The cancer epidemic, risk assessment and the requirement

for precaution

Dr. C. Vyvyan Howard FRCPath.Developmental Toxico-Pathology

University of Liverpoolc.v.howard@liv.ac.uk

The Precautionary Principle

• "When an activity raises threats of harm to human health or the environment, precautionary measures should be taken, even if some cause and effect relationships are not fully established scientifically"‘Wingspread Statement on Chemically-Induced Alterations to immune system.’ Environmental Health Perspectives, 104:4, August 1996.

Risk Assessment

• The main tool used to hinder the implementation of the Precautionary Principle

• Used as ‘proof’ that technologies are safe• Often accepted as hard proof, even when

based on questionable data models

Risk assessment was designed by engineers to assess the reliability of engineered structures, where most of the facts are known or can be measured.

Risk Assessment –Invented by Engineers

• Used to assess the integrity of structures• Most information required is available• Realistic risk assessments possible• Lead to over design of structures

– Bridges and buildings typically x 5– Aircraft typically x 1.1 to 1.2The tighter the margin – more research required

Risk Assessment – 4 phases

• Hazard identification – requires insight and understanding of the system in question

• Hazard assessment – costs time and money for hard science – positive findings require action

• Exposure assessment – can be very expensive and, for human exposure, complex

• Risk assessment – depends totally on the 1st three steps

Risk assessment in engineeringis not foolproof

• Despite sophisticated models based on hard data and years of experience unpredictable events still happen

• This represents either a failure of hazard identification or of hazard assessment

Complex Systems

• Risk assessment is now being applied to very complex systems - such as ecosystems

• It is impossible to have comprehensive hazard data for such systems

• Missing data is often provided by ‘data models’, but these can be subjective

• Sometimes the whole risk assessment can be based solely upon data models

BATNIEC vs CATNIP

• Best Available Technology Not Involving Excessive Cost

• Cheapest Available Technology Not Involving Prosecution

• However in risk assessment it could be: Confusing Alternative Theory Not Involving the Producer

Possibilities for investigation

• Man made: e.g. chemicals, radionuclides, particulate aerosols, etc.

• Lifestyle: e.g. smoking, eating, sedentarism, choosing the wrong parents, etc

• Nature: e.g. sun spot activity, volcanoes etc

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Xeno-chemical exposure

• During the period of rapid rise in incidence of cancer we have been exposed to a complex mixture of novel chemicals, some genotoxic, some acting as cancer promoters.

• This toxicity of this mixture, consisting of 10’s of thousands of congeners, enantiomers and metabolites, is beyond the current ability of toxicologists to analyse

Evidence of presence of rapidly metabolised compounds

Evidence of the presence of persistent xeno-chemicals

The developmental process is both sensitive and vulnerable

Human Reproduction VoLl6, No.5 pp. 972-978, 2001

OPINION

Testicular dysgenesis syndrome: an increasingly commondevelopmental disorder with environmental aspects------------------------------------------------------------------------------N.E.Skakkebrek1, E.Rajpert-De Meyts and K.M.Main

Department of Growth and Reproduction, Copenhagen University Hospital, Copenhagen, Denmark1To whom correspondence should be addressed at: Department of Growth and Reproduction, Copenhagen University Hospital(Rigshospitalet, Section GR-5064), 9 Blegdamsvej, DK-2100 Copenhagen, Denmark. E-mail: nes@rh.dk

Numerous reports have recently focused on various aspects of adverse trends in male reproductive health, such asthe rising incidence of testicular cancer; low and probably declining semen quality; high and possibly increasingfrequencies of undescended testis and hypospadias; and an apparently growing demand for assisted reproduction.Due to specialization in medicine and different ages at presentation of symptoms, reproductive problems used tobe analysed separately by various professional groups, e.g. paediatric endocrinologists, urologists, andrologists andoncologists. This article summarizes existing evidence supporting a new concept that poor semen quality, testiscancer, undescended testis and hypospadias are symptoms of one underlying entity, the testicular dysgenesissyndrome (TDS), which may be increasingly common due to adverse environmental influences. Experimental andepidemiological studies suggest that TDS is a result of disruption of embryonal programming and gonadaldevelopment during fetal life. Therefore, we recommend that future epidemiological studies on trends in malereproductive health should not focus on one symptom only, but be more comprehensive and take all aspects of msinto account. Otherwise, important biological information may be lost.

Keywords: environmental disrupters/inferti1ity/male reproduction/testicular cancer/ testicular development

Exposure to ionising radiation

• We have been exposed to external ionising radiation throughout evolution

• Since the start of atmospheric weapons testing we have been exposed to novel sources of radiation in the form of internalised particles of radioactive material

• This has happened over the same period during which there has been a rapid rise in cancer incidence

Elements migrate from sea to land

• It turns out that in the UK, 30% of the smallrespirable particles in the air of less than 10 microns diameter (known as PM10) come from the action of the waves, which produce small droplets of water that then evaporate and leave a suspended crystal of salt, which remains airborne. Scientists have been aware since 1984 that radioactive actinides have been coming ashore by this mechanism. Eakins JD, Lally AE (1984) ’The transfer to land of actinide bearing sediments from the Irish Sea by spray’ Science of the Total Environment 35: 23-32

Plutonium across the UK

Plutonium in teeth

Plutonium in autopsy specimens

Of Risk Assessment..

• A former director of the US EPA said:

• “We should remember that risk assessment can be likened to the captured spy: if you torture it long enough, it will tell you anything you want to know”

ICRP Phantom

External vs Internal Radiation

ICRP model averages radiation dose into the body volume

When ‘hot particles’ are internalised they intensely irradiate a very small volume

Averaging the radiation from low dose internalised radionuclides is clearly an inconsistent model.

Depleted uranium particle doses

Absorbed dose

• D = −E / −M

• −E energy in Joules• −M mass in Kilos• Unit: Gray (Gy)• 100 Rads = 1 Gy

• ICRP fundamental dosimetric quantity is the absorbed dose (energy absorbed per unit mass).

• However different radiations have differing ionisation densities

Equivalent dose

• The choice of these WR factors can be subjective and are made by committees such as the ICRP.

• Very conservative assumptions can be used to justify the status quo ante

• HT = ;R WR DT,R

• HT:equivalent dose, H, in tissue, T.

• DT,R:absorbed dose averaged over tissue

• WR:radiation weighting factor

• Unit: Sievert (1 Sv ≈ 100 rem)

ICRP radiation weighting factors

Type of radiation WR

X- and Κradiation, all energies

1

ϑ particles 1

Ι particles 20

Neutrons & protons

5 to 20

• In 1980s ICRP considered applying WR factors of 2 for Tritium and 5 for Auger emitters (e.g. Ba-140), but made no changes.

• Relative biological effectiveness (RBE) is the inverse ratio of absorbed doses (Ι,ϑ,Κ) producing the same degree of a defined biological endpoint. WRroughly equivalent to Linear Energy

Transfer (LET) along ionisation track

ECRR approach

• This approach takes the properties of individual isotopes into account. E.g. Strontium 90 ( a divalent ion) binds to chromosomes and then decays to Ytrium 90 (a trivalent ion) which bioaccumulates

• BT,E=;R NE HT,R• BT,E :Biological equivalent dose• NE :Hazard enhancement

weighting factor

• NE = ; WJ WK• WJ biophysical hazard factors• WK isotope biochemical hazard

factors

Table 6.2 from ECRR 2003 – ISBN: 1 897761 24 4

Biophysical hazard factors in low dose range

Type of exposure Factor WJ Notes1. External acute 1.0

2. External protracted 1.0 Dose rate sparing is not assumed

3. External: 2-hits in 24 hrs 10 to 50 Allows for repair interception

4. Internal atomic single decay 1.0 e.g. Potassium-40

5. Internal atomic 2nd Event 20 to 50 Depends on decay sequence and dose

6. Internal Auger or Coster-Kronig

1 to 100 Depends on location and energy

7. Internal insoluble particulate 20 to 1,000 Depends on activity , particle size and dose

Table 6.3. ECRR 2003: Specific isotope hazard enhancement factors

Isotope or class Factor WK Mechanism of enhacement3-H, Tritium 10 to 30 Transmutation & local dose;

hydrogen bonding; enzyme amplifyIonic equilibria cations e.g. K,Cs,Ba,Sr,Zn

2 to 10 Local conc. By interfacial ionic adsorption; depends on effect

DNA binding e.g. Sr, Ba, Pu

10 to 50 DNA primary, secondary and tertiary structure disruption

14-C 5 to 20 Transmutation and enzyme amplification

35-S, 132-Te 10 Transmutation and enzyme amplification; hydrogen bonding

Enzyme & co-enzyme seekers e.g. Zn,Mn,Co,Fe

10 Enzyme amplification

Fat soluble noble gases e.g. Ar-41, Kr-85

2 to 10 Depends on effect considered

Barrier transmutation series e.g. Sr-90, Y-90

2 to 1,000 Depends on effect considered

Table 13.3 from ECRR 2003 – ISBN: 1 897761 24 4Based on Table 58 of UNSCEAR 1993 and ECRR model effective dose committment

Source of exposure ICRP based collective effective dose commitment (person Sieverts)

ECRR based collective effective dose commitment (person Sieverts), using UNSCEAR isotope proportions

Global nuclear tests 22,300,000 579,800,000

Weapons fabrication 10,000 260,000

Nuclear power production 100,000 2,600,000

Radioisotope production 80,000 8,000,000

Accidents 602,120 15,655,120

Local & regional doses 380,000 9,880,000

Total 23,472,120(b4.7 mSv)

616,195,120(b123 mSv)

b based on world population of 5 x 109 assumed by UNSCEAR

Table 13.4 from ECRR 2003 – ISBN: 1 897761 24 4Based on UNSCEAR figures up to 1989

Effect ICRP yield ECRR yield

Cancer deaths 1,173,606 61,619,500

Cancer totals 2,350,000 123,239,000

Infant deaths 0 160,000,000

Fetal deaths 0 188,000,000

Loss of life quality

0 10%

Leukaemia RRs• Sellafield RR=10• Dounreay RR= 8• La Hague RR= 15

• Electrical field studies RR~ 2• Population mixing RR~ 1.5 - 2

Infant leukaemia after Chernobyl

The Nordic leukaemia studyDarby et al, 1993

Danish cancer registry leukaemia data

Effect of the Nevada tests

Conclusions 1

• Cancer incidence rates are increasing overall and for a number of individual malignancies, including leukaemia

• There have been man made chemical and radiological changes to the environment which are completely novel from an evolutionary perspective and preceded these changes

Conclusions 2

• The biological plausibility for associating these changes with the rise in cancer is strong

• The complexity of human exposure to multiple factors in a disease which is acknowledged to be multi-causal makes one to one mappings of cause and effect very difficult or impossible

Conclusions 3

• There can be little reasonable argument that exposure of the population to carcinogens should be avoided

• In the absence of scientific certainty a precautionary stance should be adopted to minimise exposure by removing sources