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Low-Level Radiation and Health


                                                                   • Ionizing radiation and its sources
 Low-Level Radiation and                                           • Spontaneous and radiation-induced
         Health                                                      damage
                                                                   • Radiation activated natural protection
                                                                     (radiation hormesis)
                      Bobby R. Scott
                                                                   • Biological basis for radiation hormesis
         Lovelace Respiratory Research Institute
              Albuquerque, NM 87108 USA                            • Hormetic cancer relative risk model
  25th Annual Meeting Doctors for Disaster Preparedness
         Hilton Oakland Airport, August 3-5, 2007

                                                                      Radiation Has Existed Since the
                Contents (continued)                                    Beginning of the Universe
                                                                    Universe created 10 - 20 billion years ago from a cosmic explosion
• Abundant evidence for radiation hormesis
• Hormesis implications for low-dose cancer
• Utopian-world LNT vs. real-world hormesis:
  Implications for radiation disaster
• Conclusions

    Radiation Sources are Everywhere                                    Man-made Radiation Sources

                             The Sun                Indoor Radon                     •   X-ray machines
                                                                                     •   Medical isotopes
                                                                                     •   Televisions
                                                                                     •   Smoke detectors
                                       Our Bodies                                    •   Weapons fallout
                                                                                     •   Radioactive waste
               Radioactive Soil and Rocks

 Low- and High-LET Forms of Radiation           Adverse Consequences of Exposure of
                                                        Humans to Radiation
• LET (linear energy transfer) is the average   • Low and high radiation doses can cause
  energy lost by radiation when traversing a      stochastic effects such as cancer and
  small thickness of material.                    genetic effects.
• Examples of low-LET radiation are X-rays      • High doses and dose rates can cause life-
  gamma-rays, and beta particles.                 threatening effects such as severe damage
• Examples of high-LET radiation are alpha        to organs as well as serious morbidity.
  particles, neutrons.                          • Damage to DNA above the spontaneous
                                                  level is largely responsible for most
                                                  detrimental radiobiological effects.

     Radiation Bystander Effects                          Deleterious Signals

• Deleterious signaling: E. Azzam EI et al.     • Activated by low and high doses of
  Current Cancer Drug Targets 2:53,               high-LET radiation and by high doses
  2004.                                           of low-LET radiation.
• Protective signaling: A. Hooker et al.        • Can lead to stochastic bystander
  Radiation Research 162:447, 2004.               effects, including genomic instability.
                                                • Elevated genomic instability elevates
                                                  cancer risk.

          Protective Signals                                Radiation Hormesis
• Form of natural defense.                      • Survival of all organisms on Earth depends
• Induced by low-dose low-LET radiation           upon their ability to adapt to environmental
  and other stressors.                            and other stresses.
• Reactive oxygen (ROS) and nitrogen            • Numerous genes evolved over time to
  (RNS) species and specific cytokines            mediate adaptive responses to both
  (e.g., TGF-β1) participate.                     internal and external genotoxic stresses.
• Enhances DNA repair capacity in               • Radiation Hormesis: low-dose radiation
  bystander cells.                                activated natural protection (ANP).
• Stimulates selective removal of aberrant      • Protective signaling regulates ANP (Scott
  bystander cells.                                2007; in press and submitted papers).
Portess et al. Cancer Res. 67:1246, 2007.

 Radiation Activated Natural Protection                                        Low-Level, Low-LET Radiation Protects Us
      Is Evolutionary Conserved
                                                                               • Protects against chromosomal damage (Ed
  Occurs in:                                                                     Azzam’s group)!
  - Single cell organisms                                                      • Protects against mutation induction (Pam
                                                                                 Sykes’ group), even when the low dose
  - Insects                                                                      follows a large dose (Tanya Day’s work)!
  - Plants                                                                     • Protects against neoplastic transformation
  - Lower vertebrates                                                            (Les Redpath’s group)!
  - Mammalian, cells                                                           • Protects against high dose chemical- and
                                                                                 radiation-induced cancer (Kazou Sakai’s
  - Mammals including humans                                                     group)!
                                                                               • Enhances immune system defense (Shu-
 Mitchel, REJ (2006 IHS Meeting presentation)                                    Zheng Liu’s group)!

        Low-LET Radiation Protects Us                                                      Hormetic Risk (J-Shaped) Curve
                (continued)                                                                                                 Increased
• Suppresses cancer induction by alpha
  radiation (Chuck Sanders group)!
                                                                                 Cancer                Spontaneous Cancer
• Suppresses metastasis of existing cancer                                     Incidence                   Frequency
  (Kiyohiko Sakamoto’s group)!
• Extends tumor latent period (Ron Mitchel’s
                                                                                               Hormetic Zone
• Protects against diseases other than
  cancer (Kazuo Sakai’s group)!                                                                                Hormetic Effect

                                                                                                 Absorbed Radiation Dose (mGy)

             Biological Basis for Hormetic
             Zone for Low-LET Radiation                                           PROFAC, A Measure of ANP Efficiency
   Occurring Genomic                                   Low Dose/Dose Rate
       Instability                                      Low-LET Radiation        • PROFAC stands for protection factor.
                                                                                 • Cancer suppression PROFAC: Expected
      DNA Damage
                                re gh f
                                  pa id                     Protective
                                                                                   fraction of cancer cases that do not occur
                                    ir/ elit
                                       ap y
                                         op DN
                                                           Intercellular           that would have occurred in the absence of
                                           to A             Signaling
       Neoplastic           *   PAM
                                             sis                                   radiation ANP.
     Transformation                   Pro
                                                                                 • ANP is regulated via protective intercellular
                                Immune functi
                                             on          Protection (ANP)          signaling and the PAM process* component
     Proliferation of
     Malignant Cells
                            *                                                      is a protective bystander effect.

         Cancer                           *   Contributes to PROFAC
                                               Indicates Suppressor Function       *Explained on next slide.
Scott 2007              ROS scavenging contributes to protection

  Protective Apoptosis Medicated (PAM) Process in
    Fibroblast: Protective Intercellular Signaling
                                                                                                           PAM Process Signaling
           Cell                      O                      TGF-β
                                                     NO                     Normal        • Can eliminate precancerous and other
                                                                             Cell           genomically-unstable cells caused by different
   O                                      ONOO                                              agents.
   O                               Induction of Apoptosis                                 • May vary for different stressing agents (e.g.,
                                                                                            ionizing radiation, UV radiation, chemical, etc.).

                                                                                          • May differ for different organs/tissue.

                                                     H O                                  • Appears independent of p53.


                                                                       P                  • TGF-β appears to play and important role in



    OH        O                Cl
G. Bauer. Histol. Histopathol. 11:237-255, 1996

                                                                                          NEOTRANS3 Model Modes of Death after
         NEOTRANS3 Model for Radiation-
                                                                                            Low Doses of Low-LET Radiation
        Induced Stochastic Effects in Cells
   • Models the induction of genomically                                                   Moderately                                               p53-related
     unstable cells by low dose radiation.                                                damaged cell                                             death sentence
   • DNA repair errors leads to mutations and
     neoplastic transformations.
   • Normal apoptosis (presumably p53-                                                                                                   rays
     dependent) when activated, removes                                               Mildly damaged                                                 p53-related
     moderately- and seriously-damaged cells.                                               cell                                                     DNA repair

   • Auxiliary apoptosis (presumably p53-
     independent) when activated, removes
     some of the remaining aberrant cells                                                                                                         p53-independent
     including already existing precancerous                                           Bystander                                                  death sentence:
     cells (PAM Process).                                                             precancerous                                                  PAM process

                                                                                                       Hormetic Relative Risk (HRR) Model
       Cancer Hormetic Relative Risk (HRR)
                                                                                                      cancer incidence at absolute zero background radiation
                     Model                                                           RR*

   • Key Assumption: Cancer arises from cells with                                                    Transition Zone A              LNT Zone
     persistent genomic instability through a series of
     stochastic changes, independent of how the
     instability originates, but dependent on the                                                                             Risk
     number of cells with this instability in an organ.                                                                ntom

                                                                                                                Ph a
   • Cancer relative risk (RR) proportional to                                            1
     neoplastic transformation RR.                                                                           RR = 1-PROFAC
                                                                                                                                          Transition Zone B
   • Neoplastic transformation RR based on
     NEOTRANS3 model developed at LRRI.                                                                         Zone of                           b indicates dose from
   • Protective and deleterious stochastic dose                                                               Maximal ANP                          natural background
     thresholds cause hormetic dose-response curve                                            0
     shape.                                                                                       0      b D*                 D** D***
                                                                                                           Absorbed Radiation Dose D

           Radiation ANP from Some Diagnostic
                   Procedures is Likely                                                                                      Stochastic Thresholds
                                                                 Doses from Other Diagnostic
    Doses from Diagnostic X Rays Fall
                                                                          Sources                            • Each of us has a different radiation
            in the Hormetic Zone                                           Source                 mGy          threshold (organ specific) for activating
                                                             Dental, full-mouth (X ray)            0.17
    Number of
      X Rays
                       Dose Rangea
                                               Induced?      Chest X ray                           0.25
                                                                                                               protective natural processes (i.e., ANP).
                            0.01 mGy -     > 0.01 mGy        Mammograms (X ray)                     4        • Each also has a different higher threshold
                               30 mGy           Yes
                       0.1 mGy – 50
                                                             CT scan, head (X ray)                 20
                                                                                                               for inhibiting some of the protection (e.g.,
          5 – 14                                 Yes         CT scan, body (X ray)                 60
                                                             Thyroid scans:                                    p53-independent PAM process).
                        1 mGy – 230
          ≥ 14                                   Yes           Iodine-131 (β + γ radiation)       50-100
                                                               Iodine-123 (γ radiation)           30-50
     aBoice    JD, Jr. et al. JAMA                             Technetium-99 (β radiation)          10
         265(10):1290-1294, 1991.

                                                             Kauffman, Journal of American
                                                             Physicians and Surgeons 8(2):54-55,

                                                                                                                 Protection Factors Against Cancer
             Cancer Relative Risk as a Fuction of
                                                                                                                            in Humans1
              the ANP-Related PROFAC for the
                                                                                                              Region or Group                        Effect       PROFAC
                       Hormetic Zone
                      1.2                                                                                                                             all
                                                                                                              High radon levels, USA                                   0.35
                                                                                                              Canada, nuclear industry
                                                                                                                                                   Leukemia            0.68
                      0.8                                                                                     workers
                                                                                                              US DOE labs workers                  Leukemia            0.78


                      0.4                                                                                     Mayak Plutonium facility                lung
                                                                                                              workers                                cancer
                                                                                                            Proportion of spontaneous and other cancers prevented!
                       0                                                                                    1Jaworowski
                            0            0.2           0.4      0.6           0.8         1
                                                                                                                         Z. Symposium “Entwicklungen im Strahleschutz”,
                                                                                                             Munich, 29 November 2001.
                                                          PROFAC                                            2Scott BR. Dose-Response, 2007 .

          Age-Dependent Protection Factors Against                                                           PROFACs for Nuclear Shipyard Workers
            Breast Cancer for Diagnostic X-Rays                                                                 Chronically Exposed to γ Rays
          0.35        Repeated Rounds of Mammograms
                                                                                                                    Cause of Death             SMR         p value      PROFAC

                                                                                                           Allergic, endocrine, metabolic 0.69 ± 0.12 4.3 x 10-3          0.31
                                                                      0.32                0.31
                                                                                                           All respiratory disease          0.62 ± 0.08 1.4 x 10-6        0.38

          0.20                                                                                                                              0.68 ± 0.04 2.4 x 10-14       0.32
                                                                                                           Emphysema                        0.63 ± 0.26 7.2 x 10-2        0.37

          0.10                                                                                             Asthma                           0.30 ± 0.43 5.1 x   10-2      0.70
                                                                                                           All infectious & parasitic       0.86 ± 0.72 4.2 x   10-1      0.14
                             50-54                  55-59             60-64               65-69
                                                                                                           Total mortality                  0.78 ± 0.04                   0.22
                                                   Age Group (years)
Based on data from Nyström et al. 2002
                                                                                                              Based on combining SMR data from Sponsler and Cameron (2005).

      Benefits of Natural Background Radiation
                                                                                                                                                             Epidemiological Studies with Appropriate
                                           Solid Cancer Mortality for Yangjiang, China 1979-1998                                                             Internal Controls that Negate the Healthy
                                                                                                                                                                Worker Effect (C. L. Sanders, 2007)
                                                                                                                                 Effective doses
                                                                                                                                     are used
                                        HRR Model                         Mean
                                                                                                                                                               Worker Comparison            All Cancer      Lung Cancer

                                                                                                  Slope of the line = - 6.33E-04/mSv                         Badged/Unbadged DOE               0.83              0.51
                                                                                                                                                                Female Workers
                                                                                                                                                            UK Radiologists/Physicians         0.71         As low as 0.00
                                                                                                                                                           High-Dose/Control Shipyard          0.84              0.93

                D* where blue curve bottoms out implicated to be at least hundreds of mSv                                                                   Monitored/Unmonitored UK           0.73              0.61
                                                                                                                                                             Nuclear Utility Workers
                                                                                                                                                             Radiation/Non-Radiation      As low as 0.30         0.89
                                                                                                                                                                UKAEA Workers
 Wei and Sugahara. Int. Congress Series 1236:91-99 (2002)

      Cancer Relative Risk In Hormetic Zone:                                                                                                              Gamma-Ray ANP Against Spontaneous Lung
                                                                                                                                                                      Cancer in Mice
          Irradiated Human Populations
      1.0                                                                                                                                                      Risk
      0.9      Cancers                        Cancers
                                                USA, Residents of High

                   Chernobyl Accident
                   Recovery Workers

                                                 Background States

                                                                           Radiologists after

                                                                            British Medical

                                                                                                      High Residential

                                                                                                        Radon, USA

                                                                                                                         Leukemia                                    All doses > 0 are in hormetic zone, and zone
      0.3                                                                                                                              Leukemia
                                                                                                                                                                     extends to at least 1000 mGy



                                                                                                                                          US DOE

                                                                                                                                                          Study involved more than 15,000 mice (R. Ulrich et al., 1976)
            RR< 0.85 cannot be due to healthy worker effect (Sponsler and
            Cameron, 2005)

       Gamma-Ray ANP Against Spontaneous Lung                                                                                                             Low-Dose-Rate, Gamma-Ray ANP Against
                 Cancer in Humans                                                                                                                          Alpha-Radiation-Induced Lung Cancer
                                              Multiple fluoroscopy examinations
                                                                                                  95% Confidence
      0.95                                                                                                                                                                Rats


               0                        100            200                300                   400               500      600         700          800
                                                                         X-Ray Dose (mGy)
Data from GR Howe. Radiat. Res. 142:295-304,1995. Similar findings have
been reported for breast cancer (Miller. N. Engl. J. Med. 321:1285-1289, 1989)                                                                              C. L. Sanders, International Hormesis Conference, 2006

Expected and Observed RR for Lung Cancer
                                                                     Gamma-Ray ANP Against Alpha-
 in Wistar Rats Exposed to Pu-239 + Yb-169
                                                                     Radiation-Induced Lung Cancer
Average       Average       Expected Observed PROFAC
 Alpha        Gamma           RR       RR                            100

  Dose          Dose                                                                                      Circles: rats
 (mGy)         (mGy)
                                                                                                          Squares: rats

                                                                                                          Triangles: dogs
    0             0              1             1                      1

   56            0.9            21             0         1.0         0.1
                                                                                                        RR = 0 plotted at
  190            1.8            67             0         1.0               1   10      100     1000       10000   100000    1000000
                                                                                    Alpha Radiation Dose (mGy)
  620            1.3           218             0         1.0
                                                               Dashed curve: unprotected α-irradiated humans

 Gamma-ray dose from Yb-169 protracted over several months.    Smooth curve: gamma-ray protected α-irradiated humans

        Low-Rate Gamma-Ray ANP Against
         MC-Induced Skin Tumors in Mice
                      MC: methylcholanthrene

                                                                                                      Diebetic mice, Sakai K
                                                                                                      IHS 2006

                                                                                                          Gamma rays

K. Sakai, International Hormesis Conference 2005

                                                                     Low-Dose vs. High-Dose
                                                                        Cancer Therapy

    Sakai K, IHS 2006

     Radiation Hormesis and Low-Dose
              Cancer Therapy                                                          High-Radiation-Dose Therapy
• Cancer cells are resistant to undergoing
  apoptosis.                                                          • Severely harms the patient via massive
• New research is demonstrating ways of                                 killing of normal cells!
  sensitizing cancer cells to undergo apoptosis                       • Suppresses the immune system, thereby
  (e.g., resveratrol, gene therapy).                                    promoting cancer metastasis!
• Applying low-dose, low-LET radiation (in the
                                                                      • Inhibits signaling associated with the PAM
  hormetic zone) alone or in combination with
  apoptosis sensitizing agents that target tumor                        process!
  cells could lead to curing cancer.                                  • Is unnecessary because multiple-low-dose
• Adding multiple small doses of antiangiogenic                         radiation therapy or chronic low-rate
  drugs may enhance efficacy some treatments.                           radiation therapy could cure cancer without
                                                                        harming the patient!

        Low-Dose Radiation Therapy                                               Low-Dose Radiation Therapy for Non-
                                                                                       Hodgkin’s Lymphoma
•   Low-dose radiation therapy has been used to             •      Total-body irradiation (TBI) (repeated doses of 100-
    successfully treat ovarian, colon, and hematologic             150 mGy) increased the four-year survival to 70-74%
    cancers without any symptomatic side effects.                  compared to 40% of untreated controls and 52% of
•   Low-dose, low-dose-rate immunotherapy (using                   patients treated with localized high doses.
    beta radiation) has been used to successfully           •      Upper half-body irradiation (HBI) (repeated doses of
    treat follicular lymphoma.                                     100-150 mGy) increased the four-year survival to 84%
                                                                   compared to 65% of patients treated with localized
Choi NC, et al. Cancer 43:1636-1642, 1979.
                                                                   high doses.
Cuttler JM. J. Amer. Phys. Surg. 8(4):108-111, 2003.        •      All patients treated with low-dose HBI or TBI survived
Kuminski MS et al. N. Engl. J. Med. 352(5):441-449, 2005.          to 10 years, compared to localized-high-dose-
Ruffolo SC and Shore GC. J. Biol. Chem. 278(27):25039-             treatment controls, who survived to nine years at a
25045, 2003.                                                       rate of 50%.
                                                                   J. Cuttler. Canadian Nuclear Society Bulletin 21(2):45, 2000

                                                                                     Current Radiation Risk Assessment
                                                                                       Paradigm: Utopian-World LNT
                                                                                     BEIR VII Low-Dose, Low-Dose-Rate Extrapolation
     Utopian-World LNT vs. Real-World                                     0.10

    Hormesis: Implications for Radiation
          Disaster Preparedness
                                                            Cancer Risk


                                                                                     LNT                                DDREF

                                                                                                                         BEIR VII discounted
                                                                                 0     20   40   60   80   100    120     140     160   180    200

                                                                                                 Utopian-World Radiation Dose (mSv)

                                                             BEIR VII vs. French Academies on
             LNT and Radiation Phobia                          LNT and Radiation Hormesis
    • The notion that any amount of radiation                      BEIR VII             French Academies
      harms us is false and drives radiation                Selectively chosen A-      LNT should not be applied to
                                                            bomb cancer data was       low-LET doses < 100 mGy
                                                            consistent with LNT
    • LNT-related radiation phobia was
      responsible for the loss of more than                 Even natural               No evidence of harm from
      100,000 lives (via abortions) following the           background low-LET         natural background
                                                            radiation harms            radiation; may be beneficial
      Chernobyl accident!
                                                            Radiation hormesis         Radiation hormesis not
                                                            dismissed                  dismissed
                                                            Looked at basic research   Considered implications of
                                                            results and ignored        basic research results

      LNT-Associated Radiation Phobia                       Things the U.S. Government Should Do Now
       Following a Dirty Bomb Incident                     to Reduce Casualties in the Event of a Future
                                                                        Dirty-Bomb Incident
                                                           Institute a well-funded program to educate the public,
                                                             medical community, news media, and governmental
                                                             agencies about:
                                                           - The many radiation-phobia-related casualties LNT
           Radiation-Phobia-Associated Impacts:              could cause: e.g., death by LNT slope factor!
•   Loss of lives associated with frantic evacuations.     - The abundant evidence for health benefits of low-
                                                             level radiation exposure!
•   Severe injuries during evacuations.
                                                           - How cancer and some other diseases could be
•   Increased suicides and abortions.                        prevented in high-risk groups by harmless low
•   Increased psychosomatic disorders.                       radiation doses!
•   Increased drug/alcohol/cigarette abuse.                - How cancers could be cured with low harmless doses
                                                             of radiation in combination with other agents!
•   Permanent abandonment of properties
    with low-level contamination.

                      Conclusions                                     Conclusions (continued)
    • The LNT risk model is invalid and promotes
                                                           • The public, news media, medical
      radiation phobia.
                                                             community, and others need to be informed
    • Radiation-phobia-related casualties after a dirty
      bomb incident in a populated area are likely to be
                                                             about the powerful cancer preventative
      more prevalent than those related to actual            aspects of low-dose radiation ANP.
      radiation-induced damage.                            • They also need to be informed about the
    • The public and others need to be better informed       great potential for curing cancer using
      about low-dose radiation ANP against diseases.         essentially harmless multiple low doses of
    • Persons receiving radiation doses in the hormetic      radiation plus other agents that sensitize
      zone would not likely be harmed and may be             cancer cells to apoptosis.
      protected from developing some diseases that
      would otherwise occur.

                                               Radiation Hormesis Presentations on
        Conclusions (concluded)                our Website (

• Governmental agencies (e.g., NIH, DOE,      • Hormesis Implications for Managing
  NSF, DOD, NASA, DHS, FDA, others) need        Radiological Terrorism Events.
  to support radiation adaptive               • Low-Dose/Dose Rate Low-LET Radiation
  response/hormesis research because of the     Protects Us from Cancer.
  enormous homeland-security, cancer-         • Medical and Therapeutic Radiation
  prevention, lifespan-prolongation, and        Hormesis: Preventing and Curing Cancer.
  cancer-therapy benefits that would be       • Biological Basis for Hormetic Relative Risk
  expected.                                     Model and Implications

Collaborators and Student Participants                    Acknowledgement

• Scientists: Pam Sykes, Tanya Day, Les        This research was supported by the Offices
  Redpath, Chuck Sanders, Zoya Tokarskaya,
                                               of Science (BER) and Environmental
  Galina Zhuntova, Ed Calabrese, Noy
                                               Management, U.S. Department of Energy,
  Rithidech and others
                                               Grant Number DE-FG02-03ER63657.
• Students: Jenni Di Palma, Munima Haque

              Backup Slides

Annual Cancer Mortality/100,000 for U.S.
         States (1950-1967)                                Natural Background Radiation

                                                   •   Atlantic and Gulf Costal Plain: 1.05 mSv/y
                                                   •   Middle America: 1.25 mSv/y
                                                   •   Rocky Mountain Plateau: 1.45 mSv/y
                                                   •   Denver, Colorado: 1.65 mSv/y
                                                   •   Ramsar, Iran: 200 mSv/y

                                                   Green indicates values that appear to be in
                                                    the hormetic zone.
     Frigerio and Stowe, IAEA Publication, 1976.

   Hormetic Relative Risk (HRR) Model                        HRR Model Continued:
          for Cancer Induction                             α + γ Irradiation, Low Doses
   Low-LET irradiation (dose-independent
                                                       RR = (1-PROFAC)[1 + F(B)KD], D>0
      RR =1, Dose =0
                                                       Low-LET radiation suppresses cancer
       RR = 1 – PROFAC, otherwise
                                                         via protection factor (PROFAC) (Scott
   PROFAC depends on dose rate pattern                   2005a,b).
   and exposure time; accounts for PAM and
   immune system stimulation. Dose-                    F(B) = (1-B)/B, for baseline incidence B.
   independent zone increases importance               PROFAC=0, for alpha radiation.
   of highly-criticized ecological studies!
                                                       D is the alpha radiation dose.

       Markov Chain Monte Carlo                           WinBUGS Sampling Hierarchies
      Implementation HRR Model                            Sampling Type            Method of Sampling
 • Why? To address stochastic threshold for
   ANP induction and inhibition.                   1. Conjugate                 Direct, using standard
 • Number of chains = 1 or 2.
                                                   2. Log-concave               Derivative-free adaptive
 • WinBUGS software used.
 • Uniform prior distributions assigned for
   model parameters.                               3. Restrictive range         Slice
 • Predictions made for fixed baseline             4. Unrestricted range        Current-point Metropolis
   incidence.                                      1. Finite upper bound        Inversion
                                                   2. Shifted Poisson          Direct, using standard
                                                   Green: continuous target dist.; red: discrete distribution


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