CANCER AND LOW DOSE RESPONSES IN VIVO: IMPLICATIONS FOR RADIATION PROTECTION Ron Mitchel Radiation Biology and Health Physics Branch Atomic Energy of Canada Limited, Chalk River Laboratories, Chalk River, ON, K0J 1J0 Canada
The Linear Dose-Risk Function (risk of cancer from irradiation) ? R R = � • D D R = risk in exposed tissue D = absorbed dose
Linear No Threshold Hypothesis Implies : 1. Risk is determined by the physics 2. Biological inputs to the risk are either constant with dose or irrelevant at all doses
Radiation at Low Doses • Dose = energy/unit mass • Radiation deposits energy in tracks • The lowest dose a cell can receive is one track • At doses < 1 track/cell, not all cells are hit. Those that are hit still receive 1 track
Linear No Threshold Hypothesis is Accepted by Regulatory Agencies ISSUE Is the LNT hypothesis true for cancer risk at low doses??
Radiation Protection: LNT Hypothesis • Dose is a surrogate for risk • Risk per unit dose is constant without a threshold, overall and for each tissue • Dose (risk) is additive (normalized using Sv) and can only increase • At low doses and dose rates risk is reduced 2 fold (DDREF=2)
Cancer Does the LNT approach adequately predict risk at all doses for: • Normal individuals • Cancer prone individuals
A radiation exposure is a change in the environment that creates a stress The Basic Rule of Biology In a Changing Environment: “ Adapt or Die ”
ADAPTIVE RESPONSE Exposure of cells or animals to radiation at a low dose and dose rate induces mechanisms that protect against the detrimental effects of other events or agents, including radiation
Radiation-Induced Chromosome Breaks
Broken Chromosomes in Micronuclei
Micronucleus frequency (%) Ability to Repair Broken Chromosomes in Cells 1 0 0 1 2 0 2 0 4 0 6 0 8 0 0 Adapted by Exposure to Low Doses Control 1 mGy 5 mGy 25 mGy 100 mGy 500 mGy 4 Gy 1 mGy - 3h - 4 Gy 5 mGy - 3h - 4 Gy 25 mGy - 3h - 4 Gy 100 mGy - 3h - 4 Gy 500 mGy - 3h - 4 Gy
No Adaptation in Human Cells at High Dose Rate 0.77 Gy/min 60 Co � Broome, Brown and Mitchel. Radiat. Res. 158, 181-186 (2002)
Sub-critical Dose for Adaptation in Human Cells 80 Micronucleus Frequency 70 60 0.1 mGy + 3h + 4 Gy 50 40 5 mGy + 3h + 4 Gy 30 4 Gy 20 0.1 mGy 10 0 5 mGy 0 Dose Broome, Brown and Mitchel. Radiat. Res. 158, 181-186 (2002)
Adaptation in Whitetail Deer Cells 18 16 BNCs with micronuclei (%) 14 12 10 8 6 4 2 0 0-3-0 1-3-0 10-3-0 100-3-0 100-6-0 0-3-4 1-3-4 10-3-4 100-3-4 Adapting (mGy)- Interval (h)- Challenge (Gy) Ulsh, Miller, Mallory, Mitchel, Morrison, and Boreham J Environ Radioact 74, 73-81 (2004)
Environmental Adaptation in Frogs in vivo Background Background 25 Frequency of Unrepaired + 1 mGy/y 3 H 20 Chromosomes 15 10 3 4 3 4 2 2 1 5 1 0 1 . Control 2 . Adapting dose (1-100 mGy ) 3 . Test Dose (4 Gy) 4 . Adapting + test dose M. Stuart, AECL, unpublished
Adaptation to radiation shown in: •Single cell organisms •Insects •Plants •Lower vertebrates •Mammalian cells including human This is an Evolutionarily Conserved Response
Low Doses Protect Cells Against Malignant Transformation by High Doses Treatment Transformation Frequency (x 10 -4 ) Control 3.7 4 Gy (high dose rate) 41 100 mGy (low dose rate) +24h 16 + 4 Gy (high dose rate)
The Influence of Low Doses On the Risk of Spontaneous Malignant Transformation Transformation Frequency Treatment (x 10 -3 ) Control 1.8 1.0 mGy 0.53 10 mGy 0.42 100 mGy 0.53
Transformation in Human Cells J. L. Redpath and R.J. Antoniono, Radiat. Res. 149, 517-520 (1998) 8 Transformation Frequency 6 (x10-5) 4 2 0 0 200 400 600 800 1000 Dose (mGy)
Low Doses Sensitize Non-Dividing Human Lymphocytes to Apoptosis 3 G y 1 0 c G y + 2 4 h + 3 G y Apoptosis Frequency 2 5 2 0 1 5 1 0 5 0 A ( e x p t 1 ) A ( e x p t 2 ) B C x I n d i v i d u a l
Increased Sensitivity for Radiation-Induced Apoptosis in Human Lymphocytes Previously Exposed to a 10 cGy Adapting Dose Number of Individuals Sensitivity Increase 18 27.5 ± 5.7 % 8 7.0 ± 3.0 % Is This Genetic Variation?
BYSTANDER EFFECT The Percentage of Human Lymphocytes Expressing IL-2 Receptors 24 h After Stimulation 50% Control Cells + Control Cells Irradiated Cells 50% Irradiated Cells (10 mGy) 17.8 ± 3.3 22.6 ± 4.8 7.7 ± 4.1 p<0.01 p<0.01 Y. Xu, C.L. Greenstock, A. Trivedi and R.E.J. Mitchel Radiation and Environmental Biophysics 35: 89-93 (1996)
DO THESE RADIATION-INDUCIBLE ADAPTIVE PROCESSES PRODUCE PROTECTIVE EFFECTS IN VIVO ??
LOSS OF LIFE FROM HIGH DOSE EXPOSURE IN NORMAL AND Trp53 +/- MICE .) 800 .E ean +/- S Trp53+/+ y = -32x + 583 600 R 2 = 0.99 isk (M 400 ays at R Trp53+/- 200 y = -39x + 378 R 2 = 0.99 D 0 0 1 2 3 4 Dose (Gy)
LOSS OF LIFE FROM HIGH DOSE EXPOSURE IN NORMAL AND TRP53 +/- MICE WITH CANCER Days at Risk (Mean +/- S.E.) 800 Trp53+/+ y = -41x + 629 R 2 = 0.99 600 400 Trp53+/- 200 y = -47x + 413 R 2 = 0.99 0 0 1 2 3 4 Dose (Gy) R. E. J. Mitchel et al. unpublished
LOSS OF LIFE IN NORMAL AND Trp53 +/- MICE WITH LYMPHOMAS 800 .) .E Trp53+/+ y = -48x + 625 ean +/- S R 2 = 0.91 600 isk (M 400 ays at R Trp53+/- 200 y = -46x + 379 R 2 = 0.94 D 0 0 1 2 3 4 Dose (Gy)
SKIN TUMORS IN MICE Protection by Radiation Against Chemical Tumor Initiation Initiation Treatment Tumors per Animal MNNG 2.04 Beta Radiation (0.5 Gy) 0 Beta + MNNG 0.39
Myeloid Leukemia in Genetically Normal Mice Trp53+/+ SURVIVAL PROBABILITY 1.0 Control 0.8 and 1 Gy ML Neg. 0.6 1 Gy ML Pos. 0.4 100 mGy + 24h + 1 Gy 0.2 ML Pos. 0.0 0 200 400 600 800 1000 TIME (days) Fig. 4A Mitchel et al.
Lymphomas in Cancer-Prone Mice 1 Trp53 +/- Survival Probability Lymphomas 0.8 0.6 0.4 4 Gy acute 10 mGy + 4 Gy acute 0.2 100 mGy + 4 Gy acute 0 Gy 0 50 150 250 350 450 550 Time (days)
Lym phom a Latency 0 Gy Trp53 +/- 10 m Gy Trp53 +/- 40 100 m Gy Trp53 +/- 0 Gy Trp53 +/+ Number of Tumors 30 20 10 0 0 200 400 600 800 Tum or Latency (days)
Spinal Osteosarcomas in Trp53+/- Mice Number of Spinal Osteosarcomas �������������� 25 ���������������� ����������������� 20 15 10 5 0 200 300 400 500 600 700 Tumor Latency (days)
Bottom Line Low doses of low LET radiation, at low dose rate, reduce, not increase, risk in vivo
IMPLICATIONS for LNT • High dose responses cannot be extrapolated to low doses • At low doses in vivo , cancer risk is not proportional to dose • Dose thresholds for increased risk exist in both normal and cancer prone individuals • Cancer susceptibility modifies threshold (zero risk) dose
IMPLICATIONS FOR DOSE ADDITIVITY • Radiation protection assumes dose (i.e risk) additivity (Sv) • If some doses protect, doses are not additive • Further complicated if some doses protect some but not all organs
IMPLICATIONS FOR DDREF • Assumed DDREF = 2 for increased risk • If risk from low dose/dose rate � 0 then DDREF may = �
IMPLICATIONS FOR W t • Tissue Weighting Factors (W t ) are not constant with dose • W t changes from positive values through zero to negative values as dose decreases • Cancer proneness and/or a second dose modify W t
IMPLICATIONS FOR W R • Radiation weighting factors (W R ) for high LET are based on the RBE ratio with low LET • BUT: Low doses of low LET are protective in vivo (negative risk) • THEREFORE: At low doses W R and dose in Sv have no meaning
IMPLICATIONS FOR “ALARA” Preventing an exposure that would induce an adaptive response will INCREASE risk!
THE BIG QUESTION Regulations are based on human epidemiological data: So Why is the accepted human epidemiological data inconsistent with data from all other organisms???
Statistically significant increases in cancer risk in humans can be only detected down to about 100mGy • 100 mGy is very close to the transition point between protection and harm in rodent and human cells and in mice.
RADIATION PROTECTION CONCLUSIONS • The assumptions of the LNT hypothesis and radiation protection practices are not compatible with the observations in vitro or in vivo • Environmental assessments must • Environmental assessments must consider real effects consider real effects • A new approach to radiation protection at low doses is needed
POTENTIAL REGULATORY SOLUTION Adopt “Linear With Threshold” hypothesis
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