The regulation of neurotoxicants has usually been based upon setting reference doses by dividing a no observed adverse effect level (NOAEL) by uncertainty factors that theoretically account for interspecies and intraspecies extraploation of experimental results in animals to humans. Recently, we have proposed a four-step alternative procedure which provides quantitative estimates of risk as a function of dose. The first step is to establish a mathematical relationship between a biological effect or biomarker and the dose of chemical administered. The second step is to determine the distribution (variability) of individual measurements of biological effects or their biomarkers about the dose response curve. The third step is to define an adverse or abnormal level of a biological effect or biomarker in an untreated population. The fourth and final step is to combine the information from the first three steps to estimate the risk (proportion of individuals exceeding on adverse or abnormal level of a biological effect or biomarker) as a function of dose. The primary purpose of this report is to enhance the certainty of the first step of this procedure by improving our understanding of the relationship between a biomarker and dose of administered chemical. Several factors which need to be considered include: 1) the pharmacokinetics of the parent chemical, 2) the target tissue concentrations of the parent chemical or its bioactivated proximate toxicant, 3) the uptake kinetics of the parent chemical or metabolite into the target cell(s) and/or membrane interactions, and 4) the interaction of the chemical or metabolite with presumed receptor site(s). Because these theoretical factors each contain a saturable step due to definitive amounts of required enzyme, reuptake or receptor site(s), a nonlinear, saturable dose-response curve would be predicted. In order to exemplify this process, effects of the neurotoxicant, methlenedioxymethamphetamine (MDMA), were reviewed and analyzed. Our results and those of others indicate that: 1) peak concentrations of MDMA and metabolites are ochieved in rat brain by 30 min and are negligible by 24 hr, 2) a metabolite of MDMA is probably responsible for its neurotoxic effects, and 3) pretreatment with monoamine uptake blockers prevents MDMA neurotoxicity. When data generated from rats administerde MDMA were plotted as bilolgical effect (decreases in hippocampal serotonin concentrations) versus dose, a saturation curve best described the observed relationship. These results support the hypothesis that at least one saturable step is involved in MDMA neurotoxicity. We conclude that the mathematical relationship between biological effect and dose of MDMA, the first step of our quantitative neurotoxicity risk assessment procedure, should reflect this biological model information generated from the whole of the dose-response curve.
Lee, Yong Jin;Hong, Min Jeong;Kim, Dae Yeon;Lee, Tong Geon;Kim, Dong Sub;Kim, Jin Baek;Lee, Byung Cheol;Han, Young Hwan;Seo, Yong Weon
Korean Journal of Breeding Science
/
v.40
no.1
/
pp.15-21
/
2008
It was previously pointed out that mutation is the ultimate source of variation. Adequate variation is needed for plant breeding if there is a limitation in natural genetic resources. When the ionizing radiation has been known to cause chromosomal and genomic alternations, it is widely used for inducing mutagenesis. The electron beam as an ionizing radiation is the principal physical mutagens that induces mutation and effectively used in plant breeding. Since dose-response relationships of electron beam in plant species are rarely known, we investigated the seed germination rate and early seedling growth of irradiated seeds of creeping bentgrass (Agrostis palustris Huds., cv Penn-A1) with various electron beam irradiating conditions (1, 1.3, 2 MeV at both 0.03 mA and 0.06 mA with dose of 100 Gy (Gray) and 0.03, 1, 1.3, 2 MeV at 0.03 mA with dose of 200 Gy, respectively) using electron accelerator at Korea Atomic Energy Research Institute. The growth parameters in terms of shoot length, primary root length, and secondary root length showed similar response between 0.06 / 1 (mA / MeV) at 100 Gy and 0.03 / 0.3 (mA / MeV) at 200 Gy. Bentgrass seed germination was mainly affected by the intensity of irradiated dose (Gray). Germination rate was lowered as the irradiated dose increased. On the other hand, early seedling growth was mainly governed not by the dose of radiation but by voltage.
Bangho Shin;Yumi Lee;Ji Won Choi;Soo Min Lee;Hyun Joon Choi;Yeon Soo Yeom
Nuclear Engineering and Technology
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v.55
no.6
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pp.1949-1958
/
2023
The International Commission on Radiological Protection (ICRP) Publication 116 was released to provide a comprehensive dataset of the dose coefficients (DCs) for external exposures produced with the adult reference voxel phantoms of ICRP Publication 110. Although an advanced skeletal dosimetry method for photons and neutrons using fluence-to-dose response functions (DRFs) was introduced in ICRP Publication 116, the ICRP-116 skeletal DCs were calculated by using the simple method conventionally used (i.e., doses to red bone marrow and endosteum approximated by doses to spongiosa and/or medullary cavities). In the present study, the photon and neutron DRFs were used to produce skeletal DCs of the ICRP-110 reference phantoms, which were then compared with the ICRP-116 DCs. For photons, there were significant differences by up to ~2.8 times especially at energies <0.3 MeV. For neutrons, the differences were generally small over the entire energy region (mostly <20%). The general impact of the DRF-based skeletal DCs on the effective dose calculations was negligibly small, supporting the validity of the ICRP-116 effective DCs despite their skeletal DCs derived from the simple method. Meanwhile, we believe that the DRF-based skeletal DCs could be beneficial in better estimates of skeletal doses of individuals for risk assessments.
Purpose : The purpose of this study is to investigate fundamental aspects of the dose response of fluorescent screen-based electronic portal imaging devices (EPIDS). Materials and Methods : We acquired scanned signal across portal planes as we varied the radiation that entered the EPID by changing the thickness and anatomy of the phantom as well as the air gap between the phantom and the EPID. In addition, we simulated the relative contribution of the scintillation light signal in the EPID system. Results : We have shown that the dose profile across portal planes is a function of the air gap and phantom thickness. We have also found that depending on the density change within the phantom geometry, errors associated with dose response based on the EPID scan can be as high as $7\%$. We also found that scintillation light scattering within the EPID system is an important source of error. Conclusion : This study revealed and demonstrated fundamental characteristics of dose response of EPID, as relative to that of ion chambers. This study showed that EPID based on fluorescent screen cannot be an accurate dosimetry system.
Jun Hyeok Kim;Sun Hong Yoon;Gil Yong Cha;Jin Hyoung Bai
Journal of Radiation Industry
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v.17
no.3
/
pp.265-273
/
2023
To effectively and safely manage the radiation exposure to nuclear power plant (NPP) workers in accidents, major overseas NPP operators such as the United States, Germany, and France have developed and applied realistic 3D model radiation dose assessment software for workers. Continuous research and development have recently been conducted, such as performing NPP accident management using 3D-VR based on As Low As Reasonably Achievable (ALARA) planning tool. In line with this global trend, it is also required to secure technology to manage radiation exposure of workers in Korea efficiently. Therefore, in this paper, it is described the application method and assessment results of radiation exposure scenarios for workers in response to accidents assessment technology, which is one of the fundamental technologies for constructing a realistic platform to be utilized for radiation exposure prediction, diagnosis, management, and training simulations following accidents. First, the post-accident sampling after the Loss of Coolant Accident(LOCA) was selected as the accident and response scenario, and the assessment area related to this work was established. Subsequently, the structures within the assessment area were modeled using MCNP, and the radiation source of the equipment was inputted. Based on this, the radiation dose distribution in the assessment area was assessed. Afterward, considering the three principles of external radiation protection (time, distance, and shielding) detailed work scenarios were developed by varying the number of workers, the presence or absence of a shield, and the location of the shield. The radiation exposure doses received by workers were compared and analyzed for each scenario, and based on the results, the optimal accident response scenario was derived. The results of this study plan to be utilized as a fundamental technology to ensure the safety of workers through simulations targeting various reactor types and accident response scenarios in the future. Furthermore, it is expected to secure the possibility of developing a data-based ALARA decision support system for predicting radiation exposure dose at NPP sites.
Objective: The aim of this study was to examine the impact of ATP-binding cassette subfamily B member 1 (ABCB1) C3435T polymorphism on the treatment response of patients to vitamin K antagonists (VKAs). Methods: In this systematic review and meta-analysis, the PubMed/Medline, Embase, and Cochrane Library databases were searched for eligible articles for the period up to November 2020. Articles that reported treatment response to VKAs according to the ABCB1 C3435T polymorphism were included in this study. Results: A total of 13 and 9 articles were included in the systematic review and meta-analysis, respectively. The weekly maintenance dose of warfarin was significantly lower in patients with the ABCB1 3435CT or TT polymorphism type than in those with the ABCB1 3435CC type (weighted mean difference [WMD], -2.53 mg/week; 95% confidence interval [CI], -3.64 to -1.43, p<0.001). However, the weekly maintenance dose of acenocoumarol was not significantly associated with the ABCB1 C3435T polymorphism (WMD, 1.02; 95% CI, -0.61 to 2.65, p=0.22). Conclusion: The ABCB1 C3435T polymorphism was significantly associated with the weekly maintenance dose of warfarin. Further research is needed to confirm the association between the ABCB1 C3435T polymorphism and the incidence rate of bleeding events.
Park, Young-Min;Park, Yoon-Kyu;Ahn, Woo-Sup;Ha, Tai-You
The Journal of the Korean Society for Microbiology
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v.22
no.2
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pp.175-184
/
1987
The use of alkylating agent cyclophosphamide(CY), a widely used antitumor drug is well known as a potent immunosuppressant and has been used as a probe for investigating the functional capabilities of lymphocyte subsets of both T and B cells that play an important role in the regulation of the immune response. The present study was undertaken in an effort to assess the effects of CY on immunological memory in murine model. CY, given as a single dose of CY(250mg/kg) before sensitization with sheep red blood cells(SRBC) enhanced the primary response of Arthus and delayed-type hypersensitivity(DTH), as measured by footpad swelling reaction, but suppressed their tertiary DTH response. The similar CY pretreatment enhanced both the primary and tertiary hemagglutinin(HA) responses to SRBC, and the tertiary antibody response against polyvinylpyrroridone(PVP), a thymus-independent antigen but not the primary response against PVP. CY, given as a single dose of 250mg/kg 2 days before the primary immunization and two doses of 100mg/kg 2 days before the secondary and tertiary immunization, markedly suppressed the tertiary DTH and HA responses to SRBC. However, CY, given as small multiple daily doses(10mg/kg) over 4 days before sensitization but not after sensitization, enhanced the secondary HA response to SRBC. Contact sensitivity to dinitrofluorobenzene(DNFB) was suppressed by the drug, given either as a single large dose(300mg/kg) or as multiple dose(10mg/kg) administered 2 days before, together with or after DNFB sensitization. This suppression was more pronounced and more significant when CY was given as multiple dose. However, the enhancement of the secondary contact sensitivity to DNFB by CY was not clear-cut. The splenectomy appears to increase the enhancing effect of CY on contact sensitivity. These results suggest that CY selectively influences the immune response depending on the time of the drug administration relative to immunization and that the secondary or tertiary immune response involve memory cells with different susceptibilities to CY. Moreover, these results suggest that multiple low doses may sesectivley inhibit suppressor T cell proliferation involving DTH, HA or contact sensitivity without effecting helper T cells, but high doses presumably inhibit helper T cells and suppressor T cells with effecting B cells.
A benchmark dose (BMD) approach has been evaluated us a replacement for the traditional NOAEL methodology currently being wed to assess the noncancer effects of toxicants. The endocrine disrupt-ing effect of endosulfan which showed decrement of sperm count and testicular testosterone level in animals, was currently reported. The amount of endosulfan used as pesticide in the country has been continuously increased. The aim of this study was to suggest the permissible intake level (PIL), corresponding to Accept-able Daily Intake (ADI), based on endocrine disrupting effect wing BMD. Various animal data were collected by consideration of critical effect showing endocrine disruption and an animal data for reproductive toxicity was selected. The Power model from BMD software for induction of $BMD_10$ having meaning which is the dose at the 95% lower confidence limit on a 10% response was used due to that the form of selected dose-response animal data was continuous data. The $BMD_10$ was estimated to be 0.393 mg/kg/day based on reproductive toxicity showing decrement of sperm count. The permissible intake level (PIL) was calculated by dividing the $BMD_10$ by the uncertainty factors of 100 with consideration of from animal to human and human variability. The PIL as 0.004 mg/kg/day was compared with traditional ADI as 0.006 mg/kg/day based on the incidence of marked progressive glomerulonephrosis and blood vessel aneurysm in males.
The methods of applied genetic toxicology are changing from qualitative hazard identification to quantitative risk assessment. Recently, quantitative analysis with point of departure (PoD) metrics and benchmark dose (BMD) modeling have been applied to in vitro genotoxicity data. Two software packages are commonly used for BMD analysis. In previous studies, we performed quantitative dose-response analysis by using the PROAST software to quantitatively evaluate the mutagenicity of four piperidine nitroxides with various substituent groups on the 4-position of the piperidine ring and six cigarette whole smoke solutions (WSSs) prepared by bubbling machine-generated whole smoke. In the present study, we reanalyzed the obtained genotoxicity data by using the EPA's BMD software (BMDS) to evaluate the inter-platform quantitative agreement of the estimates of genotoxic potency. We calculated the BMDs for 10%, 50%, and 100% (i.e., a two-fold increase), and 200% increases over the concurrent vehicle controls to achieve better discrimination of the dose-responses, along with their BMDLs (the lower 95% confidence interval of the BMD) and BMDUs (the upper 95% confidence interval of the BMD). The BMD values and rankings estimated in this study by using the EPA's BMDS were reasonably similar to those calculated in our previous studies by using PROAST. These results indicated that both software packages were suitable for dose-response analysis using the mouse lymphoma assay and that the BMD modeling results from these software packages produced comparable rank orders of the mutagenic potency.
Gamma irradiation (${\gamma}IR$) is widely used for radiotherapy as a treatment of cancer cells although it has a risk to damage normal cells. Inflammation is regarded as one of side effects of ${\gamma}IR$ while the effect of low dose of ${\gamma}IR$ on inflammation has not been researched well. Here, we investigated the inflammatory responses of low dose of ${\gamma}IR$ on murine spleen cells. It was evaluated if ${\gamma}IR$ affected the mitogen-induced lymphocyte proliferation, the regulation of various inflammatory cytokines (IFN-${\gamma}$, IL-2, IL-17, IL-4, IL-10), and the involvement of Ikaros and MAPK/NF-${\kappa}B$ medicated mechanism. Exposure of $^{137}Cs-{\gamma}IR$ below 2 Gy decreased the lymphocytes proliferative response to mitogens (LPS, ConA) except at the lowest dose, 0.05 Gy. IL-17, IL-2 and IL-4 mRNA increased at 0.5 and 2 Gy, but not altered at 0.05 Gy. IL-10, anti-inflammatory cytokine, increased only at 0.05 Gy. In regard to intracellular signaling, p-JNK, p-p38 and p-$I{\kappa}B{\alpha}$ were not changed, whereas the activation of ERK and Ikaros increased at the lowest dose. These results suggest that exposure of ${\gamma}IR$ less than 0.5 Gy (or below 0.05 Gy) has beneficial effects as a radiation hormesis on immune function.
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