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Alternative Methods for Assessing the Effects of Chemicals in the Eye
Published in David W. Hobson, Dermal and Ocular Toxicology, 2020
Leon H. Bruner, John Shadduck, Diane Essex-Sorlie
When estimating an endpoint obtained from an in vitro test, it is important to generate and use all of the data available. For example, it is possible to generate an assay endpoint (usually an estimated ED50 value) based on a very limited number of test material concentrations.21 This type of evaluation has limits because it only provides a small part of all the information available from a full dose-response curve. If a well-defined dose-response curve is generated during the assay procedure, the ED50 concentration can be determined with precision, and other useful data such as the shape and slope of the dose-response curve can be obtained. These data, although not widely used by developers of in vitro alternatives, may provide a wealth of additional information on test substance characteristics that may be useful for making a safety assessment with the in vitro test. For example, dose-response curve slope data may be useful in grouping materials according to common modes of action for further evaluation. Also, the additional data may be useful for pointing the way to further experiments that will help elucidate the mechanism(s) by which the test materials irritate and injure target tissues.
General Surgery
Published in Tjun Tang, Elizabeth O'Riordan, Stewart Walsh, Cracking the Intercollegiate General Surgery FRCS Viva, 2020
Rebecca Fish, Aisling Hogan, Aoife Lowery, Frank McDermott, Chelliah R Selvasekar, Choon Sheong Seow, Vishal G Shelat, Paul Sutton, Yew-Wei Tan, Thomas Tsang
How is chemotherapy delivered?Combination: Use different classes for broader coverage of activity and reduce risk of resistant subclonesFor example, in the FEC regime, all have single-agent activity against breast cancer, but when combined the response rate is two to three times higher.High dose Give on steeper part of sigmoid dose–response curve.
Hormesis
Published in T. D. Luckey, Radiation Hormesis, 2020
What is the significance of radiation hormesis? The biopositive nature of low doses of ionizing radiation virtually eliminates the concept that all radiation is harmful.527,530 It may be argued that stimulation is the earliest indication of the presence of minute doses of a harmful agent. A stimulant, even in low doses, is not necessarily beneficial. Nor is it generally considered to be useful to apply stimulants on a chronic basis. A few, such as caffeine or nicotine, are tolerated. Perhaps the data of radiation hormesis are only part of a bigger picture. Several questions arise. What is the shape of the complete dose-response curve? What is the optimal dose? Could ionizing radiation be essential for life? If it were, a deficiency should develop when the daily dose was significantly lowered. Conversely, if no deficiency developed when background exposure was significantly lowered, whole-body exposure to low doses of ionizing radiation could be considered to be an innocuous stimulant. Might it be a useful agent for providing optimum health? These questions indicate the real significance of radiation hormesis.
Assessing the impact of different neutron RBEs on the all solid cancer radiation risks obtained from the Japanese A-bomb survivors data
Published in International Journal of Radiation Biology, 2023
Luana Hafner, Linda Walsh, Werner Rühm
It is noted that typically results from the LSS are based on a value of the neutron RBE of 10. The curvature parameter gives evidence on the shape of the dose response curve: the closer the parameter to zero the closer to linearity is the curve. In the present study the shape of the dose response curve as a function of neutron RBE is analyzed using an LSS dataset with a longer follow-up period (1958–1998) than Little and Muirhead (2004) did, based on the DS02 system (Young and Kerr 2005). The LSS dataset with the follow-up period from 1958 to 1998 (Preston et al. 2007) is chosen in this study, because of the availability of the separate neutron and gamma absorbed doses. In the most recent published dataset Grant et al. (2017) with a follow-up until 2009, only the total weighted colon dose including the RBE = 10 weighted neutron dose is considered and no information on separate neutron and gamma absorbed doses are published. Furthermore, the LSS publicly available grouped dataset from Grant et al. (2017) and Preston et al. (2007) cannot be merged, because no unique identification number nor a unique set of matching variables is provided in the datasets, due to their grouped nature.
Regenerative responses of rabbit corneal endothelial cells to stimulation by fibroblast growth factor 1 (FGF1) derivatives, TTHX1001 and TTHX1114
Published in Growth Factors, 2021
Jessica Weant, David D. Eveleth, Amuthakannan Subramaniam, Jennifer Jenkins-Eveleth, Michael Blaber, Ling Li, David M. Ornitz, Asaf Alimardanov, Trevor Broadt, Hui Dong, Vinay Vyas, Xiaoyi Yang, Ralph A. Bradshaw
Treatment with TTHX1114 also improved clearing of corneal opacity from involvement of the entire thickness of the stroma (3+) following injury to some loss of transparency with only the epithelium and/or involvement of the anterior half of the stroma (1+) by Day 14 (Figure 6). In contrast, corneal clearing in contralateral control eyes that received only vehicle progressed to some loss of transparency with cloudiness that extended past the anterior half of the stroma (2+) by Day 14. There was significant acceleration of improvement in opacity compared to contralateral vehicle control eyes at Day 5 for the 1,000 ng/eye and 5,000 ng/eye doses of TTHX1114 and at Day 7 and 14 for all doses. There was no clear differentiation of doses between 100 and 5,000 ng/eye, suggesting that all doses are at the top of the dose response curve. Both TTHX1001 and TTHX1114 were equally effective in the corneal clearing effects.
An overview of current practices for regulatory risk assessment with lessons learnt from cosmetics in the European Union
Published in Critical Reviews in Toxicology, 2021
Emma Arnesdotter, Vera Rogiers, Tamara Vanhaecke, Mathieu Vinken
Hazard characterisation is the second stage in the hazard assessment and is defined as “the qualitative and, wherever possible, quantitative description of the inherent properties of an agent or situation having the potential to cause adverse effects” (WHO/IPCS 2009a). Hazard characterisation should include a dose–response assessment and its associated uncertainties (WHO/IPCS 2009a). The relationship between the dose and the associated adverse health effects is often represented as a dose–response curve. In human health toxicology, the point of departure (POD) is used as a reference point and is defined as the highest external dose on a dose–response curve devoid of adverse health effects, i.e. the NOAEL. The POD is usually derived from (sub)chronic animal studies in the most sensitive and relevant species, typically rodent, rabbit or dog, and based on the critical effect. There are two main approaches used for determination of the POD, namely the NOAEL approach and the bench-mark dose (BMD) approach (Figure 4(A,B)). The strengths and weaknesses of both methods have been discussed in several publications (Travis et al. 2005; Sand et al. 2008; Davis et al. 2011; Haber et al. 2018).