Toxicology Paradise: Sorting Out Adverse and Non-adverse Findings in Animal Toxicity Studies

2020 ◽  
Vol 39 (5) ◽  
pp. 365-378 ◽  
Author(s):  
Paul Baldrick ◽  
Mary Ellen Cosenza ◽  
Tessie Alapatt ◽  
Brad Bolon ◽  
Melissa Rhodes ◽  
...  
Keyword(s):  
Weight Of Evidence ◽  
Drug Marketing ◽  
Toxicity Studies ◽  
Final Study ◽  
The Us ◽  
Adverse Effect Level ◽  
Effect Level ◽  
Animal Toxicity ◽  
The Many ◽  
Threshold Setting

A challenge for all toxicologists is defining what study findings are actually adverse versus non-adverse in animal toxicity studies, and which ones are relevant for generating a no observed adverse effect level (NOAEL) to assess human risk. This article presents views on this challenge presented by toxicologists, toxicologic pathologists, and regulatory reviewers at the 2019 annual meeting of the American College of Toxicology during a workshop entitled “Toxicology Paradise: Sorting Out Adverse and Non-adverse Findings.” The speakers noted that setting a NOAEL is not always straightforward, not only for small molecules but also for biopharmaceuticals, and that a “weight of evidence” approach often is more useful than a rigid threshold-setting algorithm. Regulators from the US Food and Drug Administration and European Union told how assessment of adverse nonclinical findings is undertaken to allow clinical studies to commence and drug marketing approvals to succeed, along with the process that allows successful dialogs with regulators. Nonclinical case studies of findings judged to be adverse versus non-adverse were presented in relation to the many factors that might halt or delay clinical development. The process of defining adverse findings and the NOAEL in final study reports was discussed, as well as who should be involved in the process.

scholarly journals Toxicologic Pathology Forum*: Commentary on “Opinion on Designation of Adverse and Nonadverse Histopathological Findings in Toxicity Studies: The Pathologist’s Dilemma”

2019 ◽  
Vol 47 (5) ◽  
pp. 574-576 ◽  
Author(s):  
Daniel J. Patrick ◽  
Sean P. Troth
Keyword(s):  
Adverse Effect ◽  
Trial Design ◽  
Critical Role ◽  
Clinical Trial Design ◽  
Histopathological Findings ◽  
Toxicity Studies ◽  
Complex Process ◽  
Adverse Effect Level ◽  
Realistic View ◽  
Effect Level

In the article “Opinion on Designation of Adverse and Nonadverse Histopathological Findings in Toxicity Studies: The Pathologist’s Dilemma,” the authors Gopinath and Mowat provide a framework for designation of adversity supplemented with photomicrographic examples. Given that adversity designation can significantly impact the no observed adverse effect level and clinical trial design, it is important to carefully consider all of the criteria by which such assignments are made. We highlight some of the specific assertions within the article that could benefit from a more detailed discussion. Our primary criticism surrounds the authors’ primary reliance on histopathology in isolation for adversity designation, which in our opinion provides an overly simplified depiction of the process. We provide additional perspective on how context beyond histopathology often plays a critical role in adversity designation and highlight areas where inclusion of some of these scenarios would have provided the reader a more realistic view of the complex process of assigning adversity. [Box: see text]

Safety Evaluation of a Proprietary Food-Grade, Dried Fermentate Preparation of Saccharomyces cerevisiae

2012 ◽  
Vol 31 (1) ◽  
pp. 34-45 ◽  
Author(s):  
Alexander G. Schauss ◽  
R. Glavits ◽  
John Endres ◽  
Gitte S. Jensen ◽  
Amy Clewell
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Clinical Symptoms ◽  
Safety Evaluation ◽  
In Vivo Studies ◽  
Oral Toxicity ◽  
Toxicity Studies ◽  
Adverse Effect Level ◽  
Effect Level

A safety evaluation was performed for EpiCor, a product produced by a proprietary fermentation process using Saccharomyces cerevisiae. Studies included the following assays: bacterial reverse mutation, mouse lymphoma cell mutagenicity, mitogenicity assay in human peripheral lymphocytes, and a cytochrome P450 ([CYP] CYP1A2 and CYP3A4) induction assessment as well as 14-day acute, 90-day subchronic, and 1-year chronic oral toxicity studies in rats. No evidence of genotoxicity or mitogenicity was seen in any of the in vitro or in vivo studies. The CYP assessment showed no interactions or inductions. No toxic clinical symptoms or histopathological lesions were observed in the acute, subchronic, or chronic oral toxicity studies in the rat. Results of the studies performed indicate that EpiCor does not possess genotoxic activity and has a low order of toxicity that is well tolerated when administered orally. The no observable adverse effect level (NOAEL) was 1500 mg/kg body weight (bw)/d for the 90-day study and 800 mg/kg bw/d for the 1 year study, for the highest doses tested.

scholarly journals Tavaborole, a Novel Boron-Containing Small Molecule Pharmaceutical Agent for Topical Treatment of Onychomycosis

2016 ◽  
Vol 35 (5) ◽  
pp. 543-557
Author(s):  
Vic Ciaravino ◽  
Dina Coronado ◽  
Cheryl Lanphear ◽  
Alan Hoberman ◽  
Sanjay Chanda
Keyword(s):  
Reproductive Performance ◽  
Dose Group ◽  
Female Rats ◽  
Oral Gavage ◽  
Pharmaceutical Agent ◽  
The Us ◽  
Adverse Effect Level ◽  
Effect Level ◽  
F2 Generation ◽  
F1 Generation

Tavaborole is a topical antifungal agent approved by the US Food and Drug Administration for the treatment of toenail onychomycosis. The effects of tavaborole on gestation, parturition (delivery, labor), offspring development, and survival during the perinatal and postnatal periods were assessed in mated female rats. Females (F0 generation) were administered single daily oral (gavage) doses of 15, 60, or 100 mg/kg/d from gestation day 6 through lactation day 20. The females were allowed to deliver naturally and rear their offspring until lactation day 21, at which time the F0 females were euthanized. One male and female from each litter were selected (F1 generation) and retained for assessments, including growth, neurobehavior, fertility, and their ability to produce an F2 generation. Reproductive and offspring parameters were determined for the F1 and F2 generations, as applicable. F1 females and F2 pups were euthanized on postnatal day 7. In the F0 females, decreased activity was observed in the 100 mg/kg/d dose group. Excess salivation was observed in the 60 and 100 mg/kg/d dose groups (slight to moderate), however, this finding was not considered adverse. There were no tavaborole-related effects on the growth, viability, development, neurobehavioral assessments, or reproductive performance of the F1 generation. Survivability and mean body weight of the F2 pups were unaffected. The no observed adverse effect level (NOAEL) for maternal toxicity (F0 generation) was 60 mg/kg/d, based on the decreased activity observed in the 100 mg/kg/d dose group. The NOAEL for the offspring effects was ≥100 mg/kg/d, based on the lack of test article-related changes.

Evaluation of genotoxicity and subchronic toxicity of standardized rose hip extract

2017 ◽  
Vol 37 (7) ◽  
pp. 725-741 ◽  
Author(s):  
A Nagatomo ◽  
M Oguri ◽  
N Nishida ◽  
M Ogawa ◽  
A Ichikawa ◽  
...  
Keyword(s):  
Oral Dose ◽  
Chinese Hamster ◽  
Gene Mutations ◽  
Ethanol Extract ◽  
Female Rats ◽  
Toxicity Studies ◽  
Male And Female Rats ◽  
Adverse Effect Level ◽  
Effect Level ◽  
Rose Hip

Rose hip is the fruit of the rose plant, which is widely used in food, cosmetics and as a traditional medicine. Therefore, rose hip is considered safe and has a sufficient history of consumption as food. However, few studies have reported on the safety of rose hip extracts in toxicological analyses. Thus, to evaluate the safety of rosehip polyphenol MJ (RHPMJ), an aqueous ethanol extract standardized with the trans-tiliroside content, we performed genotoxicity and 90-day repeated oral dose toxicity studies in compliance with the Organisation for Economic Co-operation and Development-Good Laboratory Practice. RHPMJ did not induce gene mutations in reverse mutation tests of Salmonella typhimurium TA98, TA100, TA1535, TA1537 and Escherichia coli WP2 uvrA strains and did not induce chromosomal aberrations in cultured Chinese hamster lung (CHL/IU) cells. Moreover, micronucleus tests using rat bone marrow showed RHPMJ had no micronucleus-inducing potential. Finally, 90-day repeated oral dose toxicity studies (100–1000 mg/kg) in male and female rats showed no treatment-related toxicity in rats. These data indicate that the RHPMJ had no genotoxicity and a no-observed-adverse-effect level greater than 1000 mg/kg in rats.

Regulatory risk assessments: Is there a need to reduce uncertainty and enhance robustness? Update on propylparaben in relation to its EU regulatory status

2017 ◽  
Vol 36 (10) ◽  
pp. 1007-1014 ◽  
Author(s):  
D Snodin
Keyword(s):  
Adverse Effects ◽  
Food Additives ◽  
Test Material ◽  
Weight Of Evidence ◽  
European Medicines Agency ◽  
Juvenile Rats ◽  
Screening Study ◽  
Adverse Effect Level ◽  
Effect Level ◽  
The Eu

Over 10 years ago, propylparaben (propyl– p–hydroxybenzoate; PP) was withdrawn as a permitted food preservative in the EU based entirely on findings reported in a single dietary study in juvenile rats claiming to show adverse effects on male reproductive parameters [Oishi S. Effects of propyl paraben on the male reproductive system. Food Chem Toxicol 2002; 40(12): 1807 -1813]. Subsequent data reviews have cast serious doubt on the validity of the Oishi results, mainly in relation to aberrant concurrent-control values, and in two further comprehensive studies using neonatal and juvenile rats there were no adverse effects in males at oral doses up to 1000 mg/kg/day. By contrast, juvenile animal toxicity data on the two paraben preservatives currently permitted in the EU as food additives (methylparaben and ethylparaben) are non-robust and rudimentary. Although PP is a permitted preservative in cosmetics its use pattern is highly restricted based mainly on the results of a screening study in the rat using butylparaben as test material, and not taking into account the more recent data on PP. The European Medicines Agency has determined a permitted daily exposure of 2 mg/kg for PP, which applies to both adult and paediatric patients, based on an oral no-observed-adverse-effect level of 100 mg/kg/day in females, treatment-related changes suggestive of an estrogenic effect being noted at 1000 mg/kg/day. The weight of evidence strongly supports a toxicological re-evaluation of PP regarding its use in foodstuffs and cosmetics in the EU, with a view to reinstatement as a food additive, consistent with its status in other major jurisdictions.

The case for integrating low dose, beneficial responses into US EPA risk assessments

2006 ◽  
Vol 25 (1) ◽  
pp. 7-10 ◽  
Author(s):  
J M DeSesso ◽  
R E Watson
Keyword(s):  
Environmental Protection Agency ◽  
Low Dose ◽  
Risk Assessments ◽  
Protection Agency ◽  
Beneficial Effects ◽  
The Us ◽  
Adverse Effect Level ◽  
Us Epa ◽  
Effect Level ◽  
Epa Methods

When conducting risk assessments, the US Environmental Protection Agency (EPA) does not currently consider the beneficial effects from exposure to concentrations of agents below the no observed adverse effect level (NOAEL). If such benefits were observed, and if the beneficial and toxicological mechanisms of action were identical, this would probably be represented as a ‘j–shaped’ hormetic dose–response curve. If such data are available, they should be considered when assigning uncertainty factors for safe exposure calculations. However, when such data are not readily available, as is likely the case when the mechanism of action of the benefit differs from that of toxicity, current US EPA methods appear adequate.

Archaeologists and the Dead

2016 ◽  
Keyword(s):  
Historical Context ◽  
Ethical Considerations ◽  
International Context ◽  
The Public ◽  
The Us ◽  
The Dead ◽  
The Many ◽  
The Uk ◽  
The Relationship ◽  
Experience Effect

This volume addresses the relationship between archaeologists and the dead, through the many dimensions of their relationships: in the field (through practical and legal issues), in the lab (through their analysis and interpretation), and in their written, visual and exhibitionary practice--disseminated to a variety of academic and public audiences. Written from a variety of perspectives, its authors address the experience, effect, ethical considerations, and cultural politics of working with mortuary archaeology. Whilst some papers reflect institutional or organizational approaches, others are more personal in their view: creating exciting and frank insights into contemporary issues that have hitherto often remained "unspoken" among the discipline. Reframing funerary archaeologists as "death-workers" of a kind, the contributors reflect on their own experience to provide both guidance and inspiration to future practitioners, arguing strongly that we have a central role to play in engaging the public with themes of mortality and commemoration, through the lens of the past. Spurred by the recent debates in the UK, papers from Scandinavia, Austria, Italy, the US, and the mid-Atlantic, frame these issues within a much wider international context that highlights the importance of cultural and historical context in which this work takes place.

scholarly journals Palmitoylethanolamide: Prenatal Developmental Toxicity Study in Rats

2021 ◽  
pp. 109158182098607
Author(s):  
Narendra S. Deshmukh ◽  
Shailesh Gumaste ◽  
Silma Subah ◽  
Nathasha Omal Bogoda
Keyword(s):  
Body Weight ◽  
Developmental Toxicity ◽  
Reproductive Toxicity ◽  
Toxicity Study ◽  
High Dose ◽  
Pregnant Rats ◽  
Human Dose ◽  
Adverse Effect Level ◽  
Female Wistar Rats ◽  
Effect Level

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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