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Radiobiological Evaluation and Optimisation of Treatment Plans
Published in W. P. M. Mayles, A. E. Nahum, J.-C. Rosenwald, Handbook of Radiotherapy Physics, 2021
The three parameters of this model are: TD50(Vtot), the dose to the whole organ, which would lead to complication in 50% of the population (note that TD50(V/Vtot) is to be read as the TD50 value at partial volume V/Vtot);m, the parameter representing the steepness of the dose–response curve;n, the volume exponent in the power law, which relates the tolerance doses for uniform whole- and uniform partial-organ irradiation.
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.
Mouse to Man: Extrapolation from Animals
Published in Samuel C. Morris, Cancer Risk Assessment, 2020
This model is capable of reflecting both linear and nonlinear dose-response relations. It is thus more flexible in shape than either the 1-hit or the probit models and estimates of “safe” doses may range widely, depending on the experimental data. Its confidence limits should include some factors previously expressible only qualitatively as “model-dependent” uncertainties rather than quantitatively as uncertainty in the numerical value of model parameters (Guess and Crump, 1977). Whittemore (1979) notes, however, that using this model in a mode to produce “safe” doses guarantees nonthreshold linearity at low dose rates, making the procedure so insensitive to response at experimental dosages that it is unable to distinguish between low levels of potent carcinogens and noncar-cinogenic substances.
Enhancing global and local decision making for chemical safety assessments through increasing the availability of data
Published in Toxicology Mechanisms and Methods, 2023
Adrian Fowkes, Robert Foster, Steven Kane, Andrew Thresher, Anne-Laure Werner, Antonio Anax F. de Oliveira
One key component of the CPDB is the presence of TD50 values, derived from the tumor incidence dose-response data, to represent the dose at which the probability of a test subject remaining tumor-free after a lifetime exposure to the test compound is halved. These values have been used extensively in safety assessments and can be considered as a measure of relative carcinogenic potency (Munro et al. 1996; Cheeseman et al. 1999; Boobis et al. 2017; Bercu et al. 2018). Upon reviewing the supporting data and original methodology to generate TD50 values (Peto et al. 1984) it was uncovered that not all the values were reproducible. To increase the confidence in the data and support transparency, a model was created and published to generate Lhasa TD50 values (Thresher et al. 2019), which could be stored in the LCDB alongside the original TD50 values for completeness. A high correlation was observed between the two sets of TD50 values (Figure 3). The fact that both models produce similar results provides confidence in the original calculations and that the database can progress using the new transparent and reproducible approach . The efforts in developing the LCDB have ensured sustainability of the CPDB data, but also provided additional information to increase the confidence in decisions based on its data. To further evolve the resource, research can examine how new data can be incorporated to expand coverage of new chemicals and uncover how to increase confidence each study result given the variations in protocols.
Approaches for the setting of occupational exposure limits (OELs) for carcinogens
Published in Critical Reviews in Toxicology, 2023
A MoA taxonomy for carcinogenic effects of chemical exposures summarises so far categorised critical toxicological mechanisms that may lead to or facilitate cancer development (Korhonen et al. 2012). In the taxonomy (Figure 3), the division between genotoxic carcinogens and non-genotoxic/indirect acting genotoxic carcinogens is fundamental. This is of crucial importance for assessing whether a threshold or a non-threshold approach should be applied in dose–response modelling. As also seen in Figure 3, there are many non-genotoxic/indirect genotoxic MoAs. As indicated above (Section 3.2.1), hallmark characteristics may be introduced by other mechanisms than mutations, and mutations are found in non-cancer tissue. Thus, chemical agents with non-genotoxic/indirect genotoxic MoAs may cause cancer even though they are not initiators, as was shown in studies using initiation-promotion protocols. However, these studies indicate that for most carcinogenic effects of chemicals acting via non-genotoxic/indirect genotoxic MoAs, relatively high and repetitive doses are needed and that a threshold dose must be exceeded for cancer to develop.
Tebentafusp for the treatment of HLA-A*02:01–positive adult patients with unresectable or metastatic uveal melanoma
Published in Expert Review of Anticancer Therapy, 2022
Lanyi Nora Chen, Richard D. Carvajal
Given the dose–response relationship and dose-limiting hypotension/CRS seen early on in the treatment course in the first-in-man trial, a second phase I trial (Table 1) was conducted in an effort to increase the maximum tolerated dose by using a three-week step-up dosing regimen [44]. Nineteen HLA-A*0201 positive patients with advanced uveal melanoma were included in the initial-dose expansion cohort. These patients were heavily pretreated and had a median of 4 lines of prior therapy [44,50]. Each patient received 20 mcg of tebentafusp on C1D1, 30 mcg on C1D8, then an escalated dose on C1D15 and thereafter (ranging from 54 mcg to 73 mcg). Each cycle consisted of 4 weeks. Dose-limiting transaminase elevation was observed in 2 of 4 patients treated at the 73 mcg dose, which was deemed not tolerable [44]. The observed transaminase elevations resolved within 1 week without requiring steroids, and all patients were able to tolerate restarting the drug at a reduced dose. None of the six patients treated with 68 mcg experienced a dose-limiting toxicity, so 68 mcg was established as the recommended phase II dose [44]. Notably, the step-up dosing regimen permitted a 36% increase in dose compared with what was tolerable using a flat dosing regimen. Twenty-three patients were included in the subsequent expansion cohort and were treated with 68 mcg on C1D15 and thereafter.