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