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Journal articles on the topic 'Human Embryotoxicity'
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1
Huxtable, Ryan J. "Human embryotoxicity of pyrrolizidine-containing drugs." Hepatology 9, no. 3 (March 1989): 510–11. http://dx.doi.org/10.1002/hep.1840090332.
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Aikawa, Nobuo, Atsushi Kunisato, Kenji Nagao, Hideaki Kusaka, Katsumi Takaba, and Kinya Ohgami. "Detection of Thalidomide Embryotoxicity by In Vitro Embryotoxicity Testing Based on Human iPS Cells." Journal of Pharmacological Sciences 124, no. 2 (2014): 201–7. http://dx.doi.org/10.1254/jphs.13162fp.
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Van Maele-Fabry, G., P. Therasse, E. Lenoir, J. P. Desager, K. Despontin, G. Gofflot, M. C. Jacobs, et al. "Embryotoxicity of human sera from patients treated with isotretinoin." Toxicology in Vitro 7, no. 6 (November 1993): 809–15. http://dx.doi.org/10.1016/0887-2333(93)90085-j.
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Walker, Lauren Michelle, Nicole R. L. Sparks, Veronica Puig-Sanvicens, Beatriz Rodrigues, and Nicole I. zur Nieden. "An Evaluation of Human Induced Pluripotent Stem Cells to Test for Cardiac Developmental Toxicity." International Journal of Molecular Sciences 22, no. 15 (July 29, 2021): 8114. http://dx.doi.org/10.3390/ijms22158114.
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To prevent congenital defects arising from maternal exposure, safety regulations require pre-market developmental toxicity screens for industrial chemicals and pharmaceuticals. Traditional embryotoxicity approaches depend heavily on the use of low-throughput animal models which may not adequately predict human risk. The validated embryonic stem cell test (EST) developed in murine embryonic stem cells addressed the former problem over 15 years ago. Here, we present a proof-of-concept study to address the latter challenge by updating all three endpoints of the classic mouse EST with endpoints derived from human induced pluripotent stem cells (hiPSCs) and human fibroblasts. Exposure of hiPSCs to selected test chemicals inhibited differentiation at lower concentrations than observed in the mouse EST. The hiPSC-EST also discerned adverse developmental outcomes driven by novel environmental toxicants. Evaluation of the early cardiac gene TBX5 yielded similar toxicity patterns as the full-length hiPSC-EST. Together, these findings support the further development of hiPSCs and early molecular endpoints as a biologically relevant embryotoxicity screening approach for individual chemicals and mixtures.
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Krtolica, Ana, Dusko Ilic, Olga Genbacev, and Richard K. Miller. "Human embryonic stem cells as a model for embryotoxicity screening." Regenerative Medicine 4, no. 3 (May 2009): 449–59. http://dx.doi.org/10.2217/rme.09.13.
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Rettie, Allan E., Albert W. Rettenmeier, Bruce K. Beyer, Thomas A. Baillie, and Mont R. Juchau. "Valproate hydroxylation by human fetal tissues and embryotoxicity of metabolites." Clinical Pharmacology and Therapeutics 40, no. 2 (August 1986): 172–77. http://dx.doi.org/10.1038/clpt.1986.160.
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Turkez, Hasan, Ozlem Ozdemir Tozlu, Arzu Tatar, Mehmet Enes Arslan, Kenan Cadirci, Lisa Marinelli, Omer Erkan Yapca, Ivana Cacciatore, Antonio Di Stefano, and Adil Mardinoglu. "Toxicity of Glycyl-l-Prolyl-l-Glutamate Pseudotripeptides: Cytotoxic, Oxidative, Genotoxic, and Embryotoxic Perspectives." Journal of Toxicology 2022 (November 19, 2022): 1–8. http://dx.doi.org/10.1155/2022/3775194.
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The tripeptide H-Gly-Pro-Glu-OH (GPE) and its analogs began to take much interest from scientists for developing effective novel molecules in the treatment of several disorders including Alzheimer’s disease, Parkinson’s disease, and stroke. The peptidomimetics of GPEs exerted significant biological properties involving anti-inflammatory, antiapoptotic, and anticancer properties. The assessments of their hematological toxicity potentials are critically required for their possible usage in further preclinical and clinical trials against a wide range of pathological conditions. However, there is so limited information on the safety profiling of GPE and its analogs on human blood tissue from cytotoxic, oxidative, and genotoxic perspectives. And, their embryotoxicity potentials were not investigated yet. Therefore, in this study, measurements of mitochondrial viability (using MTT assay) and lactate dehydrogenase (LDH) release as well as total antioxidant capacity (TAC) assays were performed on cultured human whole blood cells after treatment with GPE and its three novel peptidomimetics for 72 h. Sister chromatid exchange (SCE), micronucleus (MN), and 8-oxo-2-deoxyguanosine (8-OH-dG) assays were performed for determining the genotoxic damage potentials. In addition, the nuclear division index (NDI) was figured out for revealing their cytostatic potentials. Embryotoxicity assessments were performed on cultured human pluripotent NT2 embryonal carcinoma cells by MTT and LDH assays. The present results from cytotoxicity, oxidative, genotoxicity, and embryotoxicity testing clearly propounded that GPEs had good biosafety profiles and were trouble-free from the toxicological point of view. Noncytotoxic, antioxidative, nongenotoxic, noncytostatic, and nonembryotoxic features of GPE analogs are worthwhile exploring further and may exert high potentials for improving the development of novel disease-modifying agents.
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Delaroche, L., P. Oger, E. Genauzeau, P. Meicler, F. Lamazou, C. Dupont, and P. Humaidan. "Embryotoxicity testing of IVF disposables: how do manufacturers test?" Human Reproduction 35, no. 2 (February 2020): 283–92. http://dx.doi.org/10.1093/humrep/dez277.
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Abstract STUDY QUESTION How do manufacturers perform embryotoxicity testing in their quality control programs when validating IVF consumables? SUMMARY ANSWER The Mouse Embryo Assay (MEA) and Human Sperm Survival Assay (HSSA) used for IVF disposables differed from one manufacturer to another. WHAT IS KNOWN ALREADY Many components used in IVF laboratories, such as culture media and disposable consumables, may negatively impact human embryonic development. STUDY DESIGN, SIZE, DURATION Through a questionnaire-based survey, the main manufacturers of IVF disposable devices were contacted during the period November to December 2018 to compare the methodology of the MEA and HSSA. We focused on catheters for embryo transfer, catheters for insemination, straws, serological pipettes, culture dishes and puncture needles used in the ART procedures. PARTICIPANTS/MATERIALS, SETTING, METHODS We approached the manufacturers of IVF disposables and asked for details about methodology of the MEA and HSSA performed for toxicity testing of their IVF disposable devices. All specific parameters like mouse strains, number of embryos used, culture conditions (media, temperature, atmosphere), extraction protocol, subcontracting, and thresholds were registered and compared between companies. MAIN RESULTS AND THE ROLE OF CHANCE Twenty-one companies were approached, of which only 11 answered the questionnaire. Significant differences existed in the methodologies and thresholds of the MEA and HSSA used for toxicity testing of IVF disposables. Importantly, some of these parameters could influence the sensitivity of the tests. LIMITATIONS, REASONS FOR CAUTION Although we approached the main IVF manufacturers, the response rate was relatively low. WIDER IMPLICATIONS OF THE FINDINGS Our study confirms the high degree of heterogeneity of the embryotoxicity tests performed by manufacturers when validating their IVF disposable devices. Currently, no regulations exist on this issue. Professionals should call for and request standardization and a future higher degree of transparency as regards embryotoxicity testing from supplying companies; moreover, companies should be urged to provide the users clear and precise information about the results of their tests and how testing was performed. Future recommendations are urgently awaited to improve the sensitivity and reproducibility of embryotoxicity assays over time. STUDY FUNDING/COMPETING INTEREST(S) This study did not receive any funding. L.D. declares a competing interest with Patrick Choay SAS. TRIAL REGISTRATION NUMBER N/A
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Aikawa, N. "The development of in vitro embryotoxicity testing using human iPS cells." Toxicology Letters 295 (October 2018): S70. http://dx.doi.org/10.1016/j.toxlet.2018.06.521.
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Verma, Vinod, A. Mehta, and S. J. S. Flora. "Human Pluripotent Stem Cells and Drug Discovery: A New Beginning." Defence Life Science Journal 1, no. 1 (June 1, 2016): 27. http://dx.doi.org/10.14429/dlsj.1.10060.
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Human pluripotent stem cells (hPSCs) offer unique opportunities to discover and develop a new generation of drugs. Their ability to differentiate into virtually any cell type renders them a cost-effective, renewable source of tissue-specific cell types capable of predicting human responses towards novel chemical entities. Using these improved in vitro models based on physiologically relevant human cell types could result in identifying highly precise and safe compounds, thereby reducing drug attrition rates. Moreover, ability to develop humanised disease models for patient-stratified drug screening makes hPSCs an impeccable tool in translational medicine. In this mini-review we focus on the positives and negatives of utilising hPSC-derived cell types as drug discovery platforms with special emphasis on cardio-, hepato- and embryotoxicity.
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Erceg, Slaven, Eva Mateo, Iván Zipancic, Francisco Rodríguez Jiménez, María Pérez Aragó, Misericordia Jiménez, José Soria, and Mª Garcia-Esparza. "Assessment of Toxic Effects of Ochratoxin A in Human Embryonic Stem Cells." Toxins 11, no. 4 (April 10, 2019): 217. http://dx.doi.org/10.3390/toxins11040217.
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Ochratoxin A (OTA) is a mycotoxin produced by different Aspergillus and Penicillium species, and it is considered a common contaminant in food and animal feed worldwide. On the other hand, human embryonic stem cells (hESCs) have been suggested as a valuable model for evaluating drug embryotoxicity. In this study, we have evaluated potentially toxic effects of OTA in hESCs. By using in vitro culture techniques, specific cellular markers, and molecular biology procedures, we found that OTA produces mild cytotoxic effects in hESCs by inhibiting cell attachment, survival, and proliferation in a dose-dependent manner. Thus, we suggest that hESCs provide a valuable human and cellular model for toxicological studies regarding preimplantation stage of human fetal development.
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Galanjuk, S., E. Zuehr, A. Doenmez, J. Tigges, and E. Fritsche. "Characterization of the Human Induced Pluripotent Stem Cell (HIPS)-Test to Predict Embryotoxicity." Toxicology Letters 350 (September 2021): S143. http://dx.doi.org/10.1016/s0378-4274(21)00579-8.
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Wang, Hongou, Yu Zhu, Yulang Chi, and Sijun Dong. "A human embryonic stem cell-based model for benzo[a]pyrene-induced embryotoxicity." Reproductive Toxicology 85 (April 2019): 26–33. http://dx.doi.org/10.1016/j.reprotox.2019.01.008.
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Ashour, Anas A., Hashim Alhussain, Umar Bin Rashid, Labiba Abughazzah, Ishita Gupta, Ahmed Malki, Semir Vranic, and Ala-Eddin Al Moustafa. "E-Cigarette Liquid Provokes Significant Embryotoxicity and Inhibits Angiogenesis." Toxics 8, no. 2 (May 27, 2020): 38. http://dx.doi.org/10.3390/toxics8020038.
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E-cigarette smoking (ECS) is a new method of tobacco smoking that is gaining popularity as it is thought to be a “healthy method” of tobacco consumption. The adverse outcomes of ECS on the respiratory and cardiovascular systems in humans have been recently demonstrated. Nevertheless, the effect of e-cigarette liquid (ECL) on the early stage of embryogenesis and angiogenesis has not been explored yet. Chicken embryo at 3 days of incubation and its chorioallantoic membrane (CAM) of 5 days were used to explore the outcome of ECL on the embryo. Real-time PCR was also employed to study the regulation of a set of key controller genes of embryogenesis as well as angiogenesis. Our study revealed that ECL exposure is associated with a high rate of mortality in embryos as around 70% of treated embryos, at 3 days of incubation, die after 5 days of exposure. Additionally, ECL inhibits angiogenesis of the CAM of 5 days of incubation by more than 30%. These effects could be explained by the upregulation of ATF-3, FOXA2, INHBA, MAPRE-2, and RIPK-1, as well as the downregulation of SERPINA-4 and VEGF-C genes, which are important key controller genes of embryogenesis as well as angiogenesis. Our data suggest clearly that ECS can have dramatic toxic outcomes on the early stage of embryogenesis as well as angiogenesis. Accordingly, we believe that further studies to assess the effects of ECS on human health are essential.
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Galanjuk, Saskia, Etta Zühr, Arif Dönmez, Deniz Bartsch, Leo Kurian, Julia Tigges, and Ellen Fritsche. "The Human Induced Pluripotent Stem Cell Test as an Alternative Method for Embryotoxicity Testing." International Journal of Molecular Sciences 23, no. 6 (March 18, 2022): 3295. http://dx.doi.org/10.3390/ijms23063295.
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The evaluation of substances for their potency to induce embryotoxicity is controlled by safety regulations. Test guidelines for reproductive and developmental toxicity rely mainly on animal studies, which make up the majority of animal usage in regulatory toxicology. Therefore, there is an urgent need for alternative in vitro methods to follow the 3R principles. To improve human safety, cell models based on human cells are of great interest to overcome species differences. Here, human induced pluripotent stem cells (hiPSCs) are an ideal cell source as they largely recapitulate embryonic stem cells without bearing ethical concerns and they are able to differentiate into most cell types of the human body. Here, we set up and characterized a fetal bovine serum (FBS)-free hiPSC-based in vitro test method, called the human induced pluripotent stem cell test (hiPS Test), to evaluate the embryotoxic potential of substances. After 10 days in culture, hiPSCs develop into beating cardiomyocytes. As terminal endpoint evaluations, cell viability, qPCR analyses as well as beating frequency and area of beating cardiomyocytes by video analyses are measured. The embryotoxic positive and non-embryotoxic negative controls, 5-Fluorouracil (5-FU) and Penicillin G (PenG), respectively, were correctly assessed in the hiPS Test. More compounds need to be screened in the future for defining the assay’s applicability domain, which will inform us of the suitability of the hiPS Test for detecting adverse effects of substances on embryonic development.
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González, Raquel, Clara Pons-Duran, Azucena Bardají, Rose G. F. Leke, Robert Clark, and Clara Menendez. "Systematic review of artemisinin embryotoxicity in animals: Implications for malaria control in human pregnancy." Toxicology and Applied Pharmacology 402 (September 2020): 115127. http://dx.doi.org/10.1016/j.taap.2020.115127.
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Cao, Hanwen, Yuan Zhi, Haibin Xu, Haiqin Fang, and Xudong Jia. "Zearalenone causes embryotoxicity and induces oxidative stress and apoptosis in differentiated human embryonic stem cells." Toxicology in Vitro 54 (February 2019): 243–50. http://dx.doi.org/10.1016/j.tiv.2018.09.020.
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Marouani, Neila, Olfa Tebourbi, Moncef Mokni, Mohamed Tahar Yacoubi, Mohsen Sakly, Moncef Benkhalifa, and Khémais Ben Rhouma. "Embryotoxicity and fetotoxicity following intraperitoneal administrations of hexavalent chromium to pregnant rats." Zygote 19, no. 3 (December 21, 2010): 229–35. http://dx.doi.org/10.1017/s0967199410000274.
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SummaryHeavy metals are omnipresent in the environment, and industrial use has greatly increased their presence in soil, water and air. Their inevitable transfer to the human food chain remains an important environmental issue as many heavy metals cause a range of toxic effects, including developmental toxicity. Administration of chromium VI (1 and 2 mg/kg as potassium dichromate) through intraperitoneal (i.p.) injection during organogenesis (days 6 to 15 of gestation) in rats revealed embryo- and fetotoxic effects. Reduced fetal weight, retarded fetal development, number of fetuses per mother and high incidences of dead fetuses and resorptions in treated mothers were also observed. Gross morphological abnormalities, such as displayed form of edema, facial defect, lack of tail, hypotrophy, severs subdermal haemorrhage patches and hypotrophy of placenta were observed in fetuses after chromium VI-treated mothers. A skeletal development of fetuses presented an incomplete ossification in nasal, cranium, abdominal or caudal bones in rats treated with 1 mg/kg of chromium, whereas rats treated with 2 mg/kg showed ossification and absence of the sacral vertebrae compared with the control. At a higher dose of chromium, histological changes were found in fetuses with atrophy of theirs vital organs. Placental histological observations revealed a pronounced morphological alteration, with atrophy of decidual cells, a degenerated of chorionic villi and hypertrophy of blood lacuna. The present study suggests a risk to the developing embryo when the mother is exposed to a high concentration of chromium VI during organogenesis.
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Et. al., M. Shenbagam,. "EMBRYOTOXICITY AND TERATOGENIC EFFECTS OF PARMOTREMA TINCTORUM (NYL) HALE ON ZEBRAFISH (DANIO RERIO) AND CYTOTOXIC ACTIVITY OF LICHEN EXTRACT ON HEK293T CELL LINE." INFORMATION TECHNOLOGY IN INDUSTRY 9, no. 2 (April 13, 2021): 1128–33. http://dx.doi.org/10.17762/itii.v9i2.464.
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Parmotrema tinctorum (Nyl) Hale an edible lichen, used as a spice and flavouring agent for meat and vegetable preparations by ethnic groups in India and Nepal. In Zebrafish embryos and larva, the therapeutic applications of P.tinctorum widely reported. However the teratogenic effects not reported. This study was aimed to examine the toxicity of P.tinctorum on the promising model for toxicity research, the Zebrafish, because their genetic structure is more similar to human beings. Additionally, we have demonstrated a toxic effect of P.tinctorum extract on the human normal cell line (HEK293T) by MTT assay. The methanol extract of P.tinctorum was extracted by Soxhlet and for embryotoxicity and teratogenicity activities, we use different concentrations (50µg/ml – 200µg/ml) of lichen extracts on twelve selected fertilized Zebrafish embryos. The extract did not exhibit any effect on Zebrafish Survival rate, hatching rate, heartbeat and teratogenicity which was similar to control groups. To conclude that, methanol extract of P.tinctorum is found to have a nontoxic property to zebrafish embryo and human normal cell line (HEK293T) and suggests that this might be safe for consumption
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Larouche, Geneviève, and Barbara F. Hales. "The impact of human superoxide dismutase 1 expression in a mouse model on the embryotoxicity of hydroxyurea." Birth Defects Research Part A: Clinical and Molecular Teratology 85, no. 9 (September 2009): 800–807. http://dx.doi.org/10.1002/bdra.20595.
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Do, Xuan-Hai, My Hanh Thi Hoang, Anh-Tuan Vu, Lai-Thanh Nguyen, Dung Thi Thuy Bui, Duy-Thanh Dinh, Xuan-Hung Nguyen, et al. "Differential Cytotoxicity of Curcumin-Loaded Micelles on Human Tumor and Stromal Cells." International Journal of Molecular Sciences 23, no. 20 (October 15, 2022): 12362. http://dx.doi.org/10.3390/ijms232012362.
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Although curcumin in the form of nanoparticles has been demonstrated as a potential anti-tumor compound, the impact of curcumin and nanocurcumin in vitro on normal cells and in vivo in animal models is largely unknown. This study evaluated the toxicity of curcumin-loaded micelles in vitro and in vivo on several tumor cell lines, primary stromal cells, and zebrafish embryos. Breast tumor cell line (MCF7) and stromal cells (human umbilical cord vein endothelial cells, human fibroblasts, and human umbilical cord-derived mesenchymal stem cells) were used in this study. A zebrafish embryotoxicity (FET) assay was conducted following the Organisation for Economic Co-operation and Development (OECD) Test 236. Compared to free curcumin, curcumin PM showed higher cytotoxicity to MCF7 cells in both monolayer culture and multicellular tumor spheroids. The curcumin-loaded micelles efficiently penetrated the MCF7 spheroids and induced apoptosis. The nanocurcumin reduced the viability and disturbed the function of stromal cells by suppressing cell migration and tube formation. The micelles demonstrated toxicity to the development of zebrafish embryos. Curcumin-loaded micelles demonstrated toxicity to both tumor and normal primary stromal cells and zebrafish embryos, indicating that the use of nanocurcumin in cancer treatment should be carefully investigated and controlled.
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Tran, Vinh Van, Vu Khac Bui Hoang, Hang-Suk Chun, Ju-Young Moon, and Young-Chul Lee. "Novel Calcium Aminoclay (CaAC)-Vitamin C Hybrid: In-Vitro Cytotoxicity Assessment in HaCaT Cells and In-Vivo Embryotoxicity Assay in Zebrafish." Journal of Nanoscience and Nanotechnology 21, no. 7 (July 1, 2021): 3667–72. http://dx.doi.org/10.1166/jnn.2021.19241.
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Vitamin C (VC) is well-known as a hydrophilic antioxidant commonly used in cosmeceutical formulations due to its protection and maintenance of youthful skin. Aminoclay (AC), a synthetic organic-nanoclay, has shown great potential for delivery of VC. However, the practical cosmeceutical applications of aminoclay for delivery of VC are severely limited due to the paucity of reported research on its cytotoxicity to human skin. Therefore, in the present study, we evaluated the biosafety of a calcium aminoclay-vitamin C (CaAC-VC) hybrid through an In-Vitro cytotoxicity assessment in HaCaT cells and an In-Vivo embryotoxicity assay in zebrafish. HaCaT cell viability and changes in the morphology and hatching rate of the zebrafish were investigated. The results indicated that the CaAC-VC hybrid showed a lower cytotoxicity relative to pure VC and that as such, it should be considered to be a promising candidate for VC-delivery applications.
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Chandrasekaran, R., DK Giri, and M. Roy Chaudhury. "Embryotoxicity and teratogenicity studies of poly (DL-Lactide-co-Glycolide) microspheres incorporated tetanus toxoid in Wistar rats." Human & Experimental Toxicology 15, no. 4 (April 1996): 349–51. http://dx.doi.org/10.1177/096032719601500411.
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Tetanus Toxoid loaded biodegradable microspheres (MTT) (poly (DL-Lactide-co-Glycolide) were administered intramuscularly to pregnant Wistar rats from Days 6 to 15 of gestation, at 1, 5 and 10-times the human equivalent dose of TT. Developmental defects in relation to soft tissues and skeleton, weight and sex of live pups and early fetal deaths from treated and control rats were analysed. The findings in treatment groups were comparable to those in the controls. These observations show that MTT was safe for pregnant rats and developing pups.
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Duy-Thanh, Dinh, Nguyen Bich-Ngoc, François Van den Bossche, Nguyen Lai-Thanh, and Marc Muller. "Discovering Novel Bioactivities of Controversial Food Additives by Means of Simple Zebrafish Embryotoxicity (ZET) Assays." Toxics 11, no. 1 (December 22, 2022): 8. http://dx.doi.org/10.3390/toxics11010008.
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The rising concerns about controversial food additives’ potential hazardous properties require extensive yet animal-minimized testing strategies. Zebrafish embryos are the ideal in vivo model representing both human and environmental health. In this study, we exposed zebrafish embryos to eight controversial food additives. Our results indicate that Sodium Benzoate is a Cat.3 aquatic toxicant, while Quinoline Yellow is a strong teratogen. At high concentrations, non-toxic chemicals induced similar phenotypes, suggesting the impact of ionic strength and the applicability of the darkened yolk phenotype as an indicator of nephrotoxicity. Three food additives showed unpredicted bioactivities on the zebrafish embryos: Brilliant Blue could weaken the embryonic yolk, Quinoline Yellow may interfere with nutrient metabolism, and Azorubine induced precocious zebrafish hatching. In conclusion, the zebrafish embryo is ideal for high throughput chemical safety and toxicity screening, allowing systematic detection of biological effects—especially those unexpected by targeted in vitro and in silico models. Additionally, our data suggest the need to reconsider the safety status of food additives Quinoline Yellow, Brilliant Blue, Sodium Benzoate, and other controversial food additives in further studies, as well as pave the way to further applications based on the newly found properties of Brilliant Blue and Azorubine.
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Chen, Feng, Wei Fan, Ziyuan Lin, Tang Deng, Lina Zhang, Wei Huang, and Huaqin Sun. "Embryotoxicity evaluation of Gentamicin, an aminoglycoside antibiotic added to human embryo culture medium, using the zebrafish (Danio rerio) model." Toxicology 483 (January 2023): 153386. http://dx.doi.org/10.1016/j.tox.2022.153386.
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Lovinskaya, Anna V., Saule Zh Kolumbayeva, Maria A. Suvorova, Akerke I. Iliyassova, Zarema M. Biyasheva, and Serikbay K. Abilev. "Complex study of potential toxicity and genotoxicity of water samples from natural sources of the suburban zone of Almaty." Ecological genetics 17, no. 2 (July 9, 2019): 69–81. http://dx.doi.org/10.17816/ecogen17269-81.
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Background. Natural aquatic ecosystems are the habitat of many organisms, a source of drinking water, a resource for human activities and are subjected to anthropogenic pressure. In this regard, interest in studying the genotoxicity and mutagenicity of surface waters has increased significantly. The aim of this study is to investigate the cytotoxic, genotoxic and mutagenic effects of the surface waters of the suburban area of Almaty.
Material and methods. The research materials were water samples of the rivers Esik, Turgen and Lake Esik. The atomic absorption method, lux-test, cytogenetic tests (Hordeum vulgare L.), phytotoxicity test (Allium cepa L.) and embryotoxicity (Danio rerio H.) were used.
Results. Physico-chemical water analysis revealed an excess of MPC for Mn, Pb, Cd, Zn. Using the lux-test on E. coli KatG strains, the pro-oxidant activity of Esik R. water. On the plant test objects revealed toxicity and mutagenicity of water samples. The results of bio-testing of natural waters with D. rerio revealed their high toxicity and teratogenicity for embryos at all stages of development.
Conclusion. The results of this study obtained on various test-systems and test-objects indicate that surface waters are contaminated by environmentally dangerous factors that pose a threat to biota and human health.
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Gaidai, E. A., K. L. Kryshen, E. A. Jain (Korsakova), D. V. Demchenko, D. R. Kargopol’tseva, A. E. Katel’nikova, D. S. Gaidai, and V. Yu Balabanyan. "Study of the specific toxic effects of the substance 1-[2-(2-benzoylphenoxy)ethyl]-6-methyluracil, the original non-nucleoside inhibitor of human immunodeficiency virus type 1 (Retroviridae; Orthoretrovirinae; Lentivirus: Human immunodeficiency virus 1) reverse transcriptase." Problems of Virology 66, no. 4 (September 18, 2021): 279–88. http://dx.doi.org/10.36233/0507-4088-59.
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Introduction. Combination antiretroviral therapy is currently the main component of treatment for human immunodeficiency virus (HIV) infected patients. At the same time, the high mutational potential of the virus and the frequency of side effects of existing drugs dictate the need for the development and preclinical study of new, more effective and safer compounds.The aim of the study is to evaluate the specific types of toxicity of a new non-nucleoside inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RNA-dependent DNA revertase) (NNRTI) based on the substance 1-[2-(2-benzoylphenoxy)ethyl]-6-methyluracil, a benzophenone derivative.Material and methods. The study investigated reproductive toxicity, embryotoxicity, immunotoxicity, genotoxic (in micronucleus test in and comet assay) and allergenic properties of the test itemcompound. It was tested on three species of animals in two doses: the estimated therapeutic dose (1 TD) and its tenfold equivalent (10 TD). Taking into account the metabolic coefficients, the doses for rats (Rattus) were 9 and 90 mg/kg, for mice (Mus musculus), 21 and 210 mg/kg, and for guinea pigs (Cavia porcellus), 8 and 80 mg/kg, respectively.Results and discussion. According to the obtained results, a favorable safety profile of the tested compound was established. Negative effects on the immune system, reproductive function, the body of pregnant animals and the fetus were not observed, as well as the compound did not have genotoxic and allergenic properties.Conclusion. These data allows to consider the studied compound as a promising therapeutic candidate for the treatment of HIV-1 infection.
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Jordaens, L., V. van Hoeck, I. Pintelon, S. Thys, P. E. J. Bols, W. F. A. Marei, and J. L. M. R. Leroy. "Altered embryotrophic capacities of the bovine oviduct under elevated free fatty acid conditions: an in vitro embryo–oviduct co-culture model." Reproduction, Fertility and Development 32, no. 6 (2020): 553. http://dx.doi.org/10.1071/rd19019.
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Maternal metabolic stress conditions are of growing importance in both human and dairy cattle settings as they can have significant repercussions on fertility. Upregulated lipolysis is a common trait associated with metabolic disorders and results in systemically elevated concentrations of non-esterified fatty acids (NEFAs). The effects of high NEFA concentrations on the follicular environment, oocyte and embryo development is well documented. However, knowledge on the effects of NEFAs within the oviduct, representing the initial embryonic growth environment, is currently lacking. Therefore, the experiments outlined here were designed to obtain fundamental insights into both the direct and indirect interactions between NEFAs, bovine oviductal cells and developing zygotes. Hence, zygotes were co-cultured with NEFA-pre-exposed bovine oviductal cells or subjected to simultaneous NEFA exposure during the co-culture period. The outcome parameters assessed were embryo development with cleavage (48h post insemination (pi)), morula (120–126h pi) and blastocyst (192h pi) rates, as well as morula intracellular lipid content and blastocyst quality using Bodipy and differential staining respectively. Our data suggest a direct embryotoxicity of NEFAs as well as impaired embryo development through a reduced oviductal ability to support and protect early embryo development.
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Ponjavic, Marijana, Marija S. Nikolic, Sanja Stevanovic, Jasmina Nikodinovic-Runic, Sanja Jeremic, Aleksandar Pavic, and Jasna Djonlagic. "Hydrolytic degradation of star-shaped poly(ε-caprolactone)s with different number of arms and their cytotoxic effects." Journal of Bioactive and Compatible Polymers 35, no. 6 (September 3, 2020): 517–37. http://dx.doi.org/10.1177/0883911520951826.
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Star-shaped polymers of biodegradable aliphatic polyester, poly( ε-caprolactone), PCL, with different number of arms (three, four, and six) were synthesized by ring-opening polymerization initiated by multifunctional alcohols used as cores. As potential biomaterials, synthesized star-shaped poly( ε-caprolactone)s, sPCL, were thoroughly characterized in terms of their degradation under different pH conditions and in respect to their cytotoxicity. The in vitro degradation was performed in phosphate buffer (pH 7.4) and hydrochloric acid solution (pH 1.0) over 5 weeks. Degradation of sPCL films was followed by the weight loss measurements, GPC, FTIR, and AFM analysis. While the most of the samples were stable against the abiotic hydrolysis at pH 7.4 after 5 weeks of degradation, degradation was significantly accelerated in the acidic medium. Degradation rate of polymer films was affected by the polymer architecture and molecular weight. The molecular weight profiles during the degradation revealed random chain scission of the ester bonds indicating bulk degradation mechanism of hydrolysis at pH 7.4, while acidic hydrolysis proceeded through the bulk degradation associated with surface erosion, confirmed by AFM. The in vitro toxicity tests, cytotoxicity applying normal human fibroblasts (MRC5) and embryotoxicity assessment (using zebra fish model, Danio rerio), suggested those polymeric materials as suitable for biomedical application.
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Kotkoskie, Lois A., Christine Freeman, and Mark A. Palmieri. "Subchronic Toxicity and Developmental Toxicity Studies in Rats With Aquateric® Aqueous Enteric Coating." International Journal of Toxicology 18, no. 2 (March 1999): 109–16. http://dx.doi.org/10.1080/109158199225675.
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Studies were conducted to evaluate the subchronic and developmental toxicity of Aquateric® Aqueous Enteric Coating. Homogeneity and stability studies were conducted over a range of 5,000 to 50,000 ppm Aquateric in the diet. In the subchronic study, groups of Sprague-Dawley rats (20/sex/group) received 0 (control), 5,000, 25,000, or 50,000 ppm Aquateric in the diet for 90 consecutive days. No mortality, clinical signs of toxicity or adverse toxicological effects on hematology or serum chemistry parameters, body weights, feed consumption, ophthalmological examinations, or histological evaluation of tissues were noted in any treatment group. In the developmental toxicity study, groups of pregnant Sprague-Dawley rats (25/group) received 0 (control), 5,000, 25,000 or 50,000 ppm Aquateric in the diet on gestational days 6-15. No evidence of maternal toxicity or fetotoxicity or embryotoxicity was noted. The no observed adverse effect level (NOAEL) exceeds 50,000 ppm in the diet, which represents a dose range of approximately 3600 to 4100 mg/kg/day. The results of these studies demonstrate the low toxicity of Aquateric. The estimated human intake is approximately 4 mg/kg/day. Based on the NOAEL from the subchronic study of 3604 mg/kg/day, the margin of safety is 900.
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Cao, Hanwen, Yuan Zhi, Haibin Xu, Haiqin Fang, and Xudong Jia. "Corrigendum to “Zearalenone causes embryotoxicity and induces oxidative stress and apoptosis in differentiated human embryonic stem cells” [Toxicology in Vitro 54 (2019) 243–250]." Toxicology in Vitro 79 (March 2022): 105209. http://dx.doi.org/10.1016/j.tiv.2021.105209.
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Manivong, Seng, Araceli Garcia Ac, Shunmoogum A. Patten, Julio C. Fernandes, Mohamed Benderdour, Xavier Banquy, Florina Moldovan, and Valérie Gaëlle Roullin. "Chitosan-Based Nanogels: Synthesis and Toxicity Profile for Drug Delivery to Articular Joints." Nanomaterials 12, no. 8 (April 13, 2022): 1337. http://dx.doi.org/10.3390/nano12081337.
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One important challenge in treating avascular-degraded cartilage is the development of new drugs for both pain management and joint preservation. Considerable efforts have been invested in developing nanosystems using biomaterials, such as chitosan, a widely used natural polymer exhibiting numerous advantages, i.e., non-toxic, biocompatible and biodegradable. However, even if chitosan is generally recognized as safe, the safety and biocompatibility of such nanomaterials must be addressed because of potential for greater interactions between nanomaterials and biological systems. Here, we developed chitosan-based nanogels as drug-delivery platforms and established an initial biological risk assessment for osteocartilaginous applications. We investigated the influence of synthesis parameters on the physicochemical characteristics of the resulting nanogels and their potential impact on the biocompatibility on all types of human osteocartilaginous cells. Monodisperse nanogels were synthesized with sizes ranging from 268 to 382 nm according to the acidic solution used (i.e., either citric or acetic acid) with overall positive charge surface. Our results demonstrated that purified chitosan-based nanogels neither affected cell proliferation nor induced nitric oxide production in vitro. However, nanogels were moderately genotoxic in a dose-dependent manner but did not significantly induce acute embryotoxicity in zebrafish embryos, up to 100 µg∙mL−1. These encouraging results hold great promise for the intra-articular delivery of drugs or diagnostic agents for joint pathologies.
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Pikula, Konstantin, Alexander Zakharenko, Vladimir Chaika, Iurii Em, Anna Nikitina, Evgenii Avtomonov, Anna Tregubenko, et al. "Toxicity of Carbon, Silicon, and Metal-Based Nanoparticles to Sea Urchin Strongylocentrotus intermedius." Nanomaterials 10, no. 9 (September 13, 2020): 1825. http://dx.doi.org/10.3390/nano10091825.
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With the increasing annual production of nanoparticles (NPs), the risks of their harmful influence on the environment and human health are rising. However, our knowledge about the mechanisms of interaction between NPs and living organisms is limited. Prior studies have shown that echinoderms, and especially sea urchins, represent one of the most suitable models for risk assessment in environmental nanotoxicology. To the best of the authors’ knowledge, the sea urchin Strongylocentrotus intermedius has not been used for testing the toxicity of NPs. The present study was designed to determine the effect of 10 types of common NPs on spermatozoa activity, egg fertilization, and early stage of embryo development of the sea urchin S. intermedius. In this research, we used two types of multiwalled carbon nanotubes (CNT-1 and CNT-2), two types of carbon nanofibers (CNF-1 and CNF-2), two types of silicon nanotubes (SNT-1 and SNT-2), nanocrystals of cadmium and zinc sulfides (CdS and ZnS), gold NPs (Au), and titanium dioxide NPs (TiO2). The results of the embryotoxicity test showed the following trend in the toxicity level of used NPs: Au > SNT-2 > SNT-1 > CdS > ZnS > CNF-2 > CNF-1 > TiO2 > CNT-1 > CNT-2. This research confirmed that the sea urchin S. intermedius can be considered as a sensitive and stable test model in marine nanotoxicology.
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Kocher-Becker, Ursula, Walter Kocher, and Heinrich Ockenfels. "Embryotoxische Wechselwirkungen zwischen einem Hydrolysenprodukt des Thalidomids und dem Tensid Tween 20 bei der Maus / Embryotoxic Interactions between a Hydrolysis Product of Thalidomide and the Surfactant Tween 20 in Mice." Zeitschrift für Naturforschung C 47, no. 1-2 (February 1, 1992): 155–70. http://dx.doi.org/10.1515/znc-1992-1-225.
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Abstract N,N-phtaloyl-ʟ-glumatic acid (NPLG), a hydrolysis product of thalidomide, and the surfactant Tween 20 were co-administred intraperitoneally to pregnant NMRI mice on days 9a and 8⅔ p.c. at doses where the hydrolysis product as well as the surfactant alone induce minimal embryotoxicity. The combined substances (350 mg/kg NPLG + 1.0 ml/kg Tween 20) caused a potentiative teratogenic and an additive embryolethal response. Enhancement of the amount of Tween 20 in the combinations to 2.5 ml/kg led to the same potentiative teratogenic and, in addition, potentiative embryolethal response. Distribution studies using 14C-NPLG showed a strongly increased NPLG content in the maternal plasma under the influence of 2.5 ml/kg Tween 20 but not after co-administration with 1.0 ml/kg Tween 20. The malformations obtained were of the same type in all groups and mostly located in the vertebrae and ribs. These axial and paraxial defects were frequently more severe and included more affected elements after application of the combined than of the single substances. Extension of our experiments with the combined substances to treatment days 8½ and 9½ p.c. revealed that the first affected segment shifts in caudal direction depending on an increasing embryonal age at treatment. Limb malformations occurred at a low frequency; most of them were of the same type as described in cases of human thalidomide embryopathy.
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Strikwold, Marije, Bert Spenkelink, Ruud A. Woutersen, Ivonne M. C. M. Rietjens, and Ans Punt. "Combining in vitro embryotoxicity data with physiologically based kinetic (PBK) modelling to define in vivo dose–response curves for developmental toxicity of phenol in rat and human." Archives of Toxicology 87, no. 9 (August 14, 2013): 1709–23. http://dx.doi.org/10.1007/s00204-013-1107-4.
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Deshmukh, Narendra S., Shailesh Gumaste, Silma Subah, and Nathasha Omal Bogoda. "Palmitoylethanolamide: Prenatal Developmental Toxicity Study in Rats." International Journal of Toxicology 40, no. 2 (February 12, 2021): 161–70. http://dx.doi.org/10.1177/1091581820986073.
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Palmitoylethanolamide (PEA) is an endogenous ethanolamine playing a protective and homeodynamic role in animals and plants. Prenatal developmental toxicity of PEA was tested following oral administration to pregnant female Wistar rats, from days 0 to 19 of gestation, at dosage of 250, 500, or 1,000 mg/kg body weight, according to Organisation for Economic Co-operation and Development Test Guideline No. 414. On gestation day 20, cesarean sections were performed on the dams, followed by examination of their ovaries and uterine contents. The fetuses were further examined for external, visceral, and skeletal abnormalities. Palmitoylethanolamide did not cause any alterations at any of the given dosages in the measured maternal parameters of systemic toxicity (body weight, food consumption, survival, thyroid functions, organ weight, histopathology), reproductive toxicity (preimplantation and postimplantation losses, uterus weight, number of live/dead implants and early/late resorptions, litter size and weights, number of fetuses, their sex ratio), and fetal external, visceral, or skeletal observations. Any alterations that were recorded were “normal variations” or “minor anomalies,” which were unrelated to treatment with PEA. Under the condition of this prenatal study, the no-observed-adverse-effect level of PEA for maternal toxicity, embryotoxicity, fetotoxicity, and teratogenicity in rats was found to be >1,000 mg/kg body weight/d. It indicates that PEA is well tolerated by and is safe to pregnant rats even at a high dose of 1,000 mg/kg body weight/d, equivalent to a human dose of greater than 9.7 g/d. This prenatal developmental toxicity study contributes greatly in building a robust safety profile for PEA.
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Albarano, Luisa, Valerio Zupo, Davide Caramiello, Maria Toscanesi, Marco Trifuoggi, Marco Guida, Giovanni Libralato, and Maria Costantini. "Sub-Chronic Effects of Slight PAH- and PCB-Contaminated Mesocosms in Paracentrotus lividus Lmk: A Multi-Endpoint Approach and De Novo Transcriptomic." International Journal of Molecular Sciences 22, no. 13 (June 22, 2021): 6674. http://dx.doi.org/10.3390/ijms22136674.
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Sediment pollution is a major issue in coastal areas, potentially endangering human health and the marine environments. We investigated the short-term sublethal effects of sediments contaminated with polycyclic aromatic hydrocarbons (PAHs) and polychlorinated biphenyls (PCBs) on the sea urchin Paracentrotus lividus for two months. Spiking occurred at concentrations below threshold limit values permitted by the law (TLVPAHs = 900 µg/L, TLVPCBs = 8 µg/L, Legislative Italian Decree 173/2016). A multi-endpoint approach was adopted, considering both adults (mortality, bioaccumulation and gonadal index) and embryos (embryotoxicity, genotoxicity and de novo transcriptome assembly). The slight concentrations of PAHs and PCBs added to the mesocosms were observed to readily compartmentalize in adults, resulting below the detection limits just one week after their addition. Reconstructed sediment and seawater, as negative controls, did not affect sea urchins. PAH- and PCB-spiked mesocosms were observed to impair P. lividus at various endpoints, including bioaccumulation and embryo development (mainly PAHs) and genotoxicity (PAHs and PCBs). In particular, genotoxicity tests revealed that PAHs and PCBs affected the development of P. lividus embryos deriving from exposed adults. Negative effects were also detected by generating a de novo transcriptome assembly and its annotation, as well as by real-time qPCR performed to identify genes differentially expressed in adults exposed to the two contaminants. The effects on sea urchins (both adults and embryos) at background concentrations of PAHs and PCBs below TLV suggest a need for further investigations on the impact of slight concentrations of such contaminants on marine biota.
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Mayer, Mascha, Alexander Berger, Christian Leischner, Olga Renner, Markus Burkard, Alexander Böcker, Seema Noor, et al. "Preclinical Efficacy and Toxicity Analysis of the Pan-Histone Deacetylase Inhibitor Gossypol for the Therapy of Colorectal Cancer or Hepatocellular Carcinoma." Pharmaceuticals 15, no. 4 (April 1, 2022): 438. http://dx.doi.org/10.3390/ph15040438.
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Gossypol, a sesquiterpenoid found in cotton seeds, exerts anticancer effects on several tumor entities due to inhibition of DNA synthesis and other mechanisms. In clinical oncology, histone deacetylase inhibitors (HDACi) are applied as anticancer compounds. In this study, we examined whether gossypol harbors HDAC inhibiting activity. In vitro analyses showed that gossypol inhibited class I, II, and IV HDAC, displaying the capability to laterally interact with the respective catalytic center and is, therefore, classified as a pan-HDAC inhibitor. Next, we studied the effects of gossypol on human-derived hepatoma (HepG2) and colon carcinoma (HCT-116) cell lines and found that gossypol induced hyperacetylation of histone protein H3 and/or tubulin within 6 h. Furthermore, incubation with different concentrations of gossypol (5–50 µM) over a time period of 96 h led to a prominent reduction in cellular viability and proliferation of hepatoma (HepG2, Hep3B) and colon carcinoma (HCT-116, HT-29) cells. In-depth analysis of underlying mechanisms showed that gossypol induced apoptosis via caspase activation. For pre-clinical evaluation, toxicity analyses showed toxic effects of gossypol in vitro toward non-malignant primary hepatocytes (PHH), the colon-derived fibroblast cell line CCD-18Co, and the intestinal epithelial cell line CCD 841 CoN at concentrations of ≥5 µM, and embryotoxicity in chicken embryos at ≥2.5 µM. In conclusion, the pronounced inhibitory capacity of gossypol on cancer cells was characterized, and pan-HDACi activity was detected in silico, in vitro, by inhibiting individual HDAC isoenzymes, and on protein level by determining histone acetylation. However, for clinical application, further chemical optimization is required to decrease cellular toxicity.
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Cho, Kyung-Hyun. "Structural and Functional Impairments of Reconstituted High-Density Lipoprotein by Incorporation of Recombinant β-Amyloid42." Molecules 26, no. 14 (July 16, 2021): 4317. http://dx.doi.org/10.3390/molecules26144317.
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Beta (β)-amyloid (Aβ) is a causative protein of Alzheimer’s disease (AD). In the pathogenesis of AD, the apolipoprotein (apo) A-I and high-density lipoprotein (HDL) metabolism is essential for the clearance of Aβ. In this study, recombinant Aβ42 was expressed and purified via the pET-30a expression vector and E.coli production system to elucidate the physiological effects of Aβ on HDL metabolism. The recombinant human Aβ protein (51 aa) was purified to at least 95% purity and characterized in either the lipid-free and lipid-bound states with apoA-I. Aβ was incorporated into the reconstituted HDL (rHDL) (molar ratio 95:5:1, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC):cholesterol:apoA-I) with various apoA-I:Aβ ratios from 1:0 to 1:0.5, 1:1 and 1:2. With an increasing molar ratio of Aβ, the α-helicity of apoA-I was decreased from 62% to 36% with a red shift of the Trp wavelength maximum fluorescence from 337 to 340 nm in apoA-I. The glycation reaction of apoA-I was accelerated further by the addition of Aβ. The treatment of fructose and Aβ caused more multimerization of apoA-I in the lipid-free state and in HDL. The phospholipid-binding ability of apoA-I was impaired severely by the addition of Aβ in a dose-dependent manner. The phagocytosis of LDL into macrophages was accelerated more by the presence of Aβ with the production of more oxidized species. Aβ severely impaired tissue regeneration, and a microinjection of Aβ enhanced embryotoxicity. In conclusion, the beneficial functions of apoA-I and HDL were severely impaired by the addition of Aβ via its detrimental effect on secondary structure. The impairment of HDL functionality occurred more synergistically by means of the co-addition of fructose and Aβ.
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Brock, William J., David P. Kelly, Susan M. Munley, Karin S. Bentley, Kathy M. McGown, and Rudolph Valentine. "Inhalation Toxicity and Genotoxicity of Hydrofluorocarbon (HFC)-236fa and HFC-236ea." International Journal of Toxicology 19, no. 2 (March 2000): 69–83. http://dx.doi.org/10.1080/109158100224881.
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The acute, subchronic, and developmental and genetic toxicity of hydrofluorocarbon (HFC)-236fa and HFC-236ea were evaluated to assist in establishing proper handling guidance. In acute inhalation studies, rats were exposed whole body for 4 hours to various concentrations of each isomer. Based on the lack of mortality, the approximate lethal concentration for HFC-236ea for male rats was > 85,000 ppm. For HFC-236fa, the LC50 for males and females (combined) was > 457,000 ppm. Narcotic-like effects, e.g., prostration, incoordination, and reduced motor activity, were observed only during exposure to either isomer, but were not evident after termination of exposure. In cardiac sensitization studies, HFC-236ea induced cardiac sensitization at ≥ 35,000 ppm, with fatal responses occurring at 50,000 ppm and greater. For HFC-236fa, a cardiac sensitization response was observed at 150,000 ppm and greater but not at 100,000 ppm. A fatal cardiac sensitization response was observed in one dog exposed to 150,000 ppm HFC-236fa. In 90-day subchronic inhalation studies, male and female rats were exposed whole body to HFC-236ea at concentrations of 0, 5000, 20,000, or 50,000 ppm for 6 hours/day, 5 days/week. Similarly, male and female rats were exposed whole body to HFC-236fa at concentrations of 0, 5000, 20,000, or 50,000 ppm for 6 hours/day, 5 days/week. During exposure, narcotic-like effect (reduced acoustic startle response) was observed at 50,000 ppm with both isomers, although there appeared to be an adaptive response to this effect as the study progressed. With HFC-236ea, dilatation of the seminiferous tubules, without effects on germ or Sertoli cells, was observed only in rats at 50,000 ppm. No other effects on in-life measures or on clinical or anatomic pathology, including histopathology, were observed for either isomer. In rat developmental toxicity studies, no evidence of embryotoxicity or teratogenicity was observed with either isomer exposed up to 50,000 ppm during gestational days 7 to 16. Also, no developmental toxicity was observed in rabbits exposed to HFC-236fa at concentrations of up to 50,000 ppm during gestational days 7 to 19. Neither of the HFC-236 isomers was mutagenic in the Ames reverse mutation assay or clastogenic in the chromosomal aberration assay with human lymphocytes. No increase in chromosomal aberrations was observed in in vivo micronucleus studies with either isomer.
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MAGRAS (Ι.Ν. ΜΑΓΡΑΣ), I. N., and Th C. TSILIGIANNI (Θ. ΤΣΙΛΙΓΙΑΝΝΗ). "Congenital malformations and environment." Journal of the Hellenic Veterinary Medical Society 54, no. 2 (January 25, 2018): 154. http://dx.doi.org/10.12681/jhvms.15845.
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The aim of the present bibliographical review was to approach the most considerable causes, in relation to the unbridled pollution of innumerable areas of our planet. Congenital malformations are created during the prenatal development and could possible cause embryonic death. They become visible after an abortion or after the birth and they could be mild or extensive malformations. Monsters always stimulate the peoplew interest and they were source of superstitions and topic of scientific research as well. In the international bibliography, there are plenty of such cases, and some of them are indicatively referred in the present review. The investigation of the causes of the congenital malformations is of a particular importance, in order to take the necessary preventive measures, when it is possible. The factors, which are responsible for the congenital malformations, are characterized as teratogenic or, insome cases, as embryo- or fetotoxic factors, and usually affect the genital cells of the parents or the organs of the pregnant female. A very important role in the mammalian congenital malformation play, except of the teratogenic factors, the animal species, the placenta type, the histochemical background of the mother and the embryo as well as the stage of the prenatal development during the exposition to the teratogenic factor. The teratogenic factors can be genetic or environmental. During the prenatal development, there is an interaction between the genome, which insure the genotypic feature of the species and the different epigenetic process, which create the phenotypic varieties. The interaction of the genome with the microenvironment, where the embryo is developed, is usually the key of the congenital malformation. Every genetic disturbance leads to the deviation from the normal development, because the embryonic development is depended on the genome. Genetical disturbance is possible to arise because of some chromosomal atypical or abnormal genes or (endo - or - exogenous) environmental factors. The environmental factors are numerous and according to their nature they can be classified to the following categories: physical factors, chemical agents and biological agents. Physical factors are the ionizing and the non - ionizing radiations.A new type of environmental pollution has been raised, after the artificial production of the radiations. A very important role in the increase of the cases of congenital malformation play the ionizing radiation, as a free nuclear energy after the bombing, the nuclear accidents and the nuclear litter. The ionizing radiation, as well as the radiowaves and the microwaves, known as radiofrequency or radiomagnetic radiation, include low energy. Their radio-embryotoxicity is not negligible, however, and depends on the area of the spectrum, the power density, the "special absorption rate", the duration of the exposure, the sensitivity of the embryo fetus and its organs. A lot of chemical substances adversely intervene in the normal embryonic and fetal development, causing congenital malformations. These substances could be natural having their origin from the external environment or from the organism itself or they could be artificial. Most of the drugs are considered as suspicious teratogens. Some plants contain dangerous embryotoxical substances and pregnant animals must not consume them. The deficiency of some nutrients is possible to cause disturbances in the prenatal development. Moreover, congenital malformations are observed after the deficiency of some elements. Infection agents, such as viruses, bacteria, protozoa, fungus and parasites, when they pass through the placental barrier are possible to cause congenital malformations. Also, the vaccination of the pregnant animals has to be avoided or to be applied on a period that is not critical for teratogenesis. Furthermore, there are a lot of unknown teratogenic agents that usually cause a considerable rate of congenital malformations. During the early embryonic development, there is a "critical period" where the embryo is particularly sensitive in the teratogenic agents. It is obvious that, if any teratogenic agent affects the embryonic development during the "critical period", the normal development of the embryo will be disorganized resulting in the embryonic deformities. In the full text of this review a detailed analysis of what can happen during this period is discussed. In the second half of the former century, the frequency of the congenital malformations has been considerably increased in human being and in animals, as well. This phenomenon is supported by a series of real events and situations, such as: the uncontrolled use of the nuclear energy and the nuclear accidents, the pollution by the major as well as the minor polemic conflicts, the unrestrained industrial development, the production of an enormous number of chemical substances, the increase of the fumes, the uncontrolled spreading of the electromagnetic radiation, the over consumption of industrial elaborated aliments, the malnutrition, the overexploitation of the land, with an excess of chemical fertilizing, pesticides and plant hormons, as well as the irresponsible use of hormones, drugs and unusual feed for livestock. The restriction of the continuing pollution and the simultaneous recovery of the environment must be the target of the humanity. The protection of the environment, beyond the improvement of health generally and the welfare of the animals and human will contribute in the diminuition of the congenital malformation cases in newborn animals and in human, as well.
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Vogel, R., and H. Spielmann. "In vitro system for embryotoxicity testing during the preimplantation period using serum supplement from in vivo exposed humans or animals." Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 181, no. 2 (December 1987): 326. http://dx.doi.org/10.1016/0027-5107(87)90144-8.
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Soćko, Renata. "Etoposide. Documentation of proposed values of occupational exposure limits (OELs)." Podstawy i Metody Oceny Środowiska Pracy 36, no. 2(100) (June 30, 2019): 73–98. http://dx.doi.org/10.5604/01.3001.0013.2532.
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Etoposide at room temperature is a solid present in the form of a white or yellow-brown crystalline powder. It is an anticancer drug with cytotoxic and anti-mitotic activity, used to treat patients with testicular cancer, acute myelogenous leukemia, lung cancer, non-small-cell lung cancer, adrenal cortex cancer, gastric cancer, hepatoblastoma, acute lymphoblastic leukemia and brain tumors. It is also recommended for the treatment of Ewing sarcoma and Kaposi's sarcoma associated with AIDS. This cytostatic is available in capsules taken by food and in concentrate for solution for infusion. Occupational exposure to etoposide occurs during its manufacture, confectioning, packaging and use in everyday treatment practices of hospital wards. The monograph, along with the proposal for a hygiene standard for etoposide, was developed as a continuation of work on the determination of the value of hygiene standards for cytostatics. According to the National Consultant's report in the field of nursing in 2010 (incomplete data, covering only 12 voivodeship), the number of nurses employed in oncology facilities totaled 5077. On the basis of data from the Central Register of Data on Exposure to Carcinogenic or Mutagenic Substances, Mixtures, Agents or Technological Process in Poland exposure to etoposide in Poland in the last three years has been growing. In 2015, 414 people were exposed to the substance. This substance has not been officially classified in the European Union. Most manufacturers of etoposide importers classify it for carcinogenic activity to category 1.B with risk phrase: May cause cancer and acute toxicity after oral exposure to category 4. The main effect of the toxicity of etoposide as a medicine is suppression of bone marrow function, which results in neutropenia, granulocytopenia and thrombocytopenia, leukopenia, an increase in the number of megaloblasts in the bone marrow and gastrointestinal symptoms (eg nausea, vomiting with mild to moderate intensity) , bronchospasm, inflammation of mucous membranes, feelings of disgust in the mouth, baldness and secondary leukemia. According to the IARC, there is limited evidence of carcinogenicity of etoposide in animals, but there is sufficient evidence of carcinogenicity of etoposide in humans when combined exposure to cisplatin and bleomycin. In IARC, etoposide was classified as probably carcinogenic to humans (Group 2.A.), and in combination with cisplatin and bleomycin as a carcinogen for humans (Group 1). The genotoxic activity of etoposide has been demonstrated in studies performed on human and animal material in vitro without metabolic activation. Etoposide caused the occurrence of chromosomal aberrations in both humans and experimental animals, increased sister chromatid exchange, double-strand break in DNA and the micronucleus formation. In experimental animal studies (mice, rats, rabbits), etoposide was teratogenic and embryotoxic. In women treated with etoposide, transient ovarian dysfunction is reported. The effect of etoposide on ovarian function, however, did not depend on the dose, but on the patient's age. In addition, spontaneous births were reported in women treated with etoposide. In some cases, the embryotoxic effects of the drug have been demonstrated. There were no congenital malformations in children whose mothers were treated with etoposide alone or in combination with other cytostatics, as well as in children of men treated with etoposide. The critical effect of the action of etoposide as a drug is bone marrow suppression. The lowest therapeutic dose of the drug was found at 2.37 mg/kg/day. In Poland, the maximum permissible concentrations of etoposide in the work environment have not yet been established. The following data was taken into account when determining the NDS of etoposide: - occupational exposure levels established by etoposide manufacturers for this substance amount to 0.0003 or 0.0007 mg/m3; - available results of human and animal studies do not allow to determine the dose-effect relationship; - due to the genotoxic, carcinogenic, teratogenic and reproductive effects of etoposide, NIOSH assumed that the OEL should be set at a level below 0.01 mg/m3; - according to the classification proposed by the group operating within the framework of the "Global strategy of risk management", etoposide should be in category 4, ie substances for which the OEL value in the work environment should be in the range of 0.001 mg/m3 ÷ 0.01 mg/m3. The MAC value of etoposide was proposed at the level of the equivalent concentration to 0.1% of the lowest therapeutic dose used in humans (2.37 mg/kg), similar to other cytostatics (eg N-hydroxyurea, fluorouracil). An additional uncertainty factor "F" was adopted at level 10 related to the long-term effects of exposure, i.e. genotoxic, carcinogenic and reprotoxic effects of the substance. The MAC of the inhalable fraction of etoposide was set at 0.0017 mg/m3. There are no substantive basis to establish the value of the short- -term (STEL) and permissible concentrations in biological material (DSB) for etoposide. Based on quantitative data characterizing skin absorption of etoposide, which has a molecular weight of 588.56 and its poor solubility in water, it has been found that the substance is characterized by a low ability to penetrate the skin. Due to the observed embryotoxicity in humans and teratogenic and embryotoxic etoposide in experimental animals, the substance was marked with the letters "Ft" - a substance harmful for reproduction. In addition, the labeling recommended by the manufacturers of "Carc 1.B" that indicated that it is a carcinogenic substance of category 1.B.
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Kilanowicz, Anna, and Małgorzata Skrzypińska-Gawrysiak. "2,2’-dichloro-4,4’-methylenedianiline – inhalable fraction and vapours. Documentation of proposed values of occupational exposure limits (OELs)." Podstawy i Metody Oceny Środowiska Pracy 36, no. 3(101) (September 30, 2019): 5–38. http://dx.doi.org/10.5604/01.3001.0013.4164.
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2,2'-Dichloro-4,4'-methylenedianiline (MOCA) is an aromatic amine. It is produced commercially by the reaction of formaldehyde and 2-chloroaniline. It is not produced in Europe and its import to Europe is estimated at 1000-10000 t/year. MOCA is mainly used as a curing agent in the production of polyurethane elastomers. Occupational exposure to MOCA occurs during production, distribution and use of this compound. In Poland in 2016, 14 people were exposed to this compound, including 10 women. Under occupational exposure conditions, MOCA is mainly absorbed through the skin; absorption in the respiratory tract is of secondary importance. Available literature does not provide data on chronic MOCA poisoning under occupational conditions. No methemoglobinogenic effect typical for aromatic amines was found in exposed subjects. MOCA has a moderate toxic effect on animals; median lethal doses after oral administration to rodents are 400 ÷ 1140 mg/kg of body weight. It also has a moderate irritant effect on the skin and eyes, but no allergenic effect. Data on subchronic and chronic animal toxicity indicate multiorgan toxicity. MOCA shows mutagenic and genotoxic potential, both in vivo and in vitro. In bacterial tests, it requires the presence of metabolic activation. It causes DNA damage and formes DNA adducts both in vitro and in vivo. MOCA also forms adducts with other macromolecules such as haemoglobin, globin or plasma albumin. No data are available on the effects of MOCA on human reproduction or on the embryotoxicity and teratogenicity of this compound. The only rat experiment showed that MOCA has no influence on the reproductive potential of parents and the growth and of pre- and postnatal development of offspring. There are no epidemiological studies in the literature that clearly indicate that occupational exposure to MOCA is the cause of cancer in workers. However, there are reports of bladder cancer, usually found in cystoscopic examination in young men occupationally exposed to MOCA. Animal studies have provided sufficient evidence for the carcinogenic effects of MOCA. It was shown that this compound administered to rats in the diet induces a dose-dependent increase in the number of lung cancer, hepatocellular carcinomas, hemangiosarcomas, mammary gland adenomas and Zymbal gland carcinomas. MOCA administered in capsules to dogs induced tumors of the bladder and urethra. The mechanism of carcinogenic action of MOCA is related to the potential of this compound and/or its metabolites to bind with macromolecules, mainly DNA. MOCA has a harmonised classification as Carc.1B. IARC considered that there was insufficient evidence of MOCA carcinogenicity in humans and that there was sufficient evidence of carcinogenicity in animals. In the overall assessment IARC classified MOCA into group 1 – compound carcinogenic to humans. SCOEL (2010) included MOCA to genotoxic carcinogens with non-threshold effect (group A). MOCA is absorbed into the body by inhalation, ingestion and dermal routes, the latter is the main route of absorption under occupational exposure conditions. There is no quantitative data on efficiency or absorption rate. In animals, regardless of the route of administration, the highest MOCA concentrations are in the liver, lower in the lungs, kidneys, adipose tissue and blood. MOCA is metabolized mainly in the liver by CYP3A4. Metabolism may proceed along the pathways of N-acetylation, N-hydroxylation/N-oxidation and ring hydroxylation. The main and the most reactive and directly carcinogenic metabolite is N-hydroxy-MOCA. MOCA is excreted from the body with urine and faeces. The relative share of these excretion routes in animals depends on both the species and the route of administration. Based on the MOCA measurement in the urine of an employee who accidentally sprayed with molten MOCA, the biological half-life was set at 23 hours. Since the main route of absorption of MOCA in occupational exposure conditions is the dermal route, biological monitoring, usually based on measurement of the total MOCA concentration in urine, is necessary for the assessment of total exposure. Modern monitoring studies have found that although the MOCA concentration in air was low, a significant percentage of urine samples exceeded the detection limit of the method, which for most methods is 0.5 µmol MOCA/mol creatinine. In addition, some studies have shown that the MOCA level in urine correlated with the amount of glove contamination, not the working surfaces. The values of the current hygiene standards in the various countries range from 0.22 mg/m3 to 0.005 mg/m3 and are usually labelled "skin" and "carcinogen". Furthermore, in many countries, no limit values have been set for MOCA due to its carcinogenic effects. Also in the EU, SCOEL did not set a standard value for MOCA. In 2018. The European Commission has proposed to include a limit value of 0.01 mg/m3 as a binding value (BOELV) with the simultaneous notation of 'skin' in Annex III to the proposal for a Directive of the European Parliament and of the Council amending Directive 2004/37/EC on the protection of workers from the risks related to exposure to carcinogens or mutagens at work. At the same time, it was proposed to set the urinary MOCA concentration at 5 µmol MOCA/mol creatinine as the Biological Guidance Value (BGV), in line with the list of recommended values of the Biological Exposure Limits (BEIs) based on the health effects and Biological Guidance Values (BGVs) provided by SCOEL, which however takes the detection limit of the method as the BGV without giving a specific numerical value for this indicator. The basis for proposing a MAC value was the carcinogenic effect of MOCA. Since MOCA is a genotoxic carcinogen with non-threshold effect, the values of hygiene standards should be based on the cancer risk assessment for this compound. All existing risk assessments are based on the results of an experiment on rats receiving MOCA in the diet under chronic exposure conditions. The MAC value currently in force in Poland of 0.02 mg/m3 was derived on the basis of the linear model with the assumed risk of 10-4. The cancer risk assessment using the two-step model gave the risk values accordingly: 4.6 - 10-4 for MOCA concentration 0.02 mg/m3 and 1.7 - 10-4 for 0.01 mg/m3. A similar risk value of 9.65 - 10-5 (≈ 1 - 10-4) for inhalation exposure to 0.01 mg/m3 was assigned by RAC using a linear model. In view of the fact that the risk assessments presented above gave compatible values for 0.01 mg/m3 and that the European Union proposed this value as a binding concentration, it was proposed to use a MOCA concentration in air of 0.01 mg/m3 as the MAC value in Poland. The main route of exposure to MOCA at occupational condition is the dermal route. MOCA levels in workers' urine samples are a better indicator for overall exposure assessment than measuring MOCA concentrations in air. MOCA is not detected in the urine of subjects not occupationally exposed, i.e. it remains below the detection limit of the method. Therefore, the Biological Guidance Value (BGV) for MOCA should correspond to the detection limit of the biomonitoring method. However, for practical reasons, it was proposed to use 5 µmol MOCA/mole creatinine in urine collected at the end of the shift as an equivalent to BEI. Under industrial conditions, total MOCA concentrations below 5 µmol/mol creatinine can be achieved under appropriate hygienic working conditions. Moreover, according to the risk assessment presented by SCOEL, this MOCA concentration in urine leads to a cancer risk of 3 ÷ 4 - 10-6. Biomonitoring should be supplemented by air monitoring and, where appropriate, measurements of dermal contamination, gloves and work surfaces contamination to identify sources of exposure. Since dermal exposure accounts for a significant proportion of the MOCA taken by workers, a 'skin' notation is required. This article discusses the problems of occupational safety and health, which are covered by health sciences and environmental engineering.
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"5 Final Report on the Safety Assessment of 2-Nitro-p-Phenylenediamine and 4-Nitro-o-Phenylenediamine." Journal of the American College of Toxicology 4, no. 3 (May 1985): 161–202. http://dx.doi.org/10.3109/10915818509078672.
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Animal data on 2NPPD and 4NOPD and cosmetic hair dyes containing these ingredients suggest that both compounds were nonirritating to rabbit skin and eyes, but were sensitizers on guinea pig skin. The results of repeated insult patch tests with hair dye products containing these ingredients indicated that neither was an irritant or a sensitizer to human subjects as normally used. In the absence of human data on the pure compounds, however, 2NPPD and 4NOPD are considered to be potential human sensitizers. Topically applied 2NPPD and 4NOPD are absorbed by experimental animals. Neither embryotoxicity nor teratogenicity was observed in animal studies when hair dyes containing 2NPPD and 4NOPD were applied to the skin. Both ingredients were mutagenic in some bacterial and in vitro mammalian systems; both compounds had some genotoxic activity. In feeding studies in mice and rats, only 2NPPD induced hepatocellular tumors in female mice. Both compounds were noncarcinogenic in male mice and in rats of either sex. Epidemiological data have not demonstrated a carcinogenic effect in man for hair dyes. For those persons not sensitized, it is concluded that 2NPPD and 4NOPD are safe as hair dye ingredients at the current concentration of use.
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Bailone, Ricardo Lacava, Hirla Costa Silva Fukushima, Luis Kluwe de Aguiar, and Ricardo Carneiro Borra. "Calcium Chloride Toxicology for Food Safety Assessment Using Zebrafish (Danio rerio) Embryos." Comparative Medicine, 2022. http://dx.doi.org/10.30802/aalas-cm-22-000009.
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The salt calcium chloride (CaCl2) is widely used in industry as a food additive; levels for human consumption are regulated by international or governmental agencies. Generally, the food industry relies on toxicity studies conducted in mammals such as mice, rats, and rabbits for determining food safety. However, testing in mammals is time-consuming and expensive. Zebrafish have been used in a range of toxicological analyses and offer advantages with regard to sensitivity, time, and cost. However, information in not available with regard to whether the sensitivity of zebrafish to CaCl2 is comparable to the concentrations of CaCl2 used as food additives. The aim of this study was to compare the CaCl2 tolerance of zebrafish embryos and larvae with concentrations currently approved as food additives. Acute toxicity, embryotoxicity, cardiotoxicity, and neurotoxicity assays were used to determine the threshold toxic concentration of CaCl2 in zebrafish embryos and larvae. The data showed that doses above 0.4% had toxic effects on development and on the activity of the cardiac and neuronal systems. Furthermore, all embryos exposed to 0.8 and 1.6% of CaCl2 died after 24 hpf. These findings are consistent with the limits of CaCl2 concentrations approved by Codex Alimentarius. Therefore, zebrafish embryos could be suitable for screening food additives
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"The effect of lead exposure on a human chorio carcinoma cell line BeWo b24. A first step in the development of a embryotoxicity predicting in vitro model." Placenta 16, no. 6 (September 1995): A.13. http://dx.doi.org/10.1016/s0143-4004(05)80032-3.
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Dong, Zhen, Shu-Sheng Tang, Xiao-Lan Ma, Chang-Hong Li, Zhao-Shan Tang, Zi-Hui Yang, and Jian-Guo Zeng. "Preclinical safety evaluation of Macleaya Cordata extract: A re-assessment of general toxicity and genotoxicity properties in rodents." Frontiers in Pharmacology 13 (August 12, 2022). http://dx.doi.org/10.3389/fphar.2022.980918.
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Macleaya cordata extract (MCE) is widely used for its diverse pharmacological actions and beneficial effects on farm animals. Modern pharmacological studies have shown that it has anti-inflammatory, anti-cancer, and anti-bacterial activities, and is gradually becoming a long-term additive veterinary drug used to improve animal intestinal health and growth performance. Although some evidence points to the DNA mutagenic potential of sanguinarine (SAN), a major component of MCE, there is a lack of sufficient basic toxicological information on the oral route, posing a potential safety risk for human consumption of food of animal origin. In this study, we assessed the acute oral toxicity, repeated 90-day oral toxicity and 180-day chronic toxicity of MCE in rats and mice and re-evaluated the genotoxicity of MCE using a standard combined in vivo and ex vivo assay. In the oral acute toxicity test, the LD50 for MCE in rats and mice was 1,564.55 mg/kg (95% confidence interval 1,386.97–1,764.95 mg/kg) and 1,024.33 mg/kg (95% confidence interval 964.27–1,087.30 mg/kg), respectively. The dose range tested had no significant effect on hematology, clinical chemistry, and histopathological findings in rodents in the long-term toxicity assessment. The results of the bacterial reverse mutation, sperm abnormality and micronucleus test showed negative results and lack of mutagenicity and teratogenicity; the results of the rat teratogenicity test showed no significant reproductive or embryotoxicity. The results indicate that MCE was safe in the dose range tested in this preclinical safety assessment. This study provides data to support the further development of maximum residue limits (MRLs) for MCE.
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Yang, Renjun, Nuoya Yin, Ying Zhao, Dandan Li, Xuanling Zhang, Xingang Li, Yang Zhang, and Francesco Faiola. "Adverse Events During Pregnancy Associated With Entecavir and Adefovir: New Insights From a Real-World Analysis of Cases Reported to FDA Adverse Event Reporting System." Frontiers in Pharmacology 12 (January 3, 2022). http://dx.doi.org/10.3389/fphar.2021.772768.
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Background: Due to the embryotoxicity found in animal studies and scarce clinical data in pregnant women, it is still controversial whether entecavir (ETV) and adefovir dipivoxil (ADV) are safe during human pregnancy. This is of paramount importance when counseling pregnant women with hepatitis B virus (HBV) on risks and benefits to their offspring.Objective: To quantify the association between administration of ETV and ADV in pregnant women and occurrence of adverse events (AEs) during pregnancy (AEDP).Methods: Pregnancy reports from the FDA Adverse Event Reporting System (FAERS) were used to perform a retrospective analysis of AEDP associated with ETV or ADV. Disproportionality analysis estimating the reporting odds ratio (ROR) was conducted to identify the risk signals. A signal was defined as ROR value >2, and lower limit of 95% confidence interval (CI)> 1.Results: A total of 1,286,367 reports involving AEDP were submitted to FAERS by healthcare professionals. Of these, there were 547 cases reporting ETV and 242 cases reporting ADV as primary suspected drugs. We found a moderate or strong signal for increased risk of spontaneous abortion when comparing ETV with tenofovir disoproxil fumarate (TDF) and telbivudine (LdT), with RORs equal to 1.58 (95% CI, 1.09–2.30) and 2.13 (95% CI, 1.04–4.36), respectively. However, when the included reports were limited to indication containing HBV infection, no signals for increased AEDP were detected. Futhermore, a strong signal for increased risk of spontaneous abortion was identified in patients with HBV infection when comparing ETV or ADV with lamivudine (LAM), with RORs of 3.55 (95% CI, 1.54–8.18) and 2.85 (95% CI, 1.15–7.08), respectively.Conclusion: We found a strong signal for increased risk of spontaneous abortion in patients with HBV infection taking ETV or ADV, in comparison with those prescribed with LAM. Moreover, no obvious signal association of human teratogenicity with exposure to ETV or ADV was identified in fetuses during pregnancy. Nevertheless, owing to the limitations of a spontaneous reporting database, which inevitably contains potential biases, there is a pressing need for well-designed comparative safety studies to validate these results in clinical practice.
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"2 Final Report on the Safety Assessment of p-Aminophenol, m-Aminophenol, and o-Aminophenol." Journal of the American College of Toxicology 7, no. 3 (May 1988): 279–333. http://dx.doi.org/10.3109/10915818809023134.
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p-Aminophenol (PAP), m-Aminophenol (MAP), and o-Aminophenol (OAP) are used in permanent (oxidative) hair dyes at concentrations from 0.1 to 5%. In vivo and in vitro skin absorption studies indicated that 11% of the dermally applied 14C-PAP was detected in the excreta, viscera, and skin of the test animals. The oral LD50s of PAP, MAP, and OAP in rats ranged from 600 to 1300 mg/kg. Topical application of PAP at concentrations up to 8.00 g/kg to the skin of New Zealand white (NZW) rabbits produced no skin irritation and no mortality. PAP, MAP, and OAP were irritating to eyes of NZW rabbits at a concentration of 2.5%. MAP at 3% was nonsensitizing in guinea pigs; PAP at 2% sensitized 9 of 10 guinea pigs. Neither PAP nor MAP produced photosensitization in guinea pigs. No treatment-related toxicity was found in three separate four-generation chronic dermal toxicity and reproduction studies of hair dye formulations containing the three Aminophenols. Additional studies on the pure ingredients were also nonteratogenic; embryotoxicity was reported. A range of results was obtained from studies assessing the mutagenic activity of the Aminophenols. PAP tested positive in six of eight mutagenicity tests. MAP and OAP gave positive results in two of eight and five of seven mutagenicity tests, respectively. Oxidative hair dye formulations containing PAP, MAP, and OAP did not produce gross or microscopic alterations or have carcinogenic effects after chronic topical application to mice. Feeding of OAP-HCl and PAP to rats at a dose of 8 mmol/kg produced neither hepatic cirrhosis nor neoplastic lesions. A 3% solution of MAP in an aqueous vehicle was neither a significant irritant nor sensitizer in two clinical studies. A variety of epidemiological studies have not indicated that occupational exposure to, and personal use of, hair dyes containing the Aminophenols presented a carcinogenic risk. A discussion of the significance of the mutagenic data in the safety assessment and the potential for human effects is presented. On the basis of the available animal and clinical data presented in this report it is concluded that p-, m-, and o-Aminophenols are safe as cosmetic ingredients in the present practices of use and concentrations.