Current Thinking on the Early Effects from Uniform and Non-Uniform Radiation
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1 Current Thinking on the Early Effects from Uniform and Non-Uniform Radiation Jacqueline Williams, PhD, FASTRO University of Rochester Medical College
2 Casualties from radiation: Medical errors/overexposures Reactor accidents** Criticality accidents Industrial accidents Nuclear weapon-related Intentional exposures Theft/loss of source Ingestion 2011 # deaths # injuries ,000* ,000* * Radiation alone ** Includes Chernobyl (additional [thyroid] injuries due to fallout; ~ 10 deaths) and Fukushima (2 injuries) Source:
3 Casualties from radiation: Medical errors/overexposures Reactor accidents** Criticality accidents Industrial accidents Nuclear weapon-related Intentional exposures Theft/loss of source Ingestion 2011 # deaths # injuries ,000* ,000* * Radiation alone ** Includes Chernobyl (additional [thyroid] injuries due to fallout; ~ 10 deaths) and Fukushima (2 injuries) Source:
4 What happens after WBI? What is the most fundamental event following irradiation? CELL DEATH Which cells are most susceptible? DIVIDING CELLS Which dividing cells are most radiosensitive? STEM / PRECURSOR CELLS
5 Tolerance Doses (TD 5/5 - TD 50/5 ) Single Dose (Gy) Ovary 2-6 VCT Bone marrow 2-10 Liver Eye (lens) 2-10 Skin Testes 2-10 Spinal cord Lymphoid 2-20 Peripheral nerve15-20 Gastrointestinal 5-10 Brain Mucosa 5-20 Heart Lung 7-10 Bone and cartilage >30 Colorectal Muscle >70 Kidney Microvascular (endothelial cells) / epithelial cells
6 Tolerance Doses (TD 5/5 - TD 50/5 ) Single Dose (Gy) Ovary 2-6 VCT Bone marrow 2-10 Liver Hematopoietic (2-10 Eye (lens) 2-10 Skin Testes 2-10 Spinal Gy; cord LD 50/ Gy) 20 Lymphoid 2-20 Peripheral nerve15-20 Gastrointestinal 5-10 Brain Mucosa 5-20 Heart Lung 7-10 Bone and cartilage >30 Colorectal Muscle >70 Kidney Microvasculature (endothelial cells) / epithelial cells
7 Tolerance Doses (TD 5/5 - TD 50/5 ) Single Dose (Gy) Ovary 2-6 VCT Bone marrow 2-10 Liver Eye (lens) 2-10 Skin Testes 2-10 Spinal cord Lymphoid 2-20 Peripheral nerve15-20 Gastrointestinal 5-10 Brain Gastrointestinal 15 - (>6 25 Mucosa 5-20 Heart Lung 7-10 Bone and cartilage >30 Colorectal Muscle >70 Kidney Microvasculature (endothelial cells) / epithelial cells Gy; LD 50/ Gy)
8 Tolerance Doses (TD 5/5 - TD 50/5 ) Single Dose (Gy) Ovary 2-6 VCT Bone marrow 2-10 Liver Eye (lens) 2-10 Skin Testes 2-10 Spinal cord Lymphoid 2-20 Peripheral nerve15-20 Gastrointestinal 5-10 Brain Mucosa 5-20 Heart Lung 7-10 Bone CNS and cardiovasc. cartilage >30 Colorectal Muscle (>15 Gy) >70 Kidney Microvasculature (endothelial cells) / epithelial cells
9 Tolerance Doses (TD 5/5 - TD 50/5 ) Single Dose (Gy) Ovary 2-6 VCT Bone marrow 2-10 Liver Eye (lens) 2-10 Skin Testes 2-10 Spinal cord Lymphoid 2-20 Peripheral nerve15-20 Gastrointestinal 5-10 Brain Mucosa 5-20 Heart Lung 7-10 Bone CNS/cardiovasc. and cartilage >30 Colorectal Muscle (>15 Gy) >70 Kidney Microvasculature (endothelial cells) / epithelial cells
10 Acute Radiation Syndromes (ARS) Hematopoietic Gastrointestinal Cardiovascular/CNS Does tolerance (radiosensitivity) and cell death in critical tissues explain syndromes?
11 Hematopoietic Syndrome Critical cells: Stem/precursor cells Dose: 0.5 Gy (lymphocytes) Cause of death: infection
12 radioresistant? hypoxic niche? Copyright by Society of Toxicologic Pathology Travlos G S Toxicol Pathol 2006;34:
13 radiosensitivity decreases with maturity Radiosensitive precursor compartment Copyright by Society of Toxicologic Pathology Travlos G S Toxicol Pathol 2006;34:
14 X X X X X X X X X X X X X X X X X X X X X X X Transit X timex X X X X 115 dys 5-9 dys 6-10 h 8-70 h 18 h Copyright by Society of Toxicologic Pathology Travlos G S Toxicol Pathol 2006;34:
15 GI Syndrome Critical cells: Epithelial lining of the g.i. tract Dose: 10 Gy (damage occurs at lower doses; sparing of bone marrow increases required dose) LD 50/7 : sterilization of crypt stem cells Cause of death: infection
16 GI Syndrome 0 Gy stem cells 10 Gy Ulceration, stenosis, ileus, perforation 14 Gy Courtesy Hauer-Jensen
17 Incident: September 1999, Tokai-mura, 3 workers Endo A, Yamaguchi Y. Radiation Research, 2003.
18 Endo A, Yamaguchi Y. Radiation Research, 2003.
19 Incident: Dose: Worker A: September 1999, Tokai-mura, 3 workers TBI: 18 Gy; ~30 Gy G.I. tract small intestine: 12 5 Gy (neutrons) Gy (grays ) Immediate: nausea, vomiting, loss of consciousness, diarrhea (1 hr) Admission: febrile, hypotensive, drowsy, abdominal pain
20 Incident: Dose: September 1999, Tokai-mura, 3 workers Worker A: Treatment: cytokines (G-CSF), BMT (day 2), PBCT, tract decontamination Symptoms: respiratory failure, severe skin lesions, g.i. bleeding, diarrhea (4 wks) Death: 82 days
21 Acute Radiation Syndromes (ARS) Hematopoietic Gastrointestinal Multi-organ syndrome (MODS/MOFS) Cardiovascular/CNS
22 Multiple Organ Dysfunction / Failure Cause: Dose: overall host response, radiation-induced systemic response >10 Gy Latency: weeks to months Symptoms: fever, tachycardia, hyperventilation, and/or hypocarbia Death: multiple organ failure (liver, kidney, lungs)
23 Radiation ROS cell death free radical scavengers anti-apoptotics
24 Radiation ROS stem/progenitor cell loss cell death stem cell transfusions cytokines/growth factors
25 Radiation ROS stem/progenitor cell loss cell death stem cell transfusions cytokines/growth factors mesenchymal stem cells
26 stem/progenitor cell loss Radiation cell death ROS altered barrier function (g.i., skin, brain) antibiotics, antifungals mesenchymal stem cells FGF-P, anti-vegf (BBB)
27 stem/progenitor cell loss Radiation cell death / injury ROS altered barrier function mitochondrial damage
28 stem/progenitor cell loss Radiation cell death / injury ROS altered barrier function inflammatory cell loss/recruitment ROS mitochondrial damage dysfunctional immune response cytokine expression anti-fungals antibiotics vaccines anti-oxidants anti-inflammatories cytokine inhibitors
29 stem/progenitor cell loss Radiation cell death / injury ROS altered barrier function inflammatory cell loss/recruitment ROS mitochondrial damage dysfunctional immune response cytokine expression anti-fibrotics anti-inflammatories small molecule inhibitors tissue remodeling
30 Conclusions Acute radiation syndrome is now recognized as more than the simple consequence of cell death in stem cell compartment Multiple approaches may be needed to treat severe radiation injury Responding medical personnel need to look beyond immediate symptoms
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