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Journal of Toxicology and Environmental... Feb 2010With the release of the landmark report Toxicity Testing in the 21st Century: A Vision and a Strategy, the U.S. National Academy of Sciences, in 2007, precipitated a...
With the release of the landmark report Toxicity Testing in the 21st Century: A Vision and a Strategy, the U.S. National Academy of Sciences, in 2007, precipitated a major change in the way toxicity testing is conducted. It envisions increased efficiency in toxicity testing and decreased animal usage by transitioning from current expensive and lengthy in vivo testing with qualitative endpoints to in vitro toxicity pathway assays on human cells or cell lines using robotic high-throughput screening with mechanistic quantitative parameters. Risk assessment in the exposed human population would focus on avoiding significant perturbations in these toxicity pathways. Computational systems biology models would be implemented to determine the dose-response models of perturbations of pathway function. Extrapolation of in vitro results to in vivo human blood and tissue concentrations would be based on pharmacokinetic models for the given exposure condition. This practice would enhance human relevance of test results, and would cover several test agents, compared to traditional toxicological testing strategies. As all the tools that are necessary to implement the vision are currently available or in an advanced stage of development, the key prerequisites to achieving this paradigm shift are a commitment to change in the scientific community, which could be facilitated by a broad discussion of the vision, and obtaining necessary resources to enhance current knowledge of pathway perturbations and pathway assays in humans and to implement computational systems biology models. Implementation of these strategies would result in a new toxicity testing paradigm firmly based on human biology.
Topics: Animals; Environmental Pollutants; History, 20th Century; History, 21st Century; Humans; National Academy of Sciences, U.S.; Risk Assessment; Toxicity Tests; United States; United States Environmental Protection Agency
PubMed: 20574894
DOI: 10.1080/10937404.2010.483176 -
ALTEX 2018For a long time, the discussion about animal testing vs its alternatives centered on animal welfare. This was a static warfare, or at least a gridlock, where life...
For a long time, the discussion about animal testing vs its alternatives centered on animal welfare. This was a static warfare, or at least a gridlock, where life scientists had to take a position and make their value choices and hardly anyone changed sides. Technical advances have changed the frontline somewhat, with in vitro and in silico methods gaining more ground. Only more recently has the economic view begun to have an impact: Many animal tests are simply too costly, take too long, and give misleading results. As an extension and update to previous articles in this series written a decade ago, we reanalyze the economic landscape of especially regulatory use of animal testing and this time also consider respective alternative tests. Despite some ambiguity and data gaps, which we have filled with crude estimates, a picture emerges of globally regulated industries that are subject to stark geographic and sectorial differences in regulation, which determine their corresponding animal use. Both animal testing and its alternatives are industries in their own right, offering remarkable business opportunities for biotech and IT companies as well as contract research organizations. In light of recent revelations as to the reproducibility and relevance issues of many animal tests, the economic consequences of incorrect results and the reasons for still maintaining often outdated animal test approaches are discussed.
Topics: Animal Testing Alternatives; Animal Welfare; Animals; Humans; Models, Animal; Reproducibility of Results; Research; Toxicity Tests
PubMed: 30008008
DOI: 10.14573/altex.1807041 -
Environmental Toxicology and Chemistry Feb 2019A review of the literature on oil toxicity tests showed a high diversity of reported test methods that may affect the composition, stability, and toxicity of oil... (Review)
Review
A review of the literature on oil toxicity tests showed a high diversity of reported test methods that may affect the composition, stability, and toxicity of oil solutions. Concentrations of oil in test solutions are dynamic because hydrocarbons evaporate, partition to test containers, bioaccumulate, biodegrade, and photo-oxidize. As a result, the composition and toxicity of test solutions may vary widely and create significant obstacles to comparing toxicity among studies and to applying existing data to new risk assessments. Some differences in toxicity can be resolved if benchmarks are based on measured concentrations of hydrocarbons in test solutions, highlighting the key role of chemical analyses. However, analyses have often been too infrequent to characterize rapid and profound changes in oil concentrations and composition during tests. The lack of practical methods to discriminate particulate from dissolved oil may also contribute to underestimating toxicity. Overall, current test protocols create uncertainty in toxicity benchmarks, with a high risk of errors in measured toxicity. Standard oil toxicity tests conducted in parallel with tests under site-specific conditions would provide an understanding of how test methods and conditions affect measured oil toxicity. Development of standard test methods could be achieved by collaborations among university, industry, and government scientists to define methods acceptable to all 3 sectors. Environ Toxicol Chem 2019;38:302-311. © 2018 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals, Inc. on behalf of SETAC.
Topics: Animals; Aquatic Organisms; Ecotoxicology; Guidelines as Topic; Petroleum; Petroleum Pollution; Toxicity Tests; Water Pollutants, Chemical
PubMed: 30365179
DOI: 10.1002/etc.4303 -
ALTEX 2014Historically, early identification and characterization of adverse effects of industrial chemicals was difficult because conventional toxicological test methods did not...
Historically, early identification and characterization of adverse effects of industrial chemicals was difficult because conventional toxicological test methods did not meet R&D needs for rapid, relatively inexpensive methods amenable to small amounts of test material. The pharmaceutical industry now front-loads toxicity testing, using in silico, in vitro, and less demanding animal tests at earlier stages of product development to identify and anticipate undesirable toxicological effects and optimize product development. The Green Chemistry movement embraces similar ideas for development of less toxic products, safer processes, and less waste and exposure. Further, the concept of benign design suggests ways to consider possible toxicities before the actual synthesis and to apply some structure/activity rules (SAR) and in silico methods. This requires not only scientific development but also a change in corporate culture in which synthetic chemists work with toxicologists. An emerging discipline called Green Toxicology (Anastas, 2012) provides a framework for integrating the principles of toxicology into the enterprise of designing safer chemicals, thereby minimizing potential toxicity as early in production as possible. Green Toxicology`s novel utility lies in driving innovation by moving safety considerations to the earliest stage in a chemical`s lifecycle, i.e., to molecular design. In principle, this field is no different than other subdisciplines of toxicology that endeavor to focus on a specific area - for example, clinical, environmental or forensic toxicology. We use the same principles and tools to evaluate an existing substance or to design a new one. The unique emphasis is in using 21st century toxicology tools as a preventative strategy to "design out" undesired human health and environmental effects, thereby increasing the likelihood of launching a successful, sustainable product. Starting with the formation of a steering group and a series of workshops, the Green Toxicology concept is currently spreading internationally and is being refined via an iterative process.
Topics: Animal Testing Alternatives; Animals; Chemical Safety; Computer Simulation; Green Chemistry Technology; Humans; Structure-Activity Relationship; Toxicity Tests; Toxicology
PubMed: 25061898
DOI: 10.14573/altex.1406181 -
The Journal of Toxicological Sciences 2016Epidemiologic evidence has demonstrated associations between early life exposure to industrial chemicals and the occurrence of disease states, including cognitive and... (Review)
Review
Epidemiologic evidence has demonstrated associations between early life exposure to industrial chemicals and the occurrence of disease states, including cognitive and behavioral abnormalities, in children. The developing brain in the fetal and infantile periods is extremely vulnerable to chemicals because the blood-brain barrier is not completely formed during these periods. The Organisation for Economic Co-operation and Development (OECD) developmental neurotoxicity (DNT) test guideline, TG426, updated in 2007, comprises in vivo behavioral observational tests and other tests intended to assess DNT induced by exposure to industrial chemicals. These chemicals may enter the market without having been subjected to DNT testing, as DNT test data is not mandated by law at the time of chemical registration. In addition, proprietary rights have led to problems concerning the non-disclosure of industrial chemical toxicity test data, including DNT test data. To overcome the disadvantages of high-cost and low time efficiency of in vivo DNT tests, in vitro or in silico tests are the proposed alternatives, but it is unlikely that the results of such tests would reflect changes in higher brain functions. Accordingly, the current DNT test guidelines need to be revised to avoid overlooking or neglecting the occurrence of DNT induced by exposure to low doses of chemicals. This review also proposes the introduction of novel in vivo DNT testing methods in light of a cost-performance analysis.
Topics: Blood-Brain Barrier; Child; Child Behavior Disorders; Child, Preschool; Cognitive Dysfunction; Costs and Cost Analysis; Environmental Exposure; Guidelines as Topic; Hazardous Substances; Humans; Infant; Neurotoxicity Syndromes; Toxicity Tests
PubMed: 28250285
DOI: 10.2131/jts.41.SP69 -
Cell Reports Methods Mar 2023Drug-induced hepatotoxicity is a leading cause of drug withdrawal from the market. High-throughput screening utilizing liver models is critical for early-stage liver... (Review)
Review
Drug-induced hepatotoxicity is a leading cause of drug withdrawal from the market. High-throughput screening utilizing liver models is critical for early-stage liver toxicity testing. Traditionally, monolayer human hepatocytes or immortalized liver cell lines (e.g., HepG2, HepaRG) have been used to test compound liver toxicity. However, monolayer-cultured liver cells sometimes lack the metabolic competence to mimic the condition and are therefore largely appropriate for short-term toxicological testing. They may not, however, be adequate for identifying chronic and recurring liver damage caused by drugs. Recently, several three-dimensional (3D) liver models have been developed. These 3D liver models better recapitulate normal liver function and metabolic capacity. This review describes the current development of 3D liver models that can be used to test drugs/chemicals for their pharmacologic and toxicologic effects, as well as the advantages and limitations of using these 3D liver models for high-throughput screening.
Topics: Humans; Liver; Hepatocytes; Cells, Cultured; Cell Line; Toxicity Tests
PubMed: 37056374
DOI: 10.1016/j.crmeth.2023.100432 -
Regulatory Toxicology and Pharmacology... Aug 2021Lithium orotate, the salt of lithium and orotic acid, has been marketed for decades as a supplemental source of lithium with few recorded adverse events. Nonetheless,...
Lithium orotate, the salt of lithium and orotic acid, has been marketed for decades as a supplemental source of lithium with few recorded adverse events. Nonetheless, there have been some concerns in the scientific literature regarding orotic acid, and pharmaceutical lithium salts are known to have a narrow therapeutic window, albeit, at lithium equivalent therapeutic doses 5.5-67 times greater than typically recommended for supplemental lithium orotate. To our knowledge, the potential toxicity of lithium orotate has not been investigated in preclinical studies; thus, we conducted a battery of genetic toxicity tests and an oral repeated-dose toxicity test in order to further explore its safety. Lithium orotate was not mutagenic or clastogenic in bacterial reverse mutation and in vitro mammalian chromosomal aberration tests, respectively, and did not exhibit in vivo genotoxicity in a micronucleus test in mice. In a 28-day, repeated-dose oral toxicity study, rats were administered 0, 100, 200, or 400 mg/kg body weight/day of lithium orotate by gavage. No toxicity or target organs were identified; therefore, a no observed adverse effect level was determined as 400 mg/kg body weight/day. These results are supportive of the lack of a postmarket safety signal from several decades of human consumption.
Topics: Administration, Oral; Animals; Cell Line; Chromosome Aberrations; Cricetulus; DNA Damage; Dietary Supplements; Dose-Response Relationship, Drug; Mice; Micronucleus Tests; No-Observed-Adverse-Effect Level; Organometallic Compounds; Rats; Toxicity Tests, Subacute
PubMed: 34146638
DOI: 10.1016/j.yrtph.2021.104973 -
International Journal of Environmental... Aug 2022Objective: This study was conducted to evaluate the acute and subchronic toxicity of anthraquinone. An acute toxicity test was performed in female Sprague Dawley (SD)...
Objective: This study was conducted to evaluate the acute and subchronic toxicity of anthraquinone. An acute toxicity test was performed in female Sprague Dawley (SD) rats, and the oral median lethal dose (LD50) of anthraquinone was estimated to be >5000 mg/kg body weight (BW). In the subchronic study, groups of 10 male and 10 female rats were dosed with anthraquinone by gavage at 0, 1.36, 5.44, 21.76, and 174.08 mg/kg BW, 7 days/week for 90 days followed by a recovery period of 28 days. No appreciable toxic-related changes were observed in the 1.36 mg/kg BW group. When the animals received 5.44 mg/kg BW or more of anthraquinone, hyaline droplet accumulation in the renal tubules was observed in both the male and female rats, and anemia was observed in the females. When the anthraquinone dose reached 174.08 mg/kg BW, mild hepatocellular hypertrophy around the central vein of the hepatic lobule and hypothyroidism were observed in the female rats. During the recovery period, changes in clinical symptoms and parameters were considerably alleviated. Based on the results of this study, the no observed adverse effect level (NOAEL) for anthraquinone in rats was set at 1.36 mg/kg BW, and the lowest observed adverse effect level (LOAEL) was 5.44 mg/kg BW.
Topics: Administration, Oral; Animals; Anthraquinones; Body Weight; Female; Male; No-Observed-Adverse-Effect Level; Organ Size; Rats; Rats, Sprague-Dawley; Toxicity Tests, Acute; Toxicity Tests, Subchronic
PubMed: 36012048
DOI: 10.3390/ijerph191610413 -
ALTEX 2021Monocyte activation tests (MAT) are widely available but rarely used in place of animal-based pyrogen tests for safety assessment of medical devices. To address this...
Monocyte activation tests (MAT) are widely available but rarely used in place of animal-based pyrogen tests for safety assessment of medical devices. To address this issue, the National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods and the PETA International Science Consortium Ltd. convened a workshop at the National Institutes of Health on September 18-19, 2018. Participants included representatives from MAT testing laboratories, medical device manufacturers, the U.S. Food and Drug Administration's Center for Devices and Radiologic Health (CDRH), the U.S. Pharmacopeia, the International Organization for Standardization, and experts in the development of MAT protocols. Discussions covered industry experiences with the MAT, remaining challenges, and how CDRH's Medical Device Development Tools (MDDT) Program, which qualifies tools for use in evaluating medical devices to streamline device development and regulatory evaluation, could be a pathway to qualify the use of MAT in place of the rabbit pyrogen test and the limulus amebocyte lysate test for medical device testing. Workshop outcomes and follow-up activities are discussed.
Topics: Animal Testing Alternatives; Animals; Endotoxins; Equipment and Supplies; Monocytes; Pyrogens; Rabbits; Toxicity Tests
PubMed: 33452530
DOI: 10.14573/altex.2012021 -
Biologicals : Journal of the... Jul 2022This online workshop Accelerating Global Deletion of the Abnormal Toxicity Test for vaccines and biologicals. Planning common next steps was organized on October 14th,...
This online workshop Accelerating Global Deletion of the Abnormal Toxicity Test for vaccines and biologicals. Planning common next steps was organized on October 14th, 2021, by the Animal Free Safety Assessment Collaboration (AFSA), the Humane Society International (HSI), the European Federation of Pharmaceutical Industries and Associations (EFPIA), in collaboration with the International Alliance of Biological Standardization (IABS). The workshop saw a participation of over a hundred representatives from international organizations, pharmaceutical industries and associations, and regulatory authorities of 28 countries. Participants reported on country- and region-specific regulatory requirements and, where present, on the perspectives on the waiving and elimination of the Abnormal Toxicity Test. With AFSA, HSI, EFPIA and IABS representatives as facilitators, the participants also discussed specific country/global actions to further secure the deletion of ATT from all regulatory requirements worldwide.
Topics: Drug Industry; Humans; Reference Standards; Toxicity Tests; Vaccines
PubMed: 35840492
DOI: 10.1016/j.biologicals.2022.06.003