Conceptual Challenges in the Translation of Toxicological Research into Practice: Low-Dose Hypothesis and Dose-Response Non-monotonicity

Ecotoxicology ◽  
2018 ◽  
pp. 185-212
Author(s):  
Francisco Jose Roma Paumgartten ◽  
Ana Cecilia Amado Xavier De-Oliveira
Keyword(s):  
Dose Response ◽  
Low Dose ◽  
Toxicological Research

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 Effects of exposure to low-dose ionizing radiation on changing platelets: a prospective cohort study

2021 ◽  
Vol 26 (1) ◽  
Author(s):  
Ning Liu ◽  
Yang Peng ◽  
Xinguang Zhong ◽  
Zheng Ma ◽  
Suiping He ◽  
...  
Keyword(s):  
Radiation Dose ◽  
Ionizing Radiation ◽  
Dose Response ◽  
Low Dose ◽  
Linear Trend ◽  
Hematological Parameters ◽  
Response Relationship ◽  
Dose Response Relationship ◽  
Spline Models ◽  
Cumulative Radiation Dose

Abstract Background Numerous studies have concentrated on high-dose radiation exposed accidentally or through therapy, and few involve low-dose occupational exposure, to investigate the correlation between low-dose ionizing radiation and changing hematological parameters among medical workers. Methods Using a prospective cohort study design, we collected health examination reports and personal dose monitoring data from medical workers and used Poisson regression and restricted cubic spline models to assess the correlation between changing hematological parameters and cumulative radiation dose and determine the dose-response relationship. Results We observed that changing platelet of 1265 medical workers followed up was statistically different among the cumulative dose groups (P = 0.010). Although the linear trend tested was not statistically significant (Ptrend = 0.258), the non-linear trend tested was statistically significant (Pnon-linear = 0.007). Overall, there was a correlation between changing platelets and cumulative radiation dose (a change of βa 0.008 × 109/L during biennially after adjusting for gender, age at baseline, service at baseline, occupation, medical level, and smoking habits; 95% confidence interval [CI] = 0.003,0.014 × 109/L). Moreover, we also found positive first and then negative dose-response relationships between cumulative radiation dose and changing platelets by restricted cubic spline models, while there were negative patterns of the baseline service not less than 10 years (− 0.015 × 109/L, 95% CI = − 0.024, − 0.007 × 109/L) and radiation nurses(− 0.033 × 109/L, 95% CI = − 0.049, − 0.016 × 109/L). Conclusion We concluded that although the exposure dose was below the limit, medical workers exposed to low-dose ionizing radiation for a short period of time might have increased first and then decreased platelets, and there was a dose-response relationship between the cumulative radiation dose and platelets changing.

Defining hormesis: the necessary tool to clarify experimentally the low dose–response relationship

2002 ◽  
Vol 21 (2) ◽  
pp. 103-104 ◽  
Author(s):  
G Carelli ◽  
I Iavicoli
Keyword(s):  
Dose Response ◽  
Low Dose ◽  
Experimental Models ◽  
Assessment Criteria ◽  
Response Relationship ◽  
Dose Response Relationship ◽  
Specific Context ◽  
Definition Of ◽  
Time Specific ◽  
Made In

The authors comment on Calabrese and Baldwin's paper ‘Defining Hormesis’, which, to date, is the first attempt to provide a definition of hormesis that goes beyond the different interpretations of this phenomenon reported in the literature. While appreciating the effort made in this study to place hormesis in a general and at the same time specific context, the authors believe some clarifications are needed as regards the quantitative features of this phenomenon. In this connection, they speculate on whether Calabrese and Baldwin think it appropriate to include hormesis assessment criteria in the document, referring in particular to those reported in a previous paper. The authors share Calabrese and Baldwin's conclusion that future experimental models designed to study hormetic phenomena must necessarily include the time factor, which not only guarantees this phenomenon will be detected, but is also able to detect the specific type of hormesis.

The Dose Response of Chromosome Aberrations in Human Lymphocytes InducedIn Vitroby Very Low-Dose γ Rays

2011 ◽  
Vol 175 (2) ◽  
pp. 208-213 ◽  
Author(s):  
Toshiyasu Iwasaki ◽  
Yoshio Takashima ◽  
Toshikazu Suzuki ◽  
Mitsuaki A. Yoshida ◽  
Isamu Hayata
Keyword(s):  
Dose Response ◽  
Chromosome Aberrations ◽  
Low Dose ◽  
Human Lymphocytes ◽  
Γ Rays

scholarly journals T1000: A reduced toxicogenomics gene set for improved decision making

2019 ◽  
Author(s):  
Othman Soufan ◽  
Jessica Ewald ◽  
Charles Viau ◽  
Doug Crump ◽  
Markus Hecker ◽  
...  
Keyword(s):  
Dose Response ◽  
Gene Clusters ◽  
Gene Set ◽  
Chemical Hazards ◽  
Gene Sets ◽  
Toxicological Research ◽  
Multiple Species ◽  
Response Modeling

There is growing interest within regulatory agencies and toxicological research communities to develop, test, and apply new approaches, such as toxicogenomics, to more efficiently evaluate chemical hazards. Given the complexity of analyzing thousands of genes simultaneously, there is a need to identify reduced gene sets.Though several gene sets have been defined for toxicological applications, few of these were purposefully derived using toxicogenomics data. Here, we developed and applied a systematic approach to identify 1000 genes (called Toxicogenomics-1000 or T1000) highly responsive to chemical exposures. First, a co-expression network of 11,210genes was built by leveraging microarray data from the Open TG-GATEs program. This network was then re-weighted based on prior knowledge of their biological (KEGG, MSigDB) and toxicological (CTD) relevance. Finally, weighted correlation network analysis was applied to identify 258 gene clusters. T1000 was defined by selecting genes from each cluster that were most associated with outcome measures. For model evaluation, we compared the performance of T1000 to that of other gene sets (L1000, S1500, Genes selected by Limma, and random set) using two external datasets. Additionally, a smaller (T384) and a larger version (T1500) of T1000 were used for dose-response modeling to test the effect of gene set size. Our findings demonstrated that the T1000 gene set is predictive of apical outcomes across a range of conditions (e.g.,in vitroand in vivo, dose-response, multiple species, tissues, and chemicals), and generally performs as well, or better than other gene sets available.

scholarly journals Syngeneic and allogeneic bone marrow engraftment after total body irradiation: dependence on dose, dose rate, and fractionation

Blood ◽  
1991 ◽  
Vol 77 (3) ◽  
pp. 661-669 ◽  
Author(s):  
JD Down ◽  
NJ Tarbell ◽  
HD Thames ◽  
PM Mauch
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Radiation Dose ◽  
Dose Rate ◽  
Dose Response ◽  
Total Body Irradiation ◽  
Low Dose ◽  
Allogeneic Bone ◽  
Low Dose Rate ◽  
Total Body

Abstract Murine bone marrow chimera models were used to assess the efficacy of host total body irradiation (TBI) given at different doses, dose rates, and fractionation schemes in providing for engraftment of syngeneic and allogeneic bone marrow. B6-Hbbd congenic and LP mice, respectively, were used as donors (10(7) bone marrow cells) for syngeneic and allogenic (H-2 compatible) transplantation in standard B6 recipients. Stable marrow chimerism was determined from host and donor stem cell- derived hemoglobin phenotypes (Hbbs and Hbbd) on gel electrophoresis at 3 months posttransplant. Partial engraftment of syngeneic marrow was seen at single doses as low as 2 Gy, with the donor component increasing steadily with increasing TBI dose to a level of 100% at 7 Gy. Immunologic resistance of the host appeared to prevent allogeneic engraftment until 5.5 Gy. A very steep radiation dose response was then observed so that the level of chimerism with 6 Gy and above became comparable with syngeneic engraftment. Low dose rate (5 cGy minute-1) and fractionated TBI required higher total doses for equivalent engraftment (radiation dose-sparing) in both syngeneic and allogenic bone marrow transplantation. This displacement in the dose-response curve on fractionation was seen with interfraction intervals of 3 and 6 hours. A further dose-sparing effect was observed on extending the interval to 18 and 24 hours, but only for allogeneic transplantation, and may therefore be related to recovery of immune-mediated graft resistance. The involvement of multiple target cell populations in determining allogenic engraftment rendered the application of the linear-quadratic model for radiation cell survival problematic in this case. The recovery in dose when low dose rate and 6-hour interfraction intervals were applied in either syngeneic or allogeneic BMT is consistent with appreciable sub-lethal damage repair in the primitive self-renewing stem cell population of the host marrow. These results contrast with the poor repair capacity of the 11-day spleen colony- forming units (CFUs) population after fractionated irradiation and support the notion that ablation of early stem cells in the pre-CFUs compartment is essential for long-term marrow engraftment.

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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