Risk Models for Radiationinduced

Risk Models for Radiationinduced Leukaemia Richard Wakeford Visiting Professor in Epidemiology, Dalton Nuclear Institute, The University of Manchester, UK (Richard.Wakeford@manchester.ac.uk)

Measures of Risk Excess Relative Risk (ERR) is the proportional increase in the risk of a disease compared to the background absolute risk in the absence of exposure. For example, an ERR of 1 is a 100% increase of the risk over background. Relative Risk (RR) is the ratio of the overall risk to the background risk (RR = ERR + 1). For example, a RR of 2 is a doubling of the risk. Excess Absolute Risk (EAR) is the additional risk above the background absolute risk in the absence of exposure.

Measures of Risk ERR = (0.00045 0.00015) / 0.00015 = 2 red / blue RR = 0.00045 / 0.00015 = 3 (red + blue) / blue EAR = 0.00045 0.00015 = 0.0003 red

Hiroshima and Nagasaki 6 th and 9 th August 1945

LSS Leukaemia Mortality Ozasa et al., Radiat Res 2012; 177: 229-243 covers 318 leukaemia deaths in the Life Span Study (LSS) between 1950 and 2003. Based on a linear-quadratic dose-response model (all ages, both sexes): ERR = 3.1 (95% CI: 1.8, 4.3) at 1 Gy ERR = 0.15 (95% CI: -0.01, 0.31) at 0.1 Gy

LSS Leukaemia Mortality Preston et al., Radiat Res 2004; 162: 377-389 covers leukaemia deaths in the LSS between 1950 and 2000. 296 deaths, 204 with RBM doses >5 msv, against an fitted background of 203. Approaching half the deaths in the non-trivially exposed are attributed to exposure. Follow up only started in 1950, although it is clear that excess deaths occurred earlier.

Leukaemia Deaths (1950-2000) (Preston et al., Radiat Res 2004; 162: 377-89)

RERF Leukaemia Mortality (Preston et al., Radiat Res 2004; 162: 377-89) EAR (or ERR) = (α.d+β.d 2 ).ω s.θ i.(t/25) τ i d, RBM dose in Sv ω s, sex dependent parameter t, time since exposure (years) θ i, τ i depend on age at exposure, e: 0-19, 20-39, 40 years of age

RERF Leukaemia Mortality

BEIR VII Leukaemia Mortality EAR or ERR = (α.d+β.d 2 ).ω s.exp[γ.e* +δ.ln(t/25)+ϕ.e*.ln(t/25)] d, RBM dose in Sv ω s, sex dependent parameter t, time since exposure (years) e* =(e-30)/10 for e<30 and =0 for e 30 e, age at exposure (years)

BEIR VII Leukaemia Mortality

BEIR VII/NCI Leukaemia Mortality

UNSCEAR Leukaemia Mortality EAR = (α.d+β.d 2 ).ω s.θ.(t/25) τ ERR = (α.d+β.d 2 ).θ.[(e+t)/25] τ d, RBM dose in Sv ω s, sex dependent parameter t, time since exposure (years) e, age at exposure (years) (e+t) = a, attained age (years)

UNSCEAR Leukaemia Mortality

LSS Leukaemia Mortality (Richardson et al., Radiat Res 2009; 172: 368-82) ERR = (α.d+β.d 2 ).ω c.exp[γ.e*+ϕ.e*.t d, RBM dose in Sv +ζ.e*.t 2 +ξ.e*.t 3 +ψ.e*.(t*) 3 ] ω c, city (H/N) dependent parameter t, time since exposure (years) t* =(t-30) for t>30 and =0 for t 30 e* =(e-30)/10 for e<30 and =0 for e 30 e, age at exposure (years)

Richardson Leukaemia Mortality

LSS Leukaemia Incidence Preston et al., Radiat Res 1994; 137: S68- S97 covers leukaemia incidence in the LSS between 1950 and 1987, using DS86 doses. 231 cases, 141 with RBM doses 100 mgy, against a fitted background of 75 cases. UNSCEAR 2006 Report gives (all ages, both sexes): ERR = 4.84 (90% CI: 3.59, 6.44) at 1 Sv

RERF Leukaemia Incidence (Preston et al., Radiat Res 1994; 137: S68-S97) EAR = (α.d+β.d 2 ).ω s.θ i.exp[τ i.(t-25)] d, RBM dose in Sv ω s, sex dependent parameter t, time since exposure (years) θ i, τ i depend on age at exposure, e: 0-19, 20-39, 40 years of age

ICRP Leukaemia Incidence

Transfer of Risk Whether the cancer risk model is expressed in terms of the ERR or the EAR is not usually of importance for the population that generated the data from which the risk model was developed (e.g. for the Japanese atomic-bomb survivors). However, whether the ERR or the EAR is transferred to another population will be important if background risks are materially different.

Transfer of Risks

Leukaemia Background Risk Leukaemia incidence rates have increased with time, especially for young children. This rise occurred earlier in the economically developed countries. Of relevance is how excess risk is transferred from the LSS EAR or ERR? Increasing success of treatment of leukaemia, especially children, has led to a decrease in mortality, but not incidence.

Transfer of Risk ICRP (2007) assumes 100% transfer of the EAR from the bomb survivors. BEIR VII assumes 30%/70% transfer of the EAR/ERR from the bomb survivors. Who is right?

Other Exposed Groups British ankylosing spondylitis patients and US cervical cancer patients are important radiotherapy groups. Little et al. (Radiat Res 1999; 152: 280-92) conducted a joint analysis of leukaemia in the LSS and these radiotherapy groups. Other groups provide information on the appropriateness of the LSS models under various circumstances.

Type of Leukaemia Main types of leukaemia: Acute lymphoid leukaemia (ALL) Acute myeloid leukaemia (AML) Chronic myeloid leukaemia (CML) Chronic lymphoid leukaemia (CLL) Distinct risk models for these different types may be necessary see Preston et al. (1994) and Richardson et al. (2009) and is indicated by Little et al. (1999).

CT Scan Cohort Study Pearce et al., Lancet 2012; 380: 499-505

Natural Background γ-radiation Kendall et al. Leukemia 2012 (in press) )

ERR/Sv Comparisons Oxford Survey of Childhood Cancers (fetal) 51 (95% CI: 28, 76) Gy -1 at ~10 mgy (X-rays) CT scan study ( 21 years of age) 36 (95% CI: 5,120) Gy -1 at ~10 mgy (X-rays) Natural background radiation study (children) 120 (95% CI: 30, 220) Gy -1 (γ-rays) NRRW-3 (adult workers highly fractionated) 1.7 (90% CI: 0.1, 4.3) Sv -1 (mainly γ-rays)

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