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Hazard Characterization and Dose–Response Assessment
Published in Ted W. Simon, Environmental Risk Assessment, 2019
The POD can be a NOAEL, a LOAEL, or a BMDL, as defined in Boxes 5.1 and 5.2. It is important to ensure the LOAEL or BMDL are based on truly adverse effects. Generally, the LOAEL will be the lowest exposure at which adverse events occur that are both statistically different in severity or frequency than background and biologically significant.
Risk Assessment in Practice and Setting Exposure Limits
Published in David Woolley, Adam Woolley, Practical Toxicology, 2017
In some studies, where there is a progressive dose–response curve for an adverse effect, there may be no NOEL. In this case, it may be necessary to use the LOAEL or the BMD. The LOAEL is the lowest dose at which adverse effects were seen and does not refer to a dose at which a defined percent response is seen–either in terms of numbers of animals affected or in extent of response relative to controls.
Overview of Approach to Noncancer Risk Assessment
Published in John C. Lipscomb, Edward V. Ohanian, Toxicokinetics and Risk Assessment, 2016
Other organizations use generally similar approaches, although they may differ in some details. For example, Health Canada includes factors to account for intraspecies variation and interspecies variation, and a combined factor of 1–100 to account for inadequacies of the database (15). These inadequacies may include lack of adequate data on developmental, chronic, or reproductive toxicity, use of a LOAEL versus a NOAEL, and inadequacies of the critical study. Other considerations and possible adjustments might be made for essential substances; severe irreversible effects; or interaction with other chemical substances commonly present in the general environment. As summarized by the International Programme on Chemical Safety (IPCS) (16), the World Health Organization (WHO) and other organizations also use an additional factor in cases where the NOAEL is derived from a severe irreversible effect, such as teratogenicity or non-genotoxic carcinogenicity.
New quinoline and isatin derivatives as apoptotic VEGFR-2 inhibitors: design, synthesis, anti-proliferative activity, docking, ADMET, toxicity, and MD simulation studies
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Eslam B. Elkaeed, Mohammed S. Taghour, Hazem A. Mahdy, Wagdy M. Eldehna, Nehal M. El-Deeb, Ahmed M. Kenawy, Bshra A. Alsfouk, Mohammed A. Dahab, Ahmed M. Metwaly, Ibrahim H. Eissa, Mohamed A. El-Zahabi
Starting with the Ames prediction model, all candidates were predicted to be non-mutagen. The carcinogenic potency TD50 in mice of the synthesised compounds ranged from 37.833 to 97.051 g/kg, which was safer than sorafenib (17.535 g/kg). The rat maximum tolerated doses (R-MTD) of these candidates were less than that of sorafenib (0.077 g/kg) with the range of 0.018 − 0.048 g/kg. Candidates 13 and 14 showed higher rat oral LD50 values of 1.404 and 1.21 g/kg, respectively than sorafenib (0.890 g/kg) while the other members showed lower oral LD50 values were in the range of 0.509–0.838 g/kg. For the rat chronic LOAEL model, except compound 8, the tested compounds showed LOAEL values in the range of 0.005–0.040 g/kg. These were safer than sorafenib (0.004 g/kg). All candidates were computed to be non-irritant and mildly irritant against the skin and the eyes, respictivly (Table 7).
Benchmark dose (BMD) modeling: current practice, issues, and challenges
Published in Critical Reviews in Toxicology, 2018
Lynne T. Haber, Michael L. Dourson, Bruce C. Allen, Richard C. Hertzberg, Ann Parker, Melissa J. Vincent, Andrew Maier, Alan R. Boobis
This case study illustrates the use of different definitions of adversity and associated differences in the critical effect, in the development of safe doses. This issue is a common one in toxicological risk assessment, regardless of whether safe doses are based on the NOAEL/LOAEL approach or on BMD modeling. Indeed, determining whether the effects seen at a specific dose are adverse is one of the more challenging aspects of toxicological risk assessment and, in our experience, one of the prime sources of controversy in the development of risk values. The perchlorate case study illustrates that, even though BMD modeling is fundamentally a mathematical curve-fitting exercise, biological considerations and biological interpretation still play a crucial role in the identification of the appropriate endpoint(s) to model and the choice of the BMR; differences in the biological interpretation can thus have a substantial impact on the final result.
Determination and application of the permitted daily exposure (PDE) for topical ocular drugs in multipurpose manufacturing facilities
Published in Pharmaceutical Development and Technology, 2018
Ester Lovsin Barle, Jean-Claude Bizec, Milica Glogovac, Kamila Gromek, Gian Christian Winkler
This scenario results in much less uncertainty for PDE calculation than the other two scenarios, because both drugs have known safety profiles, posology and the same route of administration. Human data are the most reliable for any PDE calculation. Therefore, the minimal topical ocular therapeutic dose (MinDD) or the lowest pharmacologically effective dose (expressed in mg/eye/day) should be used as a PoD. This dose is considered as a LOAEL or NOAEL, depending on the significance of effects observed (Bercu et al. 2016). Critical adverse effects must be recognized and included into considerations. Key is the considerations of an identified adverse effect potential and its dose level for local or systemic effects of topically applied drugs. With the application of adequate AFs, the calculated PDEocular will provide sufficient protection from critical adverse effects in the eye (even when applied to both eyes), as well as from adverse systemic effects.