks, such as the Registration, Evaluation, Authorization and Restriction of Chemicals (REACH) and the European Regulation of 1223/2009 on cosmetics. The RDT results for the safety evaluation of chemicals are undeniably important; however, the in vivo tests are time-consuming and very expensive. The in silico models can provide useful input to investigate sub-chronic RDT. Considering the complexity of these endpoints, involving variable experimental designs, this non-testing approach is challenging and attractive. Here, we built eight in silico models for the NOAEL and LOAEL predictions, focusing on systemic and organ-specific toxicity, looking into the effects on the liver, kidney and brain. Starting with the NOAEL and LOAEL data for oral sub-chronic toxicity in rats, retrieved from public databases, we developed and validated eight quantitative structure-activity relationship (QSAR) models based on the optimal descriptors calculated by the Monte Carlo method, using the CORAL software. The results obtained with these models represent a good achievement, to exploit them in a safety assessment, considering the importance of organ-related toxicity.

SUBMITTER: Selvestrel G

PROVIDER: S-EPMC9224506 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Monte Carlo Models for Sub-Chronic Repeated-Dose Toxicity: Systemic and Organ-Specific Toxicity.

Selvestrel Gianluca G Lavado Giovanna J GJ Toropova Alla P AP Toropov Andrey A AA Gadaleta Domenico D Marzo Marco M Baderna Diego D Benfenati Emilio E

International journal of molecular sciences 20220614 12

The risk-characterization of chemicals requires the determination of repeated-dose toxicity (RDT). This depends on two main outcomes: the no-observed-adverse-effect level (NOAEL) and the lowest-observed-adverse-effect level (LOAEL). These endpoints are fundamental requirements in several regulatory frameworks, such as the Registration, Evaluation, Authorization and Restriction of Chemicals (REACH) and the European Regulation of 1223/2009 on cosmetics. The RDT results for the safety evaluation of ...[more]

PMID: 35743059

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Project description:A recently introduced brachytherapy system for partial breast irradiation, MammoSite, consists of a balloon applicator filled with contrast solution and a catheter for insertion of an 192Ir high-dose-rate (HDR) source. In using this system, the treatment dose is typically prescribed to be delivered 1 cm from the balloon's surface. Most treatment-planning systems currently in use for brachytherapy procedures use water-based dosimetry with no correction for heterogeneity. Therefore, these systems assume that full scatter exists regardless of the amount of tissue beyond the prescription line. This assumption might not be a reasonable one, especially when the tissue beyond the prescription line is thin. In such a case, the resulting limited scatter could cause an underdose to be delivered along the prescription line. We used Monte Carlo simulations to investigate how the thickness of the tissue between the surface of the balloon and the skin or lung affected the treatment dose delivery. Calculations were based on a spherical water phantom with a diameter of 30 cm and balloons with diameters of 4 cm, 5 cm, and 6 cm. The dose modification factor is defined as the ratio of the dose rate at the typical prescription distance of 1 cm from the balloon's surface with full scatter obtained using the water phantom to the dose rate with a finite tissue thickness (from 0 cm to 10 cm) beyond the prescription line. The dose modification factor was found to be dependent on the balloon diameter and was 1.098 for the 4-cm balloon and 1.132 for the 6-cm balloon with no tissue beyond the prescription distance at the breast-skin interface. The dose modification factor at the breast-lung interface was 1.067 for the 4-cm balloon and 1.096 for the 6-cm balloon. Even 5 cm of tissue beyond the prescription distance could not result in full scatter. Thus, we found that considering the effect of diminished scatter is important to accurate dosimetry. Not accounting for the dose modification factor may result in delivering a lower dose than is prescribed.

Project description:IntroductionThe use of high-dose-rate brachytherapy is currently a widespread practice worldwide. The most common isotope source is 192Ir, but 60Co is also becoming available for HDR. One of main advantages of 60Co compared to 192Ir is the economic and practical benefit because of its longer half-live, which is 5.27 years. Recently, Eckert & Ziegler BEBIG, Germany, introduced a new afterloading brachytherapy machine (MultiSource®); it has the option to use either the 60Co or 192Ir HDR source. The source for the Monte Carlo calculations is the new 60Co source (model Co0.A86), which is referred to as the new BEBIG 60Co HDR source and is a modified version of the 60Co source (model GK60M21), which is also from BEBIG.Objective and methodsThe purpose of this work is to obtain the dosimetry parameters in accordance with the AAPM TG-43U1 formalism with Monte Carlo calculations regarding the BEBIG 60Co high-dose-rate brachytherapy to investigate the required treatment-planning parameters. The geometric design and material details of the source was provided by the manufacturer and was used to define the Monte Carlo geometry. To validate the source geometry, a few dosimetry parameters had to be calculated according to the AAPM TG-43U1 formalism. The dosimetry studies included the calculation of the air kerma strength Sk, collision kerma in water along the transverse axis with an unbounded phantom, dose rate constant and radial dose function. The Monte Carlo code system that was used was EGSnrc with a new cavity code, which is a part of EGS++ that allows calculating the radial dose function around the source. The spectrum to simulate 60Co was composed of two photon energies, 1.17 and 1.33 MeV. Only the gamma part of the spectrum was used; the contribution of the electrons to the dose is negligible because of the full absorption by the stainless-steel wall around the metallic 60Co. The XCOM photon cross-section library was used in subsequent simulations, and the photoelectric effect, pair production, Rayleigh scattering and bound Compton scattering were included in the simulation. Variance reduction techniques were used to speed up the calculation and to considerably reduce the computer time. The cut-off energy was 10 keV for electrons and photons. To obtain the dose rate distributions of the source in an unbounded liquid water phantom, the source was immersed at the center of a cube phantom of 100 cm3. The liquid water density was 0.998 g/cm3, and photon histories of up to 1010 were used to obtain the results with a standard deviation of less than 0.5% (k = 1). The obtained dose rate constant for the BEBIG 60Co source was 1.108±0.001 cGyh-1U-1, which is consistent with the values in the literature. The radial dose functions were compared with the values of the consensus data set in the literature, and they are consistent with the published data for this energy range.

Dataset Information

Monte Carlo Models for Sub-Chronic Repeated-Dose Toxicity: Systemic and Organ-Specific Toxicity.

Publications

Monte Carlo Models for Sub-Chronic Repeated-Dose Toxicity: Systemic and Organ-Specific Toxicity.

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