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- Evaluation of Novel Urinary Biomarkers in Beagle Dogs With Amphotericin
B-Induced Kidney Injury-
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Authors: Adeyemi O. Adedeji, Manisha Sonee, Yafei Chen, Karen Lynch, Katrina Peron, Nicholas King, James E. McDuffie, Petra Vinken
Abstract: International Journal of Toxicology, Ahead of Print.
Next-generation urinary protein biomarkers have been qualified to enable monitoring for drug-induced kidney injury in toxicology studies conducted in rats. However, there is limited literature on the utility of these biomarkers in dogs. To add to the existing body of knowledge on the utility of the next-generation drug-induced kidney injury (DIKI) biomarkers, we evaluated the value of these biomarkers for the early detection of DIKI in Beagle dogs using a differentiated nephrotoxicant, Amphotericin B (AmpB). In dogs with AmpB-induced kidney injury, we monitored the response of urinary albumin, total protein, clusterin, kidney injury molecule 1, neutrophil gelatinase-associated lipocalin and N-acetyl-beta-D-glucosaminidase. We also measured blood urea nitrogen, serum creatinine and cystatin C. The results showed that urinary clusterin (up to ∼ 112x) was much more sensitive to AmpB-induced kidney injury relative to other biomarkers. Moreover, other than urinary clusterin and to a much lesser extent urinary albumin and total protein, none of the other biomarkers analyzed in this study were more sensitive than blood urea nitrogen and serum creatinine. The AmpB related tubular alterations were characterized by minimal to mild, multifocal necrosis, degeneration, regeneration, dilatation and mineralization. The mild nature of these histopathologic findings further attested to the sensitivity of urinary clusterin to AmpB-induced kidney injury in dogs. These results will help drug developers make informed decisions when selecting urinary biomarkers for monitoring DIKI in dogs for toxicology studies.
Citation: International Journal of Toxicology
PubDate: 2022-11-25T06:03:29Z
DOI: 10.1177/10915818221142542
- Co-Culturing Rat Dorsal Root Ganglion Neurons With Rat Schwann Cells
Protects Them Against the Cytotoxic Effects of Silver and Gold
Nanoparticles-
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Authors: Wenjuan Gao, James C. K. Lai, Solomon W. Leung
Abstract: International Journal of Toxicology, Ahead of Print.
Previous studies using monotypic nerve cell cultures have shown that nanoparticles induced neurotoxic effects on nerve cells. Interactions between neurons and Schwann cells may protect against the neurotoxicity of nanoparticles. In this study, we developed a co-culture model consisting of immortalized rat dorsal root ganglion (DRG) neurons and rat Schwann cells and employed it to investigate our hypothesis that co-culturing DRG neurons with Schwann cells imparts protection on them against neurotoxicity induced by silver or gold nanoparticles. Our results indicated that neurons survived better in co-cultures when they were exposed to these nanoparticles at the higher concentrations compared to when they were exposed to these nanoparticles at the same concentrations in monotypic cultures. Synapsin I expression was increased in DRG neurons when they were co-cultured with Schwann cells and treated with or without nanoparticles. Glial fibrillary acidic protein (GFAP) expression was increased in Schwann cells when they were co-cultured with DRG neurons and treated with nanoparticles. Furthermore, we found co-culturing with Schwann cells stimulated neurofilament polymerization in DRG neurons and produced the morphological differentiation. Silver nanoparticles induced morphological disorganization in monotypic cultures. However, there were more cells displaying normal morphology in co-cultures than in monotypic cultures. All of these results suggested that co-culturing DRG neurons with Schwann cells imparted some protection on them against neurotoxicity induced by silver or gold nanoparticles, and altering the expression of neurofilament-L, synapsin I, and GFAP could account for the phenomenon of protection in co-cultures.
Citation: International Journal of Toxicology
PubDate: 2022-10-29T06:38:16Z
DOI: 10.1177/10915818221133508
- Mutagenic, Acute, and Subchronic Toxicity Studies of the
Hesperetin-7-Glucoside–β-Cyclodextrin Inclusion Complex-
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Authors: Masamitsu Moriwaki, Kento Kito, Ryo Nakagawa, Etsuko Tominaga, Mahendra P. Kapoor, Yoshiki Matsumiya, Tomohisa Fukuhara, Hiroshi Yamagata, Toyohisa Katsumata, Kazuyuki Minegawa
Abstract: International Journal of Toxicology, Ahead of Print.
Hesperetin glucosides such as hesperidin and hesperetin-7-glucoside are abundantly present in citrus fruits and have various pharmacological properties. However, the potential toxicity of hesperetin glucosides remains unclear. An initial assessment of the safety of hesperetin-7-glucoside–β-cyclodextrin inclusion complex (HPTGCD) as a functional food ingredient was undertaken to assess toxicity and mutagenic potential. A bacterial reverse mutation assay (Ames test) using Salmonella typhimurium (strains TA98, TA1535, TA100, and TA1537) and Escherichia coli (strain WP2 uvrA) with HPTGCD (up to 5000 µg/plate) in the absence and presence of metabolic activation was negative. In a single oral (gavage) toxicity study in male and female rats, HPTGCD at dose up to 2000 mg/kg did not produce mortality nor clinical signs of toxicity or change in body weight. In a subchronic oral (dietary admix) toxicity study in rats receiving 0, 1.5, 3, and 5% HPTGCD for 13 weeks, no adverse effects were noted and the no-observed-adverse-effect level (NOAEL) was 5% in the diet (equivalent to 3267.7 mg/kg/day for males and to 3652.4 mg/kg/day for females). These results provide initial evidence of the safety of HPTGCD.
Citation: International Journal of Toxicology
PubDate: 2022-10-25T02:07:03Z
DOI: 10.1177/10915818221134022
- Amended Safety Assessment of Persulfates as Used in Cosmetics
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Authors: Wilbur Johnson, Wilma F. Bergfeld, Donald V. Belsito, Ronald A. Hill, Curtis D. Klaassen, Daniel C. Liebler, James G. Marks, Ronald C. Shank, Thomas J. Slaga, Paul W. Snyder, Bart Heldreth
First page: 5
Abstract: International Journal of Toxicology, Ahead of Print.
The Expert Panel for Cosmetic Ingredient Safety (Panel) reassessed the safety of 3 persulfate ingredients, which function as oxidizing agents in cosmetic products. The Panel reviewed relevant data relating to the safety of these ingredients and concluded that Ammonium, Potassium, and Sodium Persulfate are safe as used as oxidizing agents in hair colorants and hair lighteners designed for brief discontinuous use followed by thorough rinsing from the hair and skin. The Panel also concluded that the available data are insufficient for determining the safety of these persulfates in leave-on products and dentifrices.
Citation: International Journal of Toxicology
PubDate: 2022-09-27T11:28:03Z
DOI: 10.1177/10915818221124299
- Amended Safety Assessment of Triglycerides as Used in Cosmetics
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Authors: Monice M. Fiume, Wilma F. Bergfeld, Donald V. Belsito, Ronald A. Hill, Curtis D. Klaassen, Daniel C. Liebler, James G. Marks, Ronald C. Shank, Thomas J. Slaga, Paul W. Snyder, Bart Heldreth
First page: 22
Abstract: International Journal of Toxicology, Ahead of Print.
The Expert Panel for Cosmetic Ingredient Safety (Panel) assessed the safety of 51 triglycerides; 25 of these ingredients were previously reviewed by the Panel, and 26 are reviewed herein for the first time. The majority of the ingredients named in this assessment have several functions, with most reported to function as skin conditioning agents (occlusive or emollient) and/or viscosity increasing agents in cosmetics; some are also reported to function as a fragrance or solvent. The Panel reviewed relevant new data, including frequency and concentration of use, and considered the data from previous reports. The Panel concluded the 51 triglycerides reviewed in this report are safe in cosmetics in the present practices of use and concentration described in this safety assessment.
Citation: International Journal of Toxicology
PubDate: 2022-10-03T05:51:08Z
DOI: 10.1177/10915818221123790
- Amended Safety Assessment of Malic Acid and Sodium Malate as Used in
Cosmetics-
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Authors: Christina L. Burnett, Wilma F. Bergfeld, Donald V. Belsito, Ronald A. Hill, Curtis D. Klaassen, Daniel C. Liebler, James G. Marks, Ronald C. Shank, Thomas J. Slaga, Paul W. Snyder, Bart Heldreth
First page: 69
Abstract: International Journal of Toxicology, Ahead of Print.
The Expert Panel for Cosmetic Ingredient Safety (Panel) re-reviewed the safety of Malic Acid and Sodium Malate in cosmetics. Malic Acid is reported to function in cosmetics as a fragrance ingredient and a pH adjuster and Sodium Malate functions as a skin-conditioning agent - humectant. The Panel reviewed the available data to determine the safety of these ingredients. The Panel concluded that Malic Acid and Sodium Malate are safe in cosmetics in the present practices of use and concentration described in this safety assessment.
Citation: International Journal of Toxicology
PubDate: 2022-08-22T02:36:33Z
DOI: 10.1177/10915818221117535
- Safety Assessment of Panthenol, Pantothenic Acid, and Derivatives as Used
in Cosmetics-
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Authors: Laura N. Scott, Monice Fiume, Wilma F. Bergfeld, Donald V. Belsito, Ronald A. Hill, Curtis D. Klaassen, Daniel C. Liebler, James G. Marks, Ronald C. Shank, Thomas J. Slaga, Paul W. Snyder, Bart Heldreth
First page: 77
Abstract: International Journal of Toxicology, Ahead of Print.
The Expert Panel for Cosmetic Ingredient Safety (Panel) assessed the safety of Panthenol, Pantothenic Acid, and 5 derivatives as used in cosmetics. These ingredients named in this report are reported to function in cosmetics as hair conditioning agents, and Panthenol also is reported to function as a skin-conditioning agent-humectant and a solvent. The Panel reviewed relevant data for these ingredients, and concluded that these 7 ingredients are safe in cosmetics in the present practices of use concentration described in this safety assessment.
Citation: International Journal of Toxicology
PubDate: 2022-09-30T08:34:40Z
DOI: 10.1177/10915818221124809
- The Dog as a Second Species for Toxicology Testing Provides Value to Drug
Development-
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Authors: Nancy Bower, William E. Achanzar, Virginie Boulifard, Peter R. Brinck, Birgit Kittel, John L. Vahle
First page: 431
Abstract: International Journal of Toxicology, Ahead of Print.
The objective of the pharmaceutical industry is to develop new drugs that are safe for human use. In many cases, the accepted approach codified in guidance from regulatory authorities to assess the nonclinical safety profile of potential pharmaceuticals is to perform toxicity testing in two species. However, the use of a second species to establish the safety of new pharmaceuticals has been the subject of much scrutiny in recent years and the industry has been repeatedly challenged to reduce, refine, or replace some or all of the animals used to establish the safety of these pharmaceutical candidates. Specifically, the value of the dog in this testing paradigm has been questioned. Publications reviewing available data for marketed drugs suggest that for many drugs, the dog does not identify unique toxicities critical to human safety. The weakness of this approach, however, is that many of the cases where the dog (or any other species) has the greatest impact on drug development are cases for which development decisions based on safety concerns are not shared publicly. The European Federation of Pharmaceutical Industries and Associations (EFPIA) Preclinical Development Expert Group (PDEG) decided to share case studies collected from its membership and the literature to illustrate the value of the dog in drug development decision-making and clinical monitoring practices to protect the safety of trial subjects.
Citation: International Journal of Toxicology
PubDate: 2022-09-15T07:01:28Z
DOI: 10.1177/10915818221125670
- Comparative Analyses of Poly(ADP-Ribose) Polymerase Inhibitors
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Authors: Mausumee Guha, Zhanna Sobol, Mathew Martin, Michelle Hemkens, Tae Sung, Elizabeth Rubitski, Richard Spellman, Martin Finkelstein, Nasir Khan, Wenyue Hu
First page: 442
Abstract: International Journal of Toxicology, Ahead of Print.
Poly(ADP-ribose) polymerase inhibitors (PARPi) are approved as monotherapies in BRCA1/2-mutated (mBRCA1/2) metastatic breast and ovarian cancers, and in advanced pancreatic and metastatic castration-resistant prostate cancers. Differential safety profiles across PARPi necessitate improved mechanistic understanding of inhibitor differences, especially with expansion of PARPi indications and drug combinations. Here, we report in vitro evaluations of PARPi (–/+ PARP trapper temozolomide, TMZ) with reference to total clinical mean concentration average or maximum (tCavg, tCmax), to elucidate contributions of primary pharmacology and structural differences to clinical efficacy and safety. In biochemical assays, rucaparib and niraparib demonstrated off-target secondary pharmacology activities, and in selectivity assays, talazoparib, olaparib, and rucaparib inhibited a broader panel of PARP enzymes. In donor-derived human bone marrow mononuclear cells, only olaparib both increased early apoptosis and decreased the cell viability half inhibitory concentration (IC50) at ≤ tCavg, whereas other PARPi only did so in the presence of TMZ. In cancer cell lines with DNA damage repair mutations, all PARPi decreased cell viability in H1048 but not TK6 cells, and only talazoparib decreased cell growth in DU145 cells at ≤ tCavg concentrations. When combined with low dose TMZ, only talazoparib left-shifted the functional consequences of PARP trapping (S-phase arrest, apoptosis, S-phase double-stranded breaks) and reduced cell viability/growth in TK6 and DU145 cell lines at ≤ tCavg, whereas the other inhibitors required high-dose TMZ. Our study suggests structural differences across PARPi may contribute to differences in PARP selectivity and off-target activities, which along with distinct pharmacokinetic properties, may influence inhibitor-specific toxicities in patients.
Citation: International Journal of Toxicology
PubDate: 2022-08-21T11:38:51Z
DOI: 10.1177/10915818221121325
- Normal Neurodevelopment and Fertility in Juvenile Male Rats Exposed to
Polyethylene Glycol Following Dosing With PEGylated rFIX (Nonacog Beta
Pegol, N9-GP): Evidence from a 10-Week Repeat-Dose Toxicity Study-
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Authors: Vivi F. H. Jensen, Line H. Schefe, Helene Jacobsen, Anne-Marie Mølck, Kasper Almholt, Ingrid Sjögren, Charlotte M. Dalsgaard, Rikke K Kirk, Andrew J. Benie, Bent O. Petersen, Mette S. Kyhn, Anne J. Overgaard, Inga Bjørnsdottir, Diane R. Stannard, Hanne K. Offenberg, Emil Egecioglu
First page: 455
Abstract: International Journal of Toxicology, Ahead of Print.
N9-GP/Rebinyn®/Refixia® is an approved PEGylated (polyethylene glycol-conjugated) recombinant human factor IX intended for prophylactic and/or on-demand treatment in adults and children with haemophilia B. A juvenile neurotoxicity study was conducted in male rats to evaluate effects on neurodevelopment, sexual maturation, and fertility following repeat-dosing of N9-GP. Male rats were dosed twice weekly from Day 21 of age with N9-GP or vehicle for 10 weeks, followed by a dosing-free recovery period for 13 weeks and terminated throughout the dosing and recovery periods. Overall, dosing N9-GP to juvenile rats did not result in any functional or pathological effects, as measured by neurobehavioural/neurocognitive tests, including motor activity, sensory function, learning and memory as well as growth, sexual maturation, and fertility. This was further supported by the extensive histopathologic evaluation of brain tissue. Exposure and distribution of polyethylene glycol was investigated in plasma, choroid plexus, cerebrospinal fluid, and brain sections. PEG did not cross the blood brain barrier and PEG exposure did not result in any effects on neurodevelopment. In conclusion, dosing of N9-GP to juvenile rats did not identify any effects on growth, sexual maturation and fertility, clinical and histological pathology, or neurodevelopment related to PEG exposure and supports the prophylactic use of N9-GP in children.
Citation: International Journal of Toxicology
PubDate: 2022-08-28T02:44:07Z
DOI: 10.1177/10915818221121054
- Tumorigenicity Assessment of Human Cancer Cell Lines Xenografted on
Immunodeficient Mice as Positive Controls of Tumorigenicity Testing-
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Authors: Seunghee Oh, Eun-Young Gu, Ji-Seok Han, Byoung-Seok Lee, Kyoung-Sik Moon, Yong-Bum Kim, Kang-Hyun Han
First page: 476
Abstract: International Journal of Toxicology, Ahead of Print.
Recent advances in human pluripotent stem cell (hPSC)-derived cell therapies and genome editing technologies such as CRISPR/Cas9 make regenerative medicines promising for curing diseases previously thought to be incurable. However, the possibility of off-target effects during genome editing and the nature of hPSCs, which can differentiate into any cell type and infinitely proliferate, inevitably raises concerns about tumorigenicity. Tumorigenicity acts as a major obstacle to the application of hPSC-derived and gene therapy products in clinical practice. Thus, regulatory authorities demand mandatory tumorigenicity testing as a key pre-clinical safety step for the products. In the tumorigenicity testing, regulatory guidelines request to include human cancer cell line injected positive control group (PC) animals, which must form tumors. As the validity of the whole test is determined by the tumor-forming rates (typically above 90%) of PC animals, establishing the stable tumorigenic condition of PC animals is critical for successful testing. We conducted several studies to establish the proper positive control conditions, including dose, administration routes, and the selection of cell lines, in compliance with Good Laboratory Practice (GLP) regulations and/or guidelines, which are essential for pre-clinical safety tests of therapeutic materials. We expect that our findings provide insights and practical information to create a successful tumorigenicity test and its guidelines.
Citation: International Journal of Toxicology
PubDate: 2022-09-07T12:49:31Z
DOI: 10.1177/10915818221124573
- Book Reviews
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Authors: John A. Budny, PharmaCal Redding
First page: 488
Abstract: International Journal of Toxicology, Ahead of Print.
Citation: International Journal of Toxicology
PubDate: 2022-08-13T09:34:49Z
DOI: 10.1177/10915818221120879
- Book Review: Reproductive and Developmental Toxicology Third Edition
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Authors: Robert W. Kapp
First page: 490
Abstract: International Journal of Toxicology, Ahead of Print.
Citation: International Journal of Toxicology
PubDate: 2022-07-21T10:31:21Z
DOI: 10.1177/10915818221115687
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