scholarly journals Toxic Responses Induced at High Doses May Affect Benchmark Doses

Dose-Response ◽  
2020 ◽  
Vol 18 (2) ◽  
pp. 155932582091960 ◽  
Author(s):  
Jürg A. Zarn ◽  
Ursina A. Zürcher ◽  
H. Christoph Geiser
Keyword(s):  
Dose Response ◽  
Low Dose ◽  
Dose Range ◽  
Reference Points ◽  
Benchmark Dose ◽  
High Dose ◽  
Low Doses ◽  
Confidence Bounds ◽  
Lower Confidence Bounds ◽  
Dose Responses

To derive reference points (RPs) for health-based guidance values, the benchmark dose (BMD) approach increasingly replaces the no-observed-adverse-effect level approach. In the BMD approach, the RP corresponds to the benchmark dose lower confidence bounds (BMDLs) of a mathematical dose–response model derived from responses of animals over the entire dose range applied. The use of the entire dose range is seen as an important advantage of the BMD approach. This assumes that responses over the entire dose range are relevant for modeling low-dose responses, the basis for the RP. However, if part of the high-dose response was unnoticed triggered by a mechanism of action (MOA) that does not work at low doses, the high-dose response distorts the modeling of low-dose responses. Hence, we investigated the effect of high-dose specific responses on BMDLs by assuming a low- and a high-dose MOA. The BMDLs resulting from modeling fictitious quantal data were scattered over a broad dose range overlapping with the toxic range. Hence, BMDLs are sensitive to high-dose responses even though they might be irrelevant to low-dose response modeling. When applying the BMD approach, care should be taken that high-dose specific responses do not unduly affect the BMDL that derives from low doses.

scholarly journals Biphasic and triphasic dose responses in zebrafish embryos to low-dose 150 kV X-rays with different levels of hardness

2016 ◽  
Vol 57 (4) ◽  
pp. 363-369 ◽  
Author(s):  
Eva Yi Kong ◽  
Shuk Han Cheng ◽  
Kwan Ngok Yu
Keyword(s):  
Dose Response ◽  
Low Dose ◽  
High Dose ◽  
X Rays ◽  
Acridine Orange Staining ◽  
Living Organisms ◽  
Dose Responses ◽  
Different Levels ◽  
Danio Rerio Embryos

Abstract The in vivo low-dose responses of zebrafish ( Danio rerio ) embryos to 150 kV X-rays with different levels of hardness were examined through the number of apoptotic events revealed at 24 h post fertilization by vital dye acridine orange staining. Our results suggested that a triphasic dose response was likely a common phenomenon in living organisms irradiated by X-rays, which comprised an ultra-low-dose inhibition, low-dose stimulation and high-dose inhibition. Our results also suggested that the hormetic zone (or the stimulation zone) was shifted towards lower doses with application of filters. The non-detection of a triphasic dose response in previous experiments could likely be attributed to the use of hard X-rays, which shifted the hormetic zone into an unmonitored ultra-low-dose region. In such cases where the subhormetic zone was missed, a biphasic dose response would be reported instead.

Hormesis, resveratrol and plant-derived polyphenols: some comments

2011 ◽  
Vol 30 (12) ◽  
pp. 2027-2030 ◽  
Author(s):  
Salvatore Chirumbolo
Keyword(s):  
Risk Assessment ◽  
Dose Response ◽  
Adaptive Response ◽  
Low Dose ◽  
High Dose ◽  
Low Doses ◽  
General Behaviour

Hormesis is a dose–response phenomenon, usually present in plants and animals, characterized by a low-dose stimulation and high-dose inhibition, often resulting in typical U-shaped or J-shaped curves. Hormesis has become an interesting model for toxicology and risk assessment, as it has been described for several nature-derived phytochemicals but also because this adaptive response to stressors might hide an underlying more general behaviour of cell towards low doses.

Dose-response relationships in phase I trials: Are patients treated at lower doses at a disadvantage?

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2519-2519
Author(s):  
R. Jain ◽  
D. Hong ◽  
A. Naing ◽  
J. Wheler ◽  
J. J. Lee ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Response ◽  
Dose Group ◽  
Low Dose ◽  
Dose Range ◽  
Cancer Therapeutics ◽  
Biologic Agent ◽  
High Dose ◽  
Phase I Trials ◽  
Dose Patient

2519 Background: A major goal of phase I trials is to determine a drug's maximally tolerated dose (MTD). However, it has been argued that low-dose patient cohorts are at a disadvantage given the clear dose/response relationships seen with cytotoxics. Since an increasing number of targeted/biologic agents are entering the clinic, and the dose/response relationship of these drugs is less clear, we analyzed response versus benefit for patients on phase I trials. Methods: We evaluated 71 consecutive trials treating 1,420 patients with solid tumors or lymphoma from August 2004 to August 2008 in the Department of Investigational Cancer Therapeutics at M.D. Anderson for inclusion in our analysis. Twenty-four trials treating 687 patients met criteria (systemic therapy that has reached an MTD or a maximum test dose). 97.7% of these patients received a targeted/biologic drug. Patients were assigned to low (≤25%), medium (25–75%), or high dose (≥75%), where dose range = maxium - minimum dose for each study (for ≤ MTD analysis, max dose = MTD if it was achieved). Time on treatment (TOT), progression free survival (PFS), overall survival (OS), and response (complete response = CR, partial response = PR, stable disease = SD, progressive disease = PD) were assessed. Results: Of all comers (n = 683), the low-dose group stayed on treatment significantly longer than the high-dose group, primarily due to increased toxicity at higher doses. In ≤ MTD subgroup analysis (n = 588), there was also a trend for the low-dose group to stay on treatment longer (p = 0.06). PFS and OS were similar among groups. Favorable responses (CR/PR/SD) were as common for low dose as other dose groups. Conclusions: In a large cohort of pts treated on phase I studies that predominantly included one or more targeted/biologic agent, there was no downside to being on low versus medium or high doses. These data should alleviate concerns about relative lack of benefit for low-dose patient cohorts on phase I trials, and support the notion that dose/response relationships for targeted agents may be less clear than for cytotoxics. [Table: see text] No significant financial relationships to disclose.

scholarly journals Skin regeneration is accelerated by a lower dose of multipotent mesenchymal stromal/stem cells—a paradigm change

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Gertraud Eylert ◽  
Reinhard Dolp ◽  
Alexandra Parousis ◽  
Richard Cheng ◽  
Christopher Auger ◽  
...  
Keyword(s):  
Stem Cells ◽  
Wound Healing ◽  
Low Dose ◽  
Dose Range ◽  
High Dose ◽  
Full Thickness ◽  
Burn Wound ◽  
Dermal Regeneration Template ◽  
Yorkshire Pigs ◽  
Stromal Stem Cells

Abstract Background Multipotent mesenchymal stromal/stem cell (MSC) therapy is under investigation in promising (pre-)clinical trials for wound healing, which is crucial for survival; however, the optimal cell dosage remains unknown. The aim was to investigate the efficacy of different low-to-high MSC dosages incorporated in a biodegradable collagen-based dermal regeneration template (DRT) Integra®. Methods We conducted a porcine study (N = 8 Yorkshire pigs) and seeded between 200 and 2,000,000 cells/cm2 of umbilical cord mesenchymal stromal/stem cells on the DRT and grafted it onto full-thickness burn excised wounds. On day 28, comparisons were made between the different low-to-high cell dose groups, the acellular control, a burn wound, and healthy skin. Result We found that the low dose range between 200 and 40,000 cells/cm2 regenerates the full-thickness burn excised wounds most efficaciously, followed by the middle dose range of 200,000–400,000 cells/cm2 and a high dose of 2,000,000 cells/cm2. The low dose of 40,000 cells/cm2 accelerated reepithelialization, reduced scarring, regenerated epidermal thickness superiorly, enhanced neovascularization, reduced fibrosis, and reduced type 1 and type 2 macrophages compared to other cell dosages and the acellular control. Conclusion This regenerative cell therapy study using MSCs shows efficacy toward a low dose, which changes the paradigm that more cells lead to better wound healing outcome.

Hormesis is central to toxicology, pharmacology and risk assessment

2010 ◽  
Vol 29 (4) ◽  
pp. 249-261 ◽  
Author(s):  
Edward J Calabrese
Keyword(s):  
Risk Assessment ◽  
Dose Response ◽  
Low Dose ◽  
Assessment Practices ◽  
Biological Organization ◽  
Setting Process ◽  
Toxicological Research ◽  
Multiple Levels ◽  
Dose Responses ◽  
Chemical Class

This paper summarizes numerous conceptual and experimental advances over the past two decades in the study of hormesis. Hormesis is now generally accepted as a real and reproducible biological phenomenon, being highly generalized and independent of biological model, endpoint measured and chemical class/physical stressor. The quantitative features of the hormetic dose response are generally highly consistent, regardless of the model and mechanism, and represent a quantitative index of biological plasticity at multiple levels of biological organization. The hormetic dose-response model has been demonstrated to make far more accurate predictions of responses in low dose zones than either the threshold or linear at low dose models. Numerous therapeutic agents widely used by humans are based on the hormetic dose response and its low dose stimulatory characteristics. It is expected that as low dose responses come to dominate toxicological research that risk assessment practices will incorporate hormetic concepts in the standard setting process.

scholarly journals Ripk3 Signaling Regulates Hematopoietic Stem Cell Number and Function during Stress

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3714-3714
Author(s):  
Lei Zhang ◽  
Huacheng Luo ◽  
Jing Li ◽  
Hong-Min Ni ◽  
Mark Sellin ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Low Dose ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
High Dose ◽  
Low Doses ◽  
Hematopoietic Stem ◽  
Increased Risk ◽  
Leukemia Development ◽  
Serial Transplantation

Background: Among all tissues, bone marrow (BM) is the most sensitive tissue to ionizing radiation (IR)-induced acute tissue damage (ATD) and chronic long-term residual damage (LT-RD). BM failure and a significant reduction in blood cells (pancytopenia) often occurs within days after exposure to IR due to the massive death of proliferative hematopoietic progenitor cells (HPCs). However, due to their quiescent cell cycle status and reduced fidelity of DNA repair feature, many hematopoietic stem cells (HSCs) cannot fully eliminate such damage and enter senescence; this results in LT-RD. Abnormal dysplastic hematopoiesis is the most common LT-RD in most victims of IR, followed by an increased risk of leukemia/lymphoma development. Thus IR exposure is an established cause of BM failure and leukemia. A significant increase in the production of inflammatory cytokines is induced by IR which contributes to the pathogenesis of both ATD and LT-RD. Such inflammatory cytokines induce the activation of Ripk3-Mlkl-mediated necroptotic signaling in HSCs. However, the role of Ripk3-Mlkl signaling in IR-induced damage has not studied. Experimental procedures: The self-renewal capacity of HSCs among Ripk3-/-, Mlkl-/- and WT mice were examined and compared by serial transplantation assay. The phenotypes of ATD and LT-RD induced by different dosages of IR were compared among Ripk3-/-, Mlkl-/- and WT mice. The mechanism by which Ripk3 signaling prevents IR-induced leukemia development was studied. Results: Ripk3-Mlkl signaling is not required for hematopoiesis during homeostatic condition. However, during serial transplantation, inactivation of such signaling prevents stress-induced loss of HSCs. Interestingly, Ripk3 signaling also induces an Mlkl-independent ROS-p38-p16-mediated senescence in HSCs. Thus Ripk3-/- HSCs showed better competitive hematopoietic ability compared to Mlkl-/- and WT HSCs during serial transplantation. A sub-lethal dosage of IR (6Gy) induces Ripk3-dependent NF-κB activation and pro-survival gene expression in HSCs, which is necessary for the survival of damaged HSCs. After 6Gy IR, although DNA damage is repaired in most HSCs within 2 days, a proportion of HSCs in WT and Mlkl-/- mice fail to fully repair the damage and undergo p53-p21-dependent senescence. However such cells in Ripk3-/- mice die from apoptosis. Thus the remaining HSCs in Ripk3-/- mice should be functionally normal, while a proportion of the remaining HSCs in Mlkl-/- and WT mice remain damaged but senescent, all as demonstrated by competitive hematopoietic reconstitution assay. Multiple low-doses of IR (1.75Gy once week × 4) induce HSC exhaustion in WT mice but not in Ripk3-/- and Mlkl-/- mice. Interestingly, almost all Ripk3-/- mice develop acute lymphoblastic leukemia within 200 days after such low dose IR, while 45% of WT and 60% of Mlkl-/- mice develop thymomas within 360 days (see Figure). Mechanistically, such low-dose IR stimulates chronic inflammatory cytokine production. Such cytokines induce Ripk3-Mlkl-mediated necroptosis in response to HSC exhaustion observed in WT mice. These cytokines also induce Ripk3-ROS-p38-p16-mediated senescence in response to impaired HSC functioning observed in both WT and Mlkl-/- mice. In Ripk3-/- mice, due to the lack of both necroptotic and senescent signaling, mutant HSCs accumulate and leukemia development is accelerated. Conclusion: Ripk3 signaling plays distinct roles in HSCs in response to different doses of IR. High-dose IR induces Ripk3-dependent NF-κB/survival signaling, which is required for the survival of HSCs which fail to repair the damage. Thus temporal inhibition of Ripk3-NF-κB signaling might help to remove the damaged HSCs thus preventing the occurrence of LT-RD. However multiple low-doses of IR induces Ripk3 activation in HSCs which represses leukemia development by inducing both ROS-p38-p16-mediated senescence and Ripk3-Mlkl-mediated necroptosis. Induced activation of Mlkl-necroptosis might help to repress leukemia development by removing damaged HSCs. Disclosures No relevant conflicts of interest to declare.

Abstract 528: Dose- And Salt-dependency Of Angiogenesis Inhibition-induced Blood Pressure Rise And Renal Toxicity

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
Stephanie Lankhorst ◽  
Mariëtte H Kappers ◽  
Stefan Sleijfer ◽  
A H Danser ◽  
Anton H van den Meiracker
Keyword(s):  
Low Dose ◽  
Renal Toxicity ◽  
Pressure Rise ◽  
High Salt ◽  
High Dose ◽  
Low Doses ◽  
High Salt Diet ◽  
Salt Diet ◽  
Angiogenesis Inhibition ◽  
Cystatine C

Angiogenesis inhibition with the VEGF inhibitor sunitinib is an established anti-cancer therapy, inducing hypertension and nephrotoxicity. We explored the dose- and salt-dependency of these side effects. In male WKY rats, mean arterial pressure (MAP) was monitored telemetrically during oral treatment with a high (27.5 mg/kg.day, n=14), an intermediate (14 mg/kg.day, n=6) and low dose (7 mg/kg.day, n=6) of sunitinib or vehicle (n=8) after normal salt diet for 2 weeks. The low dose-model was also combined with a high salt diet (8% NaCl and saline water). Eight days after administration rats were sacrificed and blood and 24h urine samples collected for biochemical measurements. With the high dose of sunitinib, MAP increased from 94.7±0.9 mmHg to 125.8±1.5 mmHg (Δ31.1±0.9 mmHg, p<0.001). The intermediate and low doses induced MAP rises of 24.3±2.7 mmHg (p<0.001) and 13.4±3.3 mmHg (p<0.001), respectively. The low dose of sunitinib with high salt, induced a MAP rise of 43.5±2.2 mmHg (p<0.001 compared to normal salt). With the high dose, circulating ET-1 increased from 0.6±0.1 pg/ml to 1.6±0.2 pg/ml (p<0.01) and serum cystatine-C from 4.5±0.1 mg/L to 6.6±0.3 mg/L (p<0.001). Comparable increases in circulating ET-1 were seen with the intermediate and low doses, whereas serum cystatine-C did increase with the intermediate dose (to 6.3±0.1 mg/L, p0.05). Serum cystatine-C levels with low and high salt were identical. With the high dose of sunitinib, proteinuria increased from 7.5±1.3 to 33.3±4.8 mg/day (p<0.05). The rise in proteinuria was attenuated with the intermediate (16.2±2.1 mg/day, p<0.01) and low dose (19.9±3.3 mg/day, p<0.01), but increased to 40.4±30.1 mg/day (p>0.05) with high salt. Angiogenesis inhibition-induced hypertension and nephrotoxicity are dose-dependent with a lower threshold for the rise in BP than for renal toxicity. The BP rise observed with the low dose of sunitinib observed in normotensive rats is comparable to the sunitinib-induced BP rise observed in patients and clearly is salt-sensitive. Since cystatine-C levels during normal and high salt diet were comparable, the BP rise during high salt seems independent of renal dysfunction.

scholarly journals SUN-042 Low Dose Cyproterone Acetate for the Treatment of Transgender Women - a Retrospective Study

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Naomi Even-Zohar ◽  
Yael Sofer ◽  
Iris Yaish ◽  
Merav Serebro ◽  
Karen Tordjman ◽  
...  
Keyword(s):  
Cyproterone Acetate ◽  
Dose Group ◽  
Low Dose ◽  
Dose Range ◽  
Hormonal Treatment ◽  
Transgender Women ◽  
High Dose ◽  
Historical Cohort ◽  
Treatment Groups ◽  
First Time

Abstract Introduction : Transgender women with intact gonads receive lifelong hormonal treatment in order to suppress physiologic androgen production. Cyproterone acetate (CA) is the most comon antiandrogenic drug prescribed for this indication in Europe, with a dose range between 25-100 mg/day. Aim: To assess the effectiveness and safety of low dose (&lt;20 mg/day), compared with high dose (&gt;50 mg/day) CA treatment. Methods: Historical cohort study of transgender women treated in our department between January 2000 and October 2018. Results: There were 42 transgender women in the low dose group (LDG) and 32 in the high dose group (HDG). Age (27.9 ± 1.6 vs.28.9 ± 1.7 years) and follow up time (16.2 ± 2.2 vs. 20.1 ± 2.1 months) were similar in the LDG and HDG, respectively. At the last available visit, testosterone levels were effectively and similarly suppressed in both treatment groups (0.6 ± 0.1 vs 0.8 ± 0.3 nmol/l; p=0.37, for LDG and HDG respectively). Prolactin (659 ± 64 vs 486 ± 42 mIU/ml, p=0.02), LDL cholesterol (96.1 ± 5 vs 78.5 ± 4 mg/dl, p= 0.02) and triglycerides (93.3 ± 9 vs 69 ± 5 mg/dl; p=0.02) were higher in the HDG compared with LDG respectively. Side effects were common in the HDG (four cases of increased liver enzymes, one case of pulmonary embolism and one case of sudden death). Conclusion: We show for the first time that anti-androgenic treatment of transgender women with low dose CA is as effective as high dose treatment, but safer. We suggest incorporation of this observation in future guidelines.

Evidence for dose and dose rate effects in human and animal radiation studies

2018 ◽  
Vol 47 (3-4) ◽  
pp. 97-112 ◽  
Author(s):  
M.P. Little
Keyword(s):  
Dose Rate ◽  
Dose Response ◽  
Low Dose ◽  
Atomic Bomb ◽  
Dose Range ◽  
Quadratic Model ◽  
Linear Quadratic ◽  
Dose Rates ◽  
Atomic Bomb Survivors ◽  
Linear Quadratic Model

For stochastic effects such as cancer, linear-quadratic models of dose are often used to extrapolate from the experience of the Japanese atomic bomb survivors to estimate risks from low doses and low dose rates. The low dose extrapolation factor (LDEF), which consists of the ratio of the low dose slope (as derived via fitting a linear-quadratic model) to the slope of the straight line fitted to a specific dose range, is used to derive the degree of overestimation (if LDEF > 1) or underestimation (if LDEF < 1) of low dose risk by linear extrapolation from effects at higher doses. Likewise, a dose rate extrapolation factor (DREF) can be defined, consisting of the ratio of the low dose slopes at high and low dose rates. This paper reviews a variety of human and animal data for cancer and non-cancer endpoints to assess evidence for curvature in the dose response (i.e. LDEF) and modifications of the dose response by dose rate (i.e. DREF). The JANUS mouse data imply that LDEF is approximately 0.2–0.8 and DREF is approximately 1.2–2.3 for many tumours following gamma exposure, with corresponding figures of approximately 0.1–0.9 and 0.0–0.2 following neutron exposure. This paper also cursorily reviews human data which allow direct estimates of low dose and low dose rate risk.

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