Slide 1

What environmental factors are linked to childhood leukaemia and are they detectable epidemiologically? Denis L Henshaw H H Wills Physics Laboratory University of Bristol 2 nd CHILDREN with LEUKAEMIA Conference 29 th & 30 th April 2008 Childhood Leukaemia Causes and Prevention Slide 2 I will consider. Natural Background Radiation low-LET stable over time; high- LET (radon) small increase Light-at-night large increase last century Power frequency magnetic fields low average exposures but a general increase Air pollution significant increase in ultrafine/nano particles (Shah & Coleman BJC 2007; 1 - 4) Childhood leukaemia is believed to have shown a real increase last century Slide 3 Natural background ionising radiation Childhood leukaemia risk has been extensively studied at medium and high level exposures in the Japanese Atomic Bomb survivors and fallout from nuclear weapons testing (Wakeford Oncogene 23: 6404-, 2004) Increased risk in relation to in utero exposure from obstetric X-rays has been demonstrated with acute doses of 10 mSv or lower (Doll & Wakeford BJR 70: 130-, 1997) Natural background radiation exposure rate in the UK is ~2.7 mSv y -1. HPA/NRPB Slide 4 Risk estimates derived from these exposures suggest that natural background radiation contributes to childhood leukaemia incidence UK COMARE 4th Report (1996) page 62: Slide 5 Natural background radiation.. For high-LET ( -particles) the 14% link divides: ~9% 210 Po RR = 1.09 at normal 210 Po levels compared with zero 210 Po ~5% Radon RR = 1.05 at 20 Bq m -3 compared with zero radon Both high and low-LET estimates are essentially undetectable in a case-control study because: (i) of ubiquitous exposure to low-LET radiation with little place-to-place variation and (ii) for radon, too few statistics in the high vs low exposure category to provide statistical power Slide 6 Radonleukaemia correlations There have been a number of reports of geographical associations between radon and leukaemia: Lucie 1989, Henshaw et al 1990, Alexander et al 1990, Butland et al 1990, Lucie 1990, Muirhead et al 1991 & 1992, Cohen 1993, Richardson et al 1995, Lyman et al 1986, Collman et al 1991, Viel 1993, Forastiere et al 1992, Hoffman et al 1993, Thorne et al 1996, Kohli et al 2000, Anne-Sophie Evrard et al 2004 But few case-control studies have reported an association Slide 7 Light-at-night (LAN) Europe in the Present Europe in the past Slide 8 The Melatonin Hypothesis and breast cancer Richard Stevens University of Connecticut 1987 Exposure to light-at-night or magnetic fields suppresses the nocturnal production of the natural anti-cancer agent melatonin in the pineal gland leading to increased risk of breast cancer Has much support for visible light: evidence that female night shift workers have elevated breast cancer risk (Meta-analysis of 13 studies: Megdal et al. Eur J Cancer 41: 2023-2032, 2005) Womens blood containing normal physiological concentrations of nocturnal melatonin prevents growth of MCF-7 breast tumours transplanted into rats (Blask et al. Cancer Res, 65: 1-11, 2005) 2007: IARC has classed night shift work as a Class 2A, probable carcinogen Slide 9 Melatonin (N-acetyl-5-methoxytrptamine) Melatonin is a hormone produced in the pineal gland mainly at night Ganglion cells in eye (not visual system) signal when there is no light pineal melatonin produced at night Powerful anti-oxidant with multiple actions, many receptor mediated By a scavenging cascade one melatonin molecule can scavenge up to 10 ROS/RNS (Tan et al J Pineal Res. 42; 28-42, 2006) Slide 10 Light-at-night and childhood leukaemia Melatonin protects against oxidative damage to the fetus in animals (Wakatsuki et al 1999a, b &c; Okatani et al 2001) Melatonin is highly protective of oxidative damage to the human haemopoietic systems (Vijayalaxmi et al Mutat Res: 371; 221-,1996): Four human volunteers took 300 mg melatonin, after 2 hours blood samples exposed to 1.5 Gy -radiation. 50-70% reduction in DNA damage in lymphocytes Melatonin inhibits proliferation of HL60 myeloid leukaemia cells (Rubio et al J Pineal Res 42: 131-, 2007, 42) Has not been studied but: Slide 11 Fig. 1. Changes of maternal serum melatonin levels at night-time (solid line) or daytime (dotted line) in the normal singleton pregnancy. Serum melatonin level and its relationship to feto-placental unit during pregnancy (Nakamura et al J Pineal Res 30: 29-33; 2001) Slide 12 Power frequency electric & magnetic fields - especially magnetic fields, MFs (Richard Boxs FIELD February 2004 Photo: Stuart Bunce, www.richardbox.com) Under powerlines MFs can be several T or evens tens of T Appliances: can be tens of T close to Average MF home levels 0.05 T Doubling of CL risk associated with 0.3/0.4 T Slide 13 Childhood leukaemia and magnetic fields (MFs) Reported MF associations with childhood leukaemia at various stages: a)Paternal peri-conceptual - Pearce et al (Pediatr Blood Cancer, 49: 280-, 2007) b)Birth address - Draper et al (BMJ, 330, 1290-, 2005); c)Diagnosis address - Ahlbom et al. (2000) and Greenland et al. (2000) doubling of risk above 0.3/0.4 T average exposure. More recently Kabuto et al (Int J Cancer 119: 643-, 2006); a)Reduced survival in children treated for ALL - Foliart et al (B J Cancer, 94, 61-, 2006); A linear no-threshold model would suggest ~11% of CL cases linked to MFs in the UK International Agency for Research on Cancer (IARC) 2001 declares magnetic fields a Class 2B possible carcinogen Statements about precaution - WHO (2007); SCENIHR (2006); UK SAGE Report (2007) Slide 14 Disease IARC 2002 2B* NIEHS 1999** 2B Calif 2002 2B 1. Childhood LeukaemiaYes 2. Adult LeukaemiaYes 3. Adult Brain CancerYes 4. MiscarriageYes 5. ALSYes But, stepping back from CL: Review bodies assessments of MF causation of various diseases. *Class 2B, possible carcinogen **US National Institute of Environmental Sciences See also OCarroll & Henshaw (Risk Analysis, 28(1), 225-, 2008) Evidence for MF link with Adult leukaemia, and at least as good as for childhood leukaemia. Alzheimer's disease also comparable (Garcia et al Meta Analysis 25 studies: Int J Epidemiol 2008) Slide 15 Illnesses associated with MFs Is there a common factor? Childhood leukaemia, Adult leukaemia, Adult brain cancer, ALS, Alzheimer's disease, Depression, Suicide, Miscarriage, Breast cancer Disruption of Melatonin Populations exposed to neighbourhood EMFs shown melatonin disruption with fields as low as 0.2 T (Review by Henshaw & Reiter, Bioelectromagnetics S7: 86-97, 2005) Slide 16 The Radical Pair Mechanism: When two radicals created from one precursor, spin states are coupled (+, -) singlet state ( ~ns) If the spin of one of the species changes, radical pair will have parallel spins triplet state ( ~ s) + - Molecule spin = 0 Singlet radical Pair (ns) Triplet radical Pair (s) + - Spin change + Separation: Free radicals Magnetic fields can increase the lifetime of free radicals - More available to damage DNA Slide 17 Low magnetic field effects previously degenerate energy states resolve (Timmel et al. Mol Phys 95: 71-89, 1998) Increases probability of transitions from singlet (ns) to triplet state ( s) of radicals Results in more triplets longer lived ( s), more available to cause biological damage Experimental support in chemical systems (e.g. Liu et al Chem Commun 174-, 2005) Magnetic fields can increase the lifetime of free radicals by driving singlet spin states to triplet states Slide 18 Biological evidence for the RP mechanism increased lifetime of free radicals Juutilainen et al. (IJRB 82; 1-12, 2006) review of 65 in vitro & animal studies MFs enhance the effects of known harmful agents, p