44
What is it?
• Put quite simply, radiation is energy
traveling in the form of particles or waves
— such as light and heat.
Radiation Dose Units
• Gray ( 1 Gy = 100 rad) absorbed dose (joules / kg)
– 1 mGy / year average dose from diagnostic medical tests
– 200 mGy average dose received by A-bomb survivors
– 1 Gy acute whole-body exposure causes acute effects and increases cancer risks by about 50% throughout life
– 4-6 Gy acute whole-body exposure likely to be fatal
– 10’s of Gy dose to specific targets areas in radiotherapy
• Sievert (1 Sv = 100 rem) equivalent dose
– Weighted by a “quality factor” to allow for biological effectiveness of different types of radiation (for x-rays & gamma rays 1 Sv = 1 Gy)
– Primarily used for radiation protection
– 2 mSv / year average natural background
– Occupational exposure limits 50 mSv in one year and no more than 100 mSv in 5 years
Human Exposures
• Natural Population exposure to
– cosmic (vary by altitude),
– terrestrial (radioactive elements in soil);
– internally deposited (radium)
– Radon
• Man-made
– medical uses – increase with age
– occupational, nuclear power, fallout, consumer products
– Radiological emergencies
Populations Studied
• Atomic Bomb Survivors
• Medical Exposures
– Diagnostic and therapeutic external : fluoroscopy (TB patients), mastitis pts, ringworm of scalp, Ct scans
– Therapeutic internal exposure (I131)
– Cancer survivors (Hodgkins disease)
• Occupational – military, miners, radium dial
• Environmental – indoor radon, fallout, Chernobyl (accidents), Techa River
Cancer Associations
• Frequent
– Leukemia, thyroid, breast
• Occasional
– Lung, stomach, colon, esophagus, bladder, ovary, myeloma
• Rarely
– Brain, kidney, liver, plus
• Uncertain
– CLL, certain childhood cancers
Radiation Tumor Biology
Implications of Radiation
Biology Findings• Rethink dose risk estimation
• Rethink use of low and high dose radiation
in diagnostic and therapeutic settings
Radiation Impacts in Humans
• All Cancers – Examples
– contamination of the Techa River
– Uranium exposure – environmental
• Other Health Effects
– Cardiovascular
– cataract
Project Team (2003-present)
• URCRM
– Alexander Akleyev (Director)
– Ludmila Krestinina (Epidemiology)
• US
– Faith Davis (UIC/UA)
– Dale Preston (Hirosoft Corp)
Funded by the US Department of Energy (DE-FC02-07HS00701
Goals
• Obtain comprehensive data on cancer
incidence for members of the TRC
• To investigate how cancer incidence varies
with radiation dose.
• Born before 1.1.1950 exposed along Techa
River
• Primarily strontium, cesium, I131 exposures
Death Certificates
Medical Records
ResettlementLists
Internal Passports
Tax Books
Interviews
Alive &Unknown
Dead
Oncology Clinics
URCRM Clinic
Health Centers
ZAGS Certificate
Medical Death Certificate
(Statistics office)Autopsy/ Pathology
BureauCancer Death Non-Cancer Death
Cancer Cases
Cause of Death
TRC
Vital Status Address Bureaus
Population Census
FOLLOWUP
COHORT IDENTIFICATION
CANCER OUTCOMES
Data Organization
• Cases/person-years (rates) stratified on:
– Fixed factors• Gender, Ethnicity, Initial oblast, Entry period , Entry
age
– Time-dependent factors• Catchment area, Attained age,
Time period, Time since entry,Lagged dose (stomach / marrow, or both)
• Allowed for individual residence histories• Time-dependent stratification on catchment area
• Exclusion of periods when residence unknown or out of area
Solid Cancer Mortality:1950-2007(Schonfeld et al, 2013)
Stomach
Dose (Gy)PYR Cases Expected
Fitted
Excess
< 0.01 624,541 1,287 1,281 4
0.01 - 157,110 350 346 8
0.05 - 18,662 38 38 2
0.1 - 28,792 75 63 8
0.2 - 9,147 24 17 4
0.3 + 20,035 74 56 20
Total 858,286 1,848 1,802 46
Non-CLL Leukemia 1953-2007(Krestinina et al, 2013)
Marrow
Dose (Gy)PYR Cases Expected
Fitted
Excess
< 0.01 143,479 5 3.6 0.1
0.01 - 67,237 1 1.7 0.3
0.05 - 79,304 3 2.2 1.0
0.1 - 170,860 10 4.8 4.7
0.2 - 124,088 5 3.6 5.3
0.3 - 118,670 15 3.2 7.8
0.5 - 131,952 17 3.6 15.7
1 + 22,696 6 0.5 3.9
Total 858,286 62 23.2 38.8
Non-CLL Leukemia(Krestinina et al 2013)
ERR / Gy 6.2 (95% CI 2; 19)
P < 0.001
Nonlinearity P >0.4 upward
Gender P = 0.4 F > M
Age P = 0.5
Age at entry P > 0.5
Time since entryP = 0.50.00 0.25 0.50 0.75 1.00 1.25
0
2
4
6
8
10 Linear
Linear-Quadratic
Excess R
ela
tive R
isk
Dose (Gy)
Non-CLL deaths only ERR / Gy 5.0
Techa River Incidence CohortDavis et al, 2015
• 17,435 cohort members
• 1956-2007
• 1933 solid cancer cases
• 472,788 Person-years
• 42% of the cohort initially exposed prior to
age 20 accounts for almost half of the
person-years and less than 30% of the
cases.
Methods Overview
• TDRS2009: individualized dose estimates
• Time-dependent five-year-lagged stomach
dose (mean 60mGy)
• Follow-up >50 years
• Site specific cancer incidence risk
estimates
• Smoking adjusted estimates
Study Cohort: Age at Entry
Cases PersonYrs Stomach Dose mGy
Entry Age Median 90%tile
0-19 570 234,966 21 136
20-39 843 167,912 13 118
40+ 520 69,910 13 115
To put this exposure in context:ABS average dose was 200mGy (so an order of magnitude lessAverage dose from Dx tests in 1982 was 0.5 mGyAverage dose from Dx tests in 2006 was 3.0 mGy(In 7 years get similar Dx dose as youngest age group)
Study Cohort: Smoking
Smoking People Cases PersonYears
Male never 1,092 95 234,966
Male ever 2,239 200 167,912
Male unknown 4,190 569 69,910
Female never 4,560 354 234,966
Female ever 89 5 167,912
Female unknown 5,265 611 69,910
Solid Cancer Incidence Rates
Pyrs Cases Crude
Rates/10,000
Pyrs
Ethnicity
Tartar/Bashkir 72,562 305 42.0
Slav 119,124 658 55.2
Birth year
1860-1924 47,800 463 96.9
1925-1934 52,966 280 52.9
1935-1949 90,920 220 24.2
Fitted Excess Cancer Cases (linear smoking adjusted models 1956-2007,TRDS-2009)
Dose (Gy) PYr Cases Excess
0 11,870 17 0.0
-0.1 154,221 630 2.5
-0.05 196,764 799 16.6
-0.1 58,522 246 9.1
-0.15 23,616 105 8.6
-0.3 16,731 71 9.2
0.3+ 11.065 65 15.3
Total 472,788 1933 61.3
Davis et al, 2015
Solid Cancer Dose-ResponseDavis et al. 2015
Linear trend (P=0.02) in smoking-adjusted all-solid cancer incidence. ERR following exposure to 100 mGy of 0.077 (95% CI of 0.013 to 0.15). 61.3 excess cases
Selected Site Specific Cancers
Men Women %DC Mean
age
ERR 95%CI Excess
Esophagus 50 58 20 67 0.46 0.04-1.20 20.2
Stomach 209 156 26 65 0.13 -0.02-0.34 18.7
Uterine 0 203 14 57 0.21 0.01-0.51 15.5
Breast 0 118 4 59 0.19 -0.06-0.61 8.5
Observed and fitted esophageal cases from smoking adjusted linear ERR models
People Pyrs Cases Fitted*
Background
Fitted*
Excess
Sex
Male 7,521 191,686 50 -1.36 -1.36
Female 9,914 281,102 58 25.24 25.24
Ethnic group
Slav 11,810 291,724 36 1.65 1.65
Tartar/Bashkir 5,625 181,064 72 23.6 23.60
What we have learned
• TRC provides strong, clear evidence of radiation risks
from moderate environmental radiation doses at low
dose rates.
– Significant dose response for solid cancer and leukemia
– Consistent estimates for solid cancer incidence and mortality
• Solid cancer estimates similar to those in the ABS
• All Leukemia estimates similar to those observed in
other cohorts - absence of a CLL effect unexplained.
• Site specific analysis limited by sample size.
• Uncertainty in the shape of the dose-response
especially at doses below 100mGy.
Radiation impact on Human Health (Shore, 2014)
Outcome Dose Evidence
Solid cancer and
Leukemia
Mod-high established
100-200mSv fuzzy
10-20 mSv unknown
Cardiovascular <1Sv fuzzy
Cataract 32% excess at 1Gy Becoming strong
Uranium
• Heavy metal - naturally occurring
radionuclide
• 3 primary isotopes I234 I235 I238 - Alpha
particles
• Weakly radioactive – long half lives 275k yrs,
700mm yrs 4.5 b yrs and slow decay rates
• Most types soluble - leaves body in few
days
• Ubiquitous – breathing, eating, drinking and contact
with consumer products. (inhaled – lung, ingested –
poorly absorbed in GI system, excreted through kidney)
Populations living near Uranium facilities
What about CT Scans?
• Doses in adults considered to be at levels
of concern for carcinogenesis.
• 700,000 per year
• Most common exposure to low-medium IR
in the general US population
• 5-10% of imaging is CT reflecting 49-67%
of all medical radiation exposure
• About 1/3 of CT scans are medically
unnecessary
Uncertainties
• Shape of dose-response curve – particularly
at low doses for sparsely ionizing radiation (x-rays,
gamma rays)?
• Is risk diminished when exposure is
spread over time?
• Type of exposure? X-rays vs Uranium?
• Internal vs external exposure?
• Biological modifiers?
• Estimates of life-time risk may be four
times larger than previously thought (NAS,
1990)
Case Control Study
• Cases: adult glioma patients from Duke
University and Evanston Hospital. English
speaking US residents with mental
capacity to consent within 3 months of
diagnosis (2003 – 2007).
• Controls: Friend controls
• 273 cases had friend controls.
• Surveys: 205 cases and 333 friend
controls.
3.73 (1.24, 11.19)
0.80 (0.22, 2.85)
.51
.52
.53
.54
.5
Ad
juste
d*
Odd
s R
atio
(9
5%
CI)
Yes No
Family History of Cancer*Adjusted for age and gender
CT Scans in Subjects with a
Family Hx of Cancer
Family Hx of
Cancer = Yes
Number of CT
Scans
Cases Controls Adj OR P-value for
trend
3+ 13 5 3.7 (1,2-11.3)
1-2 24 37 1.1 (0.6-1.9) 0.06
Zero 80 131 Ref
P-value for overall interaction effect (2df) =0.21;p – value for family hx interaction with 1-2 CT scans = 0.86 and with 3* scans is 0.08
