The Internal Radiation Dosimetry of Diagnostic ...

The Internal Radiation Dosimetry of Diagnostic Radiopharmaceuticals across Different Asian Populations Edvin Hansson M.Sc. Thesis, September 2011-January 2012

Supervisors: Brian J. McParland, PhD1 Peter Bernhardt, PhD2 1GE

Healthcare Medical Diagnostics, Amersham, Buckinghamshire, England 2Department

of Radiation Physics, Sahlgrenska University Hospital, Gothenburg, Sweden

Address

Edvin Hansson, M.Sc. Medical Physics student Department of Radiation Physics Institution of Clinical Science Sahlgrenska Academy, University of Gothenburg S-413 45 Gothenburg

E-mail

[email protected]

Telephone

+46(0)76-81 88 089

ABSTRACT This study compares the nuclear medicine dosimetry of Chinese, Indian, Japanese and Korean populations with the Caucasian Reference Man for the following radiopharmaceuticals: 18F-FDG, 123I-ioflupane and 99mTc-tetrofosmin. Due to the differences in body habitus between these populations and the adult Caucasian male, which is typically the standard phantom for internal dosimetry calculations, the dosimetry profiles are expected to differ. From a radiation protection perspective it is important to determine and quantify the dosimetric differences with respect to variations in anatomy and biodistribution. Methods: Anatomical data for the four Asian populations were collected and reviewed. Asian anthropomorphic phantoms were modelled by manipulation of anatomical data of the Caucasian adult male in OLINDA/EXM. Biodistribution data were collected from the literature, and the dosimetry profiles calculated using OLINDA/EXM. The Caucasian adult female and adolescent (15-year old) phantoms were investigated as potential surrogates for the Asian adult male. Results and Discussion: The Asian male phantoms, and especially the Indian, receive mean absorbed and effective doses higher than the Caucasian adult male. For the Asian male phantoms, doses to critical organs differ between -9% and 15% compared to their Caucasian counterpart, and effective doses with -3% to 22%. When variations in anatomical data and biodistribution for a Reference Man are considered, the differences appear to be insignificant due to intra-racial variations. The Caucasian adult female receives absorbed and effective doses greater than both the Caucasian and Asian male phantoms, but the overlap due to variations in anatomy and biodistribution appears to be substantial. Conclusions: Inter-racial differences in internal radiation dosimetry profiles are small compared to intra-racial variations in anatomy and biodistribution. It is therefore concluded that dosimetry profiles evaluated for the unmodified Caucasian adult male phantom are applicable to the Chinese, Indian, Japanese and Korean populations. OLINDA/EXM uses a simplified model which may underestimate some absorbed doses to Asian phantoms. Under the assumption that using OLINDA/EXM for phantom modification is sufficiently accurate, the Caucasian adult female and adolescent phantoms should not be used as surrogates for the adult Asian male.

1

TABLE OF CONTENTS 1

LIST OF ABBREVIATIONS AND TERMS ....................................................................................................... 4

2

INTRODUCTION ................................................................................................................................... 5

3

2.1

Radiopharmaceuticals............................................................................................................. 6

2.2

Dosimetry calculations ............................................................................................................ 6

REVIEW.............................................................................................................................................. 8 3.1

3.1.1

Chinese ............................................................................................................................ 9

3.1.2

Indian .............................................................................................................................. 9

3.1.3

Japanese ........................................................................................................................ 10

3.1.4

Korean ........................................................................................................................... 10

3.2

4

5

Asian Reference Populations .................................................................................................. 8

Radiopharmaceutical biodistribution data ........................................................................... 11

3.2.1

18

3.2.2

123

3.2.3

99m

F-FDG .......................................................................................................................... 11 I-iofluplane ................................................................................................................ 12 Tc-tetrofosmin .......................................................................................................... 12

METHODS AND MATERIALS ................................................................................................................. 13 4.1

Absorbed doses..................................................................................................................... 14

4.2

Effective dose ........................................................................................................................ 14

4.3

Phantom modelling ............................................................................................................... 15

4.4

Error estimates...................................................................................................................... 16

RESULTS ........................................................................................................................................... 16 5.1

Anatomical data .................................................................................................................... 16

5.2

Absorbed doses..................................................................................................................... 17

5.2.1

18

5.2.2

123

5.2.3

99m

5.2.4

99m

5.3

F-FDG .......................................................................................................................... 18 I-iofluplane ................................................................................................................ 19 Tc-tetrofosmin (rest) ................................................................................................ 19 Tc-tetrofosmin (exercise) ......................................................................................... 19

Effective doses ...................................................................................................................... 21

5.3.1

18

5.3.2

123

5.3.3

99m

5.3.4

99m

F-FDG .......................................................................................................................... 21 I-iofluplane ................................................................................................................ 21 Tc-tetrofosmin (rest) ................................................................................................ 22 Tc-tetrofosmin (exercise) ......................................................................................... 22

5.4

Phantom modelling ............................................................................................................... 25

5.5

Error estimates...................................................................................................................... 25 2

6

5.5.1

18

5.5.2

123

F-FDG .......................................................................................................................... 25 I-ioflupane ................................................................................................................. 25

DISCUSSION ...................................................................................................................................... 27 6.1

Absorbed and effective doses ............................................................................................... 27

6.2

Phantom modelling and choice of phantom ........................................................................ 27

6.3

Uncertainties ......................................................................................................................... 29

6.3.1

Asian Reference Populations ........................................................................................ 29

6.3.2

Radiopharmaceutical biodistribution data ................................................................... 30

6.3.3

Absorbed dose calculations .......................................................................................... 30

6.3.4

Effective dose ................................................................................................................ 31

6.4

Future aspects ....................................................................................................................... 31

7

CONCLUSIONS ................................................................................................................................... 32

8

ACKNOWLEDGEMENTS ....................................................................................................................... 33

9

REFERENCES ..................................................................................................................................... 33

Appendix 1 – Anatomical data for adult female and paediatric phantoms.......................................... 38 Appendix 2 – Mean absorbed doses for female and paediatric phantoms.......................................... 44 Appendix 3 – Effective doses for female and paediatric phantoms ..................................................... 47 Appendix 4 – Error estimates for 123I-ioflupane .................................................................................... 50

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1 LIST OF ABBREVIATIONS AND TERMS Item

Absorbed fraction Cross-irradiation Cumulated activity

Dose factor

Equivalent dose FDA FDG IAEA ICRP LLI MIRD MIRDOSE Normalised cumulated activity OLINDA/EXM PET

Residence time S-factor SAF Self-irradiation Specific Absorbed Fraction SPECT SSM ULI

Description Administered activity (MBq) Cumulated activity (MBq·h) in region S Normalised cumulated activity (MBq·h) in region S Fraction of energy released from a source region that is absorbed in a target region Irradiation from a source region to a target region Total number of nuclear disintegrations in a given volume (MBq·h) Normalised mean absorbed dose to colon normalised to administered activity (mGy/MBq) Normalised mean absorbed dose to lower large intestine normalised to administered activity (mGy/MBq) Normalised mean absorbed dose to region Normalised mean absorbed dose in tissue T normalised to administered activity (mGy/MBq) Normalised mean absorbed dose in upper large intestine normalised to administered activity (mGy/MBq) See S-factor Effective dose (mSv) Effective dose normalised to administered activity (mSv/MBq) Absorbed dose weighted for type of radiation (mSv) Food and Drug Administration Fludeoxyglucose International Atomic Energy Agency International Commission on Radiological Protection Lower Large Intestine Medical Internal Radiation Dose Software package for dosimetry calculations in nuclear medicine Cumulated activity normalised to administered activity Organ Level Internal Dosimetry Assessment/Exponential Modeling Positron Emission Tomography Source region Target region Former term for normalised cumulated activity Fraction of energy released per nuclear decay in a source volume reaching a target region, normalised to target region mass (mGy/MBq·h) Specific Absorbed Fraction Special case of cross-irradiation when the target region is also the source region Absorbed fraction normalised to target region mass Single-Photon Emission Computed Tomography Strålsäkerhetsmyndigheten, Swedish Radiation Safety Authority Upper Large Intestine Tissue weighting factor for tissue or organ used for calculation of the effective dose. 4

2 INTRODUCTION Evaluating the internal radiation dosimetry is an essential part of the development of new radiopharmaceuticals. Conventionally, the evaluation is carried out by carrying out model-based calculations on mathematical phantoms representing the Western Reference Man1, which is an anatomical and physiological description of the typical Caucasian man, developed by the International Commission on Radiological Protection (ICRP) (ICRP 2003). Anatomical descriptions of non-Western populations exist (see section 3.1), and there are significant anatomical differences between the ICRP Western Reference Man and these non-Western Reference Men. Pure physics arguments predict differing inter-racial dosimetry profiles, for example the literature indicates that absorbed fractions can vary with 0.5%-1.0% per kilogram change in body weight (Stabin 2008a). The need for quantifying inter-racial differences is justified by the fact that the Asian population grows rapidly, and consists of more than half of the world population (United Nations 2011). It is of interest to determine whether it's safe to evaluated the dosimetry (phase I-studies) on one population (Caucasian) and apply the results onto another (Asian). The dosimetry profile for a given diagnostic radiopharmaceutical is determined by estimating the effective dose and the mean absorbed dose to the critical organ or tissue. This allows for risk comparisons across different radiopharmaceuticals and simplifies dose estimations in case of misadministration. Furthermore, regulatory authorities such as the Food and Drug Administration (FDA) require sufficient benefit-to-risk ratio to approve a given radiopharmaceutical for marketing (McParland 2010). Diagnostic nuclear medicine examinations are associated with low radiation doses, and one may question the need for thorough dosimetry investigation and optimising as long as image quality is sufficient. For the individual, the benefit from the examination is probably worth the small excess risk of inducing cancer, but looking at a population this excess risk may turn into significant numbers and become a burden for society. (McParland 2010) Over the years, the ICRP also developed a Western Reference Woman and Reference Children. These phantoms have physiques generally anatomically closer to the typical Asian male than the Western Reference Man. It is to be investigated if any of these phantoms can, or should, be used as surrogates for the Asian male? This study compares the dosimetry of Chinese, Indian, Japanese and Korean populations with phantoms from the Cristy-Eckerman series, which is based on Western Reference Man data from the ICRP (Cristy and Eckerman 1987). The phantoms used are the adult male (hermaphroditic), adult female and adolescent (hermaphroditic). Three different radiopharmaceuticals are examined: 18Ffludeoxyglucose (18F-FDG), 123I-ioflupane (DaTSCANTM) and 99mTc-tetrofosmin (MyoViewTM). The selected radiopharmaceuticals were deliberately chosen for the following reasons:

1

Reference Man refers to a phantom representative for a specific age group, and can be male, female or hermaphroditic. Hence man does not necessarily refer to a male.

5

  

They are three of the most commonly used radiopharmaceuticals; Their biodistributions differ significantly; and, Data are openly available in the literature.

2.1 Radiopharmaceuticals 18

F-FDG, a positron emitting glucose analogue, is transported with the blood. After phosphorylation to 18F-FDG-6-phosphate, the compound gets trapped in tissue, in proportion to the rate of metabolism, due to low membrane permeability. 18F-FDG is used to image glucose metabolism in the brain or heart, and detect tumours with high metabolism by detection of annihilation photons in a PET scanner, where a strong signal indicates high metabolism (Eberlein et al. 2011, Drug Information Online 2011). The substance is taken up predominantly in brain, heart wall, liver and lung, and is excreted with urine (ICRP 2007). Typical administered activity is 185-370 MBq (The Internet Drug Index 2011). 123

I-ioflupane is a cocaine analogue that binds to neurons in the nigrostriatal pathway, one of the dopamine pathways in the brain (BrainInfo 2011). By detecting emitted gamma radiation using the SPECT-technique, the tracer is used to image a loss of dopamine neurons, which may indicate Parkinson’s disease (Parkinson’s UK 2011). The substance is taken up predominantly in brain, liver and lungs, and is excreted with urine and faeces (Booij et al. 1998a). Typical administered activity is 111-185 MBq (GE Healthcare 2010). 99m

Tc-tetrofosmin is a diphosphine ligand used to image myocardial ischemia by detection of gamma radiation using gamma cameras (SPECT or planar imaging), where a weak signal indicates ischemia. The substance is taken up predominantly in muscular tissue (including heart), kidneys and liver, and is excreted with urine and faeces (ICRP 2007). Typical administered activity is 185-1221 MBq (GE Healthcare 2006).

2.2 Dosimetry calculations Dosimetry calculations for diagnostic radiopharmaceuticals are typically carried out using calculation codes such as the Java based Organ Level Internal Dose Assessment/EXponential Modelling (OLINDA/EXM). OLINDA/EXM, the successor to Medical Internal Radiation Dose (MIRDOSE), was developed at Vanderbilt University, Tennessee and released in 2004-2005 (Stabin et al. 2005). The code, which has been granted an exemption by the FDA (The Journal of Nuclear Medicine 2004), uses the schema developed by the Medical Internal Radiation Dose (MIRD) committee of the Society of Nuclear Medicine (Loevinger et al. 1988), i.e. dose calculations are based on the multiplication of normalised cumulated activity (formerly called residence time) in a source region, , and S-factors (dose factors) predefined for simplistic mathematical phantoms (Eq. 1) from the Cristy-Eckerman series. The S-factor,

(mGy/MBq·h), is defined as ,

6

(1)

where is a proportionality constant (Gy·kg/(MBq·s·MeV)), is the number of radiations with energy (MeV) emitted per nuclear transition, is the absorbed fraction (fraction of energy emitted from source region that is absorbed in target region, ) and is the mass (g) of the target region (Stabin 2008a). Absorbed fractions are based on Monte Carlo simulations and depend of the size and shape of the target and source region, the physical distance between them and properties of the radionuclide. The normalised mean absorbed dose (mGy/MBq) to a target region is calculated as the sum of the contributions from all source regions, ,

(2)

where (MBq·h/MBq) is the normalised cumulated activity (formerly called residence time, ) in region , i.e. cumulated activity normalised to administered activity (MBq); . OLINDA/EXM allows the user to choose from a large number of radionuclides and several different phantoms; adult male (which is in fact hermaphroditic), adult female (including different stages of pregnancy), various paediatric phantoms (hermaphroditic) and special models for prostate gland, peritoneal cavity, sphere-shaped tumours and kidneys. Phantom organ masses and total body weight can be altered, which causes the program to scale the specific absorbed fractions for selfirradiation by organ mass ratios. This is done differently for charged particles and photons when altering an organ mass to , as described by Stabin et al. 2005: Charged particles:

(3)

Photons:

(4)

Equation 3-4 are based on the assumption that the radionuclide is uniformly distributed in an organ which can be modelled as a sphere. This is an approximation which holds for organs whose shapes are not spherical “in an approximate sense”, according to Snyder 1970. Charged particles have an absorbed fractions close to one, hence specific absorbed fraction changes linearly with mass. The photon mean free path in the sphere is proportional to the radius, which is proportional to the cube root of the mass (Snyder 1970). Data on normalised cumulated activities must be provided by the user, or derived from activity versus time data using the program’s exponential modelling function, which carries out regression analysis for curve-fitting. This report focuses on the dosimetry of the adult male phantom, which is the most commonly used phantom in nuclear medicine dosimetry. Including discussions on doses to the adult female and adolescent would not result in a comprehensive report, why these results are attached in appendices.

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3 REVIEW This work covers dosimetry calculations for three different radiopharmaceuticals across four Asian populations, and compares the results with calculations for the Western Reference Man. Since any observed differences will be caused by anatomical and/or biokinetic differences, it is crucial to have a solid understanding of the data upon which the calculations are based, which is the purpose of this review covering:  

The development and most current description of Chinese, Indian, Japanese and Korean Reference Men. Biokinetic data (normalised cumulated activities) for 18F-FDG, 99mTc-tetrofosmin and 123Iiofluplane, with focus on inter-racial differences (Caucasian/Asian).

3.1 Asian Reference Populations The development of the Western Reference Man started in the 1950s by the ICRP to develop a model for radiological protection purposes. A standardised description of the typical Caucasian would simplify dosimetry comparisons and development of radiation safety standards. (ICRP 2003) While the development of the ICRP Western Reference Man has continued over the years, and includes not only anatomical and physiological descriptions, but also metabolism, natural intake of radionuclides etc., very little work has been done on non-Western populations, which may differ significantly from the Western Reference Man. The ICRP has for practical reasons left the development of population-specific non-Western Reference Men to respective country. (ICRP 2003, McParland 2010) While many Asian phantoms exist, these are in most cases voxellated phantoms, i.e. based on images of one single individual (e.g. Lee et al. 2006 who scaled CT-images of one healthy Korean to produce paediatric phantoms). Voxellated phantoms can in many cases provide impressive amounts of detail, and allow for accurate Monte Carlo calculations, but are, due to high individual variability, unsuitable for model-based calculations such as dosimetry profiles of diagnostic radiopharmaceuticals. During 1988-1993, the International Atomic Energy Agency (IAEA) led a project to establish reference data for radioprotection purposes for Bengladeshi, Chinese, Indian, Indonesian, Japanese, Korean, Pakistani, Filipino and Vietnamese populations (IAEA 1998). These data are based predominantly on national surveys and autopsies of individuals considered healthy and representative for their population. Results are presented in IAEA-TECDOC-105 Volume 1-2, where Volume 1 is a data summary and Volume 2 is a compilation of country reports. Hence, the data in Volume 2 are to a large extent based on the data from Volume 1. Despite the fact that the project was carried out many years ago, this collection of anatomical data was the most complete to be found, and was considered a solid base for dosimetry calculations and comparison.

8

Focusing on the MIRD-specified target organs (Stabin and Siegel 2003), data were reviewed for the adult and 15-year old male and female, respectively.

3.1.1 Chinese Data for a Chinese Reference Man can be found in an article by Jain et al. 1995a, who used anatomical data to compare radiation doses for Chinese, Indian and Japanese populations for 131I, 99m Tc-labelled red blood cells (99mTc-RBC) and 99mTc-iminodiacetic acid (99mTc-IDA, binds to blood proteins for hepatobiliary imaging). The Chinese anatomical data are referred to by Jain et al. as based on private communication with XA Chen 1988. In 1998 the IAEA reports were published, and neither Volume 1 (Wang 1998) nor Volume 2 (Wang and Chen 1998) refer to the work by Jain et al., but instead a large number of surveys and work on an Asian Reference Man. The IAEA Volume 2 report appears to provide the most up-to-date data on the Chinese Reference Man, and was referenced to by Qiu et al. 2008, who used the data to construct a mathematical phantom for specific absorbed fraction (SAF) calculations. Data on height and weight in the IAEA report (Wang and Chen 1998), are based on 920,000 people from four survey reports, and the data on organ masses are based on 19,976 autopsies. Wang and Chen present values for a Reference Chinese Man, which take into account growth trends as well as differences between city and countryside dwellers. Reference organ masses are proposed for the adult male and female, where adult is defined as 2050 years of age. Data for 15-year old male and female are presented as average organ masses. Data are presented for the following organs: adrenal glands, brain, heart wall, lungs, kidneys, liver, pancreas, spleen and thyroid gland. Standard deviations are presented separately for different age-groups, but are, for the adult male and female, of the magnitude of approximately 4% and 10%-13% for body height and total body mass, respectively. Organ masses have relative standard deviations of approximately 20%-25%, but greater (up to 45%) for some organs (especially spleen) (Appendix 1). Body dimensions are in agreement with Wang 1998 (IAEA TECDOC Volume 2) and organ masses are in agreement with Kawamura 1998 (IAEA TECDOC Volume 1). Jain et al. 1995a used 32% lower lungs and spleen masses than the IAEA reports, but other organ masses and total body weight were in agreement. For this study organ masses for testes and thymus were collected from Kawamura 1998. Testes mass data for the 15-year old male were unavailable.

3.1.2 Indian Anatomical data for brain, heart wall, kidneys, liver, lungs and spleen for an Indian Reference Man were proposed by Jain_et_al_1995b. These data are based on 3,000 post-mortem records of physiologically and nutritionally normal Indians from various Indian hospitals. In the IAEA report Volume 2 (Dang et al. 1998) data on body weight and height were collected from three extensive reports from the National Nutrition Monitoring Board. These data take into account origin of population groups, socioeconomic status, religion, etc. Organ masses are based on data from 14,500 post-mortem cases. For younger age groups, the data are based on only 10-50 cases per age group. It is unclear if the data by Jain et al. are included in the IAEA report. Tyagi et al. 2001 refer 9

to data by both Dang et al. and Jain et al. to estimate radiation doses in Indian adults for different nuclear medicine examinations with 99mTc-labelled radiopharmaceuticals. The IAEA report, which appears to be most up-to-date, proposes reference values for weight, height and organ masses for the adult Indian male and female, where adult is defined as over 18 years of age. For the 15-year old male and female, average values are presented. The article provides data on the following organs: adrenal glands, brain, heart wall, kidneys, liver, lungs, spleen, pancreas, prostate, spleen, stomach, testes, and thyroid gland. The relative standard deviation for height is approximately 5% and 15%-20% for weight. For organ masses the relative standard deviations are approximately 15%-25%, but greater for some organs such as spleen, pancreas and thyroid (Appendix 1). Body height and weight are in agreement with Wang 1998 (IAEA TECDOC Volume 1), and organ masses are in agreement with Kawamura 1998 (IAEA TECDOC Volume 1). Comparison with Jain et al 1995b shows good agreement with organ masses as well as height and weight. Jain et al. 1995b used a 30% greater testes mass than the IAEA value when investigating the dosimetry for Chinese, Indian and Japanese populations for 131I, 99mTc-RBC and 99mTc-IDA.

3.1.3 Japanese The development of a Japanese Reference Man started as early as in the 1960s, and continuous reports have been published since the 1970s, with the IAEA Volume 2 report (Tanaka and Kawamura 1998) being the latest addition. Tanaka and Kawamura refer to several articles on the subject - both Japanese Reference Men and Asian Reference Men (which are, to a great extent, based on Japanese data). Jain et al. 1995b refer to earlier reports by Tanaka. The IAEA report presents data on height and weight based on national survey data on approximately 7.78 million people, and organ masses based on 5,370 autopsies. Body height and weight for a Reference Japanese adult male and female are proposed, where the adult is defined as 20-50 years of age. Account is taken to secular trends; for example body height for the adult male is increased with 5 cm compared to the earlier version of the Japanese Reference Man. Average organ masses are presented for adrenal glands, brain, heart wall, kidneys, liver, lungs, pancreas, pituitary gland, red marrow, spleen, testes, thymus and thyroid gland. Relative standard deviations for organ masses are not presented, but the authors point out that the number of organ measurements for younger age groups were small, and that a large variation for thymus was seen. Body height presented by Tanaka and Kawamura is in agreement with Wang 1998, and organ masses with Kawamura 1998, except for thymus mass for 15-year old female (36.7 g), which is very slightly above the value presented by Tanaka and Kawamura 1998 (30.7 ± 5.8 g). The organ mass values used by Jain et al. 1995b were in good agreement with values in the IAEA report.

3.1.4 Korean The development of a Korean Reference Man has been slower than for the other Asian populations. The IAEA report in 1998 (Kim et al. 1998) was the first reasonably solid collection of data, with physical data based on 21,406 subjects and organ masses based on autopsies of 1,344 males and

10

577 females. However, data are only available for 6 organs: brain, heart wall, kidneys, lung, pancreas and spleen. Another set of data was presented by Park et al. 2006, who used in vivo magnetic resonance images to determine organ masses. A total of 66 males and 55 females, whose body dimensions were considered close to that of the average Korean adult, were imaged. Organ masses are presented for brain, eyes, gall bladder, heart (including contents), kidneys, liver, lungs, pancreas, spleen, stomach (including contents), testes, thymus, thyroid gland, urinary bladder (including contents) and uterus. Kim et al. don't present standard deviations for organ masses, but considering the significantly greater number of subjects, they are assumed to be lower than for Park et al., whose relative standard deviations are roughly between 25%-60% for most organs. Brain, liver and kidneys show lower relative standard deviations (between 8%-16%) (Appendix 1). The organ mass for pancreas presented by Park et al. is very low, especially for adult male; only 34.0 g compared to 94.3 g for the Caucasian equivalent and 100-129 g for other Asian populations. Kim et al. present values of 56.4 g and 89.7 g. Whether the data by Kim et al. or Park et al. should be used is debatable, and depends on which organs are of interest. Later work such as Kim et al. 2011, who used Korean data to scale a polygonsurface phantom, has referred to Park's et al. data as the Reference Korean. Since organ masses for many organs were needed for the present study, and linear scaling by body mass ratios often is invalid, organ mass data provided by Park et al. 2006 were used despite the few subjects. Data on body height and weight for this study were taken from the article by Kim et al. 1998 (averaged data for adult, defined as 21-50 years of age). Data for a paediatric Reference Korean appears to be unavailable in the literature.

3.2 Radiopharmaceutical biodistribution data Biodistribution data for a radiopharmaceutical include activity vs. time data for specific organs, excretion information and normalised cumulated activities, where the latter describe the total number of radioactive decays in source organs when activity vs. time curves have been extrapolated (generally) to infinity. This review covers normalised cumulated activities for 18F-FDG, 123I-iofluplane and 99mTc-tetrofosmin. Data were collected from ICRP publications and the literature, and efforts were made to obtain data for Asian as well as Caucasian populations to enable direct comparisons. The available material was, however, very limited, and a comparison was only possible for 18F-FDG.

3.2.1

18F-FDG

Normalised cumulated activities for 18F-FDG are presented in ICRP Publication 106 (ICRP 2007) for the following organs: brain, heart wall, lungs, liver, other organs and tissues (remainder) and urinary bladder contents. The data are based primarily on biokinetics and dosimetry studies by Deloar et al.

11

1998 and Hays et al. 2002. Data from a similar study by Mejia et al. 1991 were used to derive values for uptake in liver and lungs. The data on normalised cumulated activities presented by Hays et al. 2002 are weighted means of data from earlier publications, including Hays and Segall et al. 1999. The datasets by Deloar et al. and Mejia et al. are based on 6 and 18 healthy Japanese subjects, respectively. Data by Hays et al. 1999 are based on 5 American subjects. The individual variations in uptake appear to be greater than any inter-racial differences. Uncertainties are not presented in ICRP Publication 106. The publications by Deloar et al., Mejia et al. and Hays and Segall show relative standard deviations of at least 15%-40% for most organs and approximately 5% for the remainder.

3.2.2

123I-iofluplane

The only published normalised cumulated activities for 123I-iofluplane were presented by Booij et al. 1998a, who studied the biokinetics and dosimetry in 12 healthy, Western volunteers. A potentially interesting article was presented by Takano et al. 1999. The latter was available only in Japanese, and tables on cumulated activities were not presented. Booij et al. present normalised cumulated activities for brain, gallbladder contents, small intestine contents, lower large intestine contents, upper large intestine contents, liver, lungs, urinary bladder contents and remainder. The value for gallbladder contents in the original paper was corrected with the value from the erratum (Booij et al. 1998b). The relative standard deviations are around 15% for most organs, but higher for brain (31%), liver (19%), lungs (35%) and urinary bladder contents (20%). The relative standard deviation for remainder of body is 13%.

3.2.3

99mTc-tetrofosmin

Normalised cumulated activities for resting and exercising subjects are presented in ICRP publication 106 (ICRP 2007). The data are based on publications by Smith et al. 1992 and Higley et al 1993, who used 12 subjects each for biokinetcs and dosimetry studies. In these publications the subjects were all Western. ICRP 106 provides normalised cumulated activities for resting as well as exercising subjects for gallbladder contents, small intestine contents, upper large intestine contents, lower large intestine contents, heart wall, kidneys, liver, other organs and tissues (remainder), salivary glands, thyroid gland and urinary bladder contents. Due to the lack of Asian-specific biodistribution data, the same data were used across all populations. The assumption that the biodistribution for 99mTc-tetrofosmin is similar for the Indian adult and ICRP adult was also made by Jain et al. 1995b. No standard deviations are presented in ICRP 106.

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4 METHODS AND MATERIALS Data on organ masses and total body weight were collected and reviewed for Chinese, Indian, Japanese and Korean populations. For the various Caucasian phantoms, the default values in OLINDA/EXM version 1.1 were used. When population-specific organ masses were missing, these were approximated by scaling the organ mass of the Caucasian adult male with the total body mass ratio of the Asian and Caucasian populations. Hence, unknown organ masses in the Asian populations were assumed to vary proportionally to body weight. Reference Man data2, i.e. data that take growth trends etc. into account, were used when available. When unavailable, average data (not adjusted for growth trends etc.) were used. When organ masses were presented as the combined mass of wall and contents (Korean stomach, heart and urinary bladder), the wall mass was derived by assuming the same wall to total organ weight ratios as in the Cristy-Eckerman data. 18

123

99m

Table 1: Biodistribution data for F-FDG, I-iofluplane, Tc-tetrofosmin presented as normalised cumulated activities 99m (MBq·h/MBq) for each source organ. For Tc-tetrofosmin, rest and exercise refers to a subject in rest or

exercising, respectively.

Organ Brain Thyroid Salivary Glands Heart Wall Kidneys Liver Lungs Gallbladder Contents Small Intestine Upper Gastrointestinal Large Tract Contents intestine Lower Large Intestine Urinary Bladder Contents (adult and 15-year old)**** Remainder

18

F-FDG*

123

I-iofluplane**

0.21

99m

Tc-tetrofosmin* Rest Exercise

0.582 0.0064 0.100 0.055 0.21 0.088

0.0044 0.070 0.060 0.15 0.045

0.24

0.18

0.244

0.51

0.36

0.479

0.67

0.46

0.38

0.33

0.23

0.26

0.606

0.33

0.25

1.7

9.34

4.8

5.8

0.11 0.079 0.13

1.12 1.48 0.048***

*

ICRP Publication 106 (ICRP 2007) Booij et al.1998a *** Booij et al. 1998b **** Corrected for 3.5 h voiding interval **

2

Populations change anatomically and physiologically over time, and so does the reference man (McParland 2010). Proposed data for a Reference Man should take these time-dependent properties into account.

13

Biodistribution data (Table 1), i.e. normalised cumulated activities, were collected and reviewed for 18 F-FDG, 123I-ioflupane and 99mTc-tetrofosmin (rest and exercise) as described in the Review section. It was assumed that biokinetics datafor a given radiopharmaceutical apply equally well to all populations. A big assumption indeed, but necessary due to no (123I-ioflupane and 99mTc-tetrofosmin) or little (18F-FDG) data allowing inter-racial comparisons. This assumption is further discussed in the Discussion. Asian phantoms were modelled in OLINDA/EXM by replacing Caucasian organ masses with Asian, hence allowing the program to perform scaling of the S-factors according to equation 3-4. The Caucasian phantom to be modified was always the same age and sex as the Asian, i.e. the adult Asian male phantom was always derived from the adult Caucasian male phantom etc.

4.1 Absorbed doses Absorbed dose calculations were carried out for each radiopharmaceutical and populations using OLINDA/EXM version 1.1, and the Caucasian adult male, female and adolescent were always included for comparison. Absorbed dose calculations for 99mTc-tetrofosmin were carried out separately for data based on resting and exercising subjects. The fractional contributions from selfirradiation to absorbed doses were noted for each radiopharmaceutical. The five organs receiving the highest absorbed doses were compared with the reference values calculated for the Caucasian phantoms.

4.2 Effective dose The normalised effective dose, ENorm (mSv/MBq), was calculated as ,

where is the weighting factor for tissue T presented in table 2 and dose (mGy/MBq) for tissue T.

(5)

is the mean normalised

In addition to the normalised effective dose, the total effective dose, E (mSv), was calculated as , where

(6)

is the total administered activity (MBq).

Special consideration was taken to oesophagus and colon (which are not specified organs in OLINDA/EXM), as recommended by the ICRP Publication 80 (ICRP 1998). The normalised mean absorbed dose to the oesophagus was approximated by the mean absorbed dose to thymus. The normalised mean absorbed dose to colon was calculated as the mass weighted sum of absorbed doses to upper and lower large intestines: . One of the ICRP specified organs for effective dose calculation is bone surface, which is not presented in OLINDA/EXM. The mean absorbed dose to osteogenic cells (which are found in contact with the endosteum and periosteum) was used as an approximation (McParland 2010).

14

For the hermaphroditic phantoms (Caucasian adult male and adolescent), OLINDA/EXM will always declare absorbed doses to all organs, even if the mass for a given organ is set to zero, and for the adult female phantom testes dose will always be zero (Caucasian adult female is not considered hermaphroditic). The mean absorbed dose to gonads for the hermaphroditic phantoms (adult male and 15-year old Caucasians), was defined as the arithmetic mean of the absorbed doses to testes and ovaries as recommended by ICRP Publication 53 (ICRP 1988). To allow for easier comparisons of absorbed and effective doses of the Asian adult male phantoms with the hermaphroditic Caucasian male, the Asian adult male phantoms were considered hermaphroditic as well, despite the fact that anatomical data were based exclusively on male subjects3. Table 2: Tissue weighting factors for calculation of effective dose according to ICRP Publication 60 (ICRP 1991)

Tissue, Gonads Bone Marrow (red) Colon Lung Stomach Bladder Breast Liver Oesophagus Thyroid Skin Bone Surface Remainder*

Tissue weighting factor, 0.20 0.12 0.12 0.12 0.12 0.05 0.05 0.05 0.05 0.05 0.01 0.01 0.05**

*

4

Remainder consists of: adrenals, brain, upper large intestine , small intestine, kidneys, muscle, pancreas, spleen, thymus and uterus. ** In the event of one of the tissues or organs in the remainder category receiving an absorbed dose in excess of the absorbed dose in any of the specified organs, a weighting factor of 0.025 is applied to that tissue organ and a weighting factor of 0.025 applied to the average absorbed dose in the remainder.

For comparison, effective doses for the Caucasian male and female phantoms were calculated using the ICRP 103 weighting factors (ICRP 2007).

4.3 Phantom modelling As described in equations 3-4, S-factor scaling only affects organ self-irradiation - scaling with respect to body height or body surface is not possible. Hence, scaling the Caucasian male using Asian organ masses will, due to the greater body height, result in exaggerated organ separation.

3

This method is debatable. Had the adult Asian males not been assigned female-specific organs, this would have affected the effective doses up to 10%, depending on uptake in sex-specific organs. 4 Due to the special consideration taken to the colon mentioned earlier, the upper large intestine was excluded from the remainder as recommended by the ICRP Publication 80 (ICRP 1998).

15

An attempt to quantify the effect of the overestimated spatial separation of organs was made by deriving an adult Chinese male phantom from the adult Caucasian female phantom, i.e. the phantom closest in body height (ICRP 2003). This was done for each radiopharmaceutical, and absorbed and effective doses were compared with doses acquired when the adult Caucasian male phantom was scaled. Since OLINDA/EXM does not assign testes doses when the female phantom is used, the previously acquired testes doses were used as an approximation.

4.4 Error estimates Uncertainties in absorbed and effective doses were estimated by assuming a ±20% variability in organ masses, ±15% in total body masses and ±30% in radionuclide organ uptake (normalised cumulated activities for organs). These (rough) values were determined by examining standard deviations in the literature, focusing on the key organs for the radiopharmaceutical in question. While the individual may have anatomical characteristics considered untypical for the populations, and hence show greater radiation dose variability than the population (Stabin 2008b), this study focuses on variability across Reference Men only. The biodistribution uncertainty analysis was based on keeping the sum of normalised cumulated activities the same by using the remainder of body as a buffer. For example: if brain uptake was assumed to be 30% higher, resulting in being 0.06 MBq·h/MBq greater, an amount of 0.06 MBq·h/MBq was subtracted from the remainder. Error estimates were carried out by varying organ masses and biodistributions separately for 18F-FDG and 123I-ioflupane for the adult Caucasian male and female, adult Chinese and adult Indian male. The Japanese population and 99mTc-tetrofosmin were excluded due to lack of standard deviations in respective material. The Korean population was excluded due to much greater organ mass standard deviations (due to the small number of subjects), which would complicate direct comparison. No standard deviations were presented for anatomical data on the Caucasian Reference Man (ICRP 2003), so these were assumed to be the same as for the Asian populations.

5 RESULTS 5.1 Anatomical data Table 3 shows organ masses and body dimensions for dose calculations for male phantoms, with Asian data presented with the same number of decimals as the Caucasian equivalent. Data for the remaining phantoms are presented in Appendix 1. The 15-year old Caucasian phantom is hermaphroditic, and used to compare both male and female Asian 15-year olds, which explains why the Caucasian data are identical in tables 8-9.

16

Table 3: Organ masses and body dimensions for the adult male phantoms.

Organ

Caucasian (hermaph rodite) 16.3 1420 351 10.5

Organ mass (g) Population Chinese Indian Japanese

Korean

14.0 1480 286* 8.5*

15.0 1250 250* 7.5*

14.0 1469 286* 8.5*

14.0* 1522 302* 13

167

136*

119*

136*

144*

677

551*

482*

551*

583*

158

129*

135

129*

125***

220

179*

157*

179*

190*

Heart Wall Kidneys Liver Lungs (desanguinated) Muscle Osteogenic Cells Ovaries Pancreas Red Marrow Skin Spleen Testes Thymus Gland Thyroid Gland Urinary Bladder Wall Uterine Wall

316 299 1910 1000 28000 120 8.71 94.3 1120 3010 183 39.1 20.9 20.7 47.6 79

330 290 1470 1320 22795* 98* 7.09* 120.0 912* 2450* 220 56.0 36.0 27.0 38.8* 64*

250 230 1175 870 19946* 85* 6.20* 100.0 798* 2144* 140 35.0 14.9* 19.0 33.9* 56*

362 318 1585 1151 22795* 98* 7.09* 129.0 962 2450* 141 37.1 31.0 19.0 38.8* 64*

261*** 338 1438 1123 24125* 103* 7.50* 34.0 965* 2593* 170 29.0 40.0 15.0 38.7*** 73*

Whole Body Body Height (m)

73700 1.76

60000 1.69

52500 1.64

60000 1.70

63500 1.67**

Adrenal Glands Brain Breasts (excluding skin) Gallbladder Wall

Gastrointestinal Tract Walls

Lower Large Intestine Small Intestine Stomach Upper Large Intestine

*

Estimated by scaling Caucasian organ masses by the ratio of total body masses Average value from Kim et al. 1998 (table II) *** Calculated from total weight assuming same proportions as Cristy-Eckerman phantom **

5.2 Absorbed doses OLINDA/EXM automatically applies radiation weighting factors to the absorbed doses to compute equivalent doses. Hence, the results are presented as normalised equivalent doses (mSv/MBq). A

17

factor 1 is used for photons and beta particles, and a factor 55 for alpha particles. Auger and CosterKronig electrons are ignored. None of the radiopharmaceuticals studied in this work emit alpha particles, which means that the normalised equivalent dose (mSv/MBq) is numerically the same as the normalised absorbed dose (mGy/MBq). Absorbed doses in the literature are generally presented as absorbed rather than equivalent doses, which is also the case in this work. Self-irradiation is the dominating contribution to the total mean absorbed organ dose for all radiopharmaceuticals, as indicated by table 4. Table 4: Contribution in % from self-irradiation for the adult Caucasian male phantom. For the gallbladder, small intestine, upper large intestine, lower large intestine and urinary bladder, which are hollow organs, the contribution represents the contribution from contents. Absorbed doses to organs not presented in table 4 have 100% cross-irradiation (i.e. no uptake in the organ).

Organ Brain Thyroid Heart Wall Kidneys Liver Lungs Gallbladder Wall Small Intestine Upper Gastrointestinal Large Tract Contents Intestine Lower Large Intestine Urinary Bladder Contents Total body

18

F-FDG

99m

123

I-iofluplane

95.0

Rest

Tc-tetrofosmin Exercise

87.9

91.2 89.1 76.9

64.6 51.5 76.3 25.4

51.0 50.7 70.4 15.7

83.4

80.6

30.2

50.5

44.7

62.8

75.4

69.8

72.1

73.5

66.3

82.1 65.5

76.1 61.5

70.1 76.0

79.7 85.4 40.9

93.1 70.1

Figure 1 shows absorbed doses normalised to administered activity for the five organs receiving the highest radiation doses for the adult male phantoms for the different radiopharmaceuticals. Graphs for the adult female and adolescent phantoms are presented in Appendix 2. Graphs may contain more than five organs if not all phantoms had the same five organs receiving the highest absorbed doses. Adult Caucasian male, female and 15-year old are always included as reference levels.

5.2.1

18F-FDG

The five organs receiving the highest absorbed doses were the urinary bladder wall, heart wall, kidneys, brain and liver. The adult Caucasian female received a higher absorbed dose than the adult Asian males for all five organs. The Indian phantom tended to receive higher absorbed doses than the other Asian phantoms. Using male organs to scale the adult female phantom resulted in a higher 5

Despite the fact that the ICRP recommends a radiation weighting factor 20 for alpha particles. (Stabin et al. 2005)

18

dose to the urinary bladder wall than if the adult male phantom was scaled. Organ absorbed dose variations across the male phantoms were highest for heart wall and lungs. The absorbed dose to kidneys for the adult Caucasian male ( mGy/MBq) was more than -2 300% greater than calculated by the ICRP (1.7·10 mGy/MBq) and the liver absorbed dose was 60% higher (ICRP 2007). Doses to heart wall, brain and liver differed less than 5% compared to the ICRP values.

5.2.2

123I-iofluplane

The six organs receiving the highest absorbed dose were the urinary bladder wall, lower large intestine wall, upper large intestine wall, osteogenic cells, liver and lungs. Except for lungs, the Asian phantoms received higher absorbed doses than the Caucasian male, and the Indian received higher doses than the other Asian phantoms. Variations in organ doses were highest for lungs. The absorbed dose to osteogenic cells for the adult Caucasian male ( mGy/MBq) was 60% higher than calculated by Booij et al 1998a ( mGy/MBq). Urinary bladder wall, lower large intestine wall, upper large intestine wall, liver and lung absorbed doses agreed within 5% with Booij et al. Sydoff et al. 2011 evaluated the biokinetics in 8 patients with suspected Parkinsonism or Lewy body dementia. Their lung and liver doses were within 20% agreement with this work, whereas brain, spleen and heart doses deviated up to 74%.

5.2.3

99mTc-tetrofosmin

(rest)

The five organs receiving the highest absorbed doses were gallbladder wall, upper large intestine wall, lower large intestine wall, urinary bladder wall and small intestine wall. The Asian males received higher absorbed doses than the Caucasian male, and Indian higher than the other Asians. Variations in organ absorbed doses across the male phantoms were highest for gallbladder wall. The absorbed doses were in good agreement with the doses reported by Nycomed Amersham plc 1999. Doses to upper large intestine wall, lower large intestine wall and urinary bladder wall were approximately 10% lower than reported by Nycomed Amersham plc, and 30% lower for gallbladder wall. The absorbed doses in this work were 20%-40% higher than doses presented in the ICRP Publication 106 (ICRP 2007).

5.2.4

99mTc-tetrofosmin

(exercise)

The five organs receiving the highest absorbed doses were gallbladder wall, upper large intestine wall, lower large intestine wall, urinary bladder wall and small intestine wall. Mean absorbed doses were lower than for resting subjects. Except for Korean phantom, Asian males received higher absorbed doses than the Caucasian male, and the Indian male received higher doses than the other Asian males. Variations in absorbed doses across the male phantoms (Caucasian and Asian) were highest for the gallbladder wall. The absorbed dose to the gallbladder wall ( mGy/MBq) was 20% lower than calculated by Nycomed Amersham plc 1999, but the same as presented in ICRP Publication 106 (ICRP 2007). Absorbed doses to upper large intestine wall, lower large intestine wall, urinary bladder wall and small intestine wall agreed within 5% with those of Nycomed Amersham plc. Values in the present work compared well to the ICRP.

19

UB Wall

Heart Wall

Kidneys

Adult Caucasian female Adult Chinese male Adult Japanese male

Brain

Mean Absorbed Dose (mGy/MBq)

Absorbed Dose (mGy/MBq)

Adult Caucasian male 15-year old Caucasian Adult Indian male Adult Korean male

2.00E-01 1.80E-01 1.60E-01 1.40E-01 1.20E-01 1.00E-01 8.00E-02 6.00E-02 4.00E-02 2.00E-02 0.00E+00


8.00E-02 7.00E-02 6.00E-02 5.00E-02 4.00E-02 3.00E-02 2.00E-02 1.00E-02 0.00E+00

Liver

UB Wall

4.50E-02 4.00E-02 3.50E-02


3.00E-02 2.50E-02 2.00E-02 1.50E-02 1.00E-02 5.00E-03 0.00E+00 GB Wall

ULI Wall c)

LLI Wall

UB Wall

SI Wall

Tc-tetrofosmin (rest) 123

ULI Wall Ost. Cells

b) I-ioflupane Adult Caucasian male 15-year old Caucasian Adult Indian male Adult Korean male

4.50E-02 4.00E-02 3.50E-02

Liver

Lungs

2.50E-02 2.00E-02 1.50E-02 1.00E-02 5.00E-03 0.00E+00 d)

99m

99m


3.00E-02

GB Wall

99m

18

LLI Wall 123



18

a) F-FDG Adult Caucasian male 15-year old Caucasian Adult Indian male Adult Korean male


ULI Wall 99m

LLI Wall

UB Wall

SI Wall

Tc-tetrofosmin (exercise)

Figure 1: Mean absorbed doses for a) F-FDG, b) I-ioflupane, c) Tc-tetrofosmin (rest) and d) Tc-tetrofosmin (exercise) for the different male phantoms. UB refers to Urinary Bladder, LLI to Lower Large Intestine, ULI to Upper Large Intestine, Ost. Cells to Osteogenic Cells, GB to Gallbladder and SI to Small Intestine. Absorbed dose to UB wall is based on a 3.5 h voiding interval.

20

A comparison of the mean absorbed doses to the critical organ for the adult male phantoms for each radiopharmaceutical is presented in Table 5. The differences reflect variations in critical organ mass. Table 5: Mean absorbed dose (mGy/MBq) to the critical organ for each of the anthropomorphic male phantoms for each radionuclide. The greatest inter-racial difference across the male phantoms is presented in %. UB refers to Urinary Bladder and GB to Gallbladder.

Radiopharmaceutical 18

F-FDG 123 I-ioflupane 99m Tc-tetrofosmin (rest) 99m Tc-tetrofosmin (exercise)

Chinese 1.39E-01 5.78E-02

Population Indian 1.44E-01 6.13E-02

Japanese 1.39E-01 5.78E-02

Korean 1.39E-01 5.78E-02

Variation (%) 9 15

3.50E-02

3.75E-02

3.91E-02

3.75E-02

3.30E-02

18

2.71E-02

2.92E-02

3.05E-02

2.92E-02

2.56E-02

19

Critical organ UB Wall UB Wall

Caucasian 1.32E-01 5.31E-02

GB Wall GB Wall

5.3 Effective doses Figure 2 shows the effective doses normalised to administered activity for the adult male phantoms for each radiopharmaceutical. Figures for adult female and 15-year old male and female are presented in Appendix 3. The adult Caucasian male, female and 15-year old are always included for comparison. The effective doses are based on the ICRP 60 tissue weighting factors. Usage of the ICRP 103 tissue weighting factors resulted in slightly lower effective doses; 3%-7% lower for the Caucasian adult male and 7%-10% lower for the Caucasian adult female.

5.3.1

18F-FDG

The adult female and 15-year old Caucasian received 31% and 26% greater effective doses, respectively, than the Caucasian male. The adult Asian males received higher effective doses than the Caucasian male, but lower than the Caucasian female and 15-year old. Compared to the Caucasian male, the Asian phantoms received between 7% (Korean) and 22% (Indian) greater effective doses. The effective dose for the adult Caucasian male ( the ICRP (ICRP 2007).

5.3.2

mSv/MBq) was the same as calculated by

123I-iofluplane

The adult female and 15-year old Caucasian received 32% higher effective doses than the adult Caucasian male. The Chinese, Japanese and Korean males received approximately the same effective doses as the adult Caucasian male, whereas the Indian male received an effective dose intermediate the adult Caucasian male and female. The calculated effective dose for the adult Caucasian male ( mSv/MBq) was 8% lower than calculated by Booij et al. 1998a ( mSv/MBq) and 16% lower than calculated by Sydoff et al. 2011.

21

5.3.3

99mTc-tetrofosmin

(rest)

The Caucasian adult female and 15-year old received approximately 31% higher effective doses than the adult male. The Chinese, Japanese and Korean males received effective doses similar to the adult Caucasian male, whereas the Indian male effective dose was slightly higher. The calculated effective dose for the adult Caucasian male ( than calculated by the ICRP ( mSv/MBq) (ICRP 2007).

5.3.4

99mTc-tetrofosmin

mSv/MBq) was 13% higher

(exercise)

The Caucasian adult female and 15-year old received approximately 30% higher effective dose than the adult male. The Chinese, Japanese and Korean males received effective doses similar to the adult Caucasian male, whereas the Indian male effective dose was slightly higher. The calculated effective dose for the adult Caucasian male ( agreement with the ICRP value ( mSv/MBq) (ICRP 2007).

22

mSv/MBq) was in close

2.50E-02



3.50E-02 Effective Dose (mSv/MBq)

Effective Dose (mSv/MBq)

3.00E-02


2.00E-02 1.50E-02 1.00E-02 5.00E-03

0.00E+00

3.00E-02 2.50E-02 2.00E-02 1.50E-02 1.00E-02 5.00E-03

0.00E+00 18

123

a) F-FDG Adult Caucasian male 15-year old Caucasian Adult Indian male Adult Korean male

1.00E-02


b) I-ioflupane Adult Caucasian male 15-year old Caucasian Adult Indian male Adult Korean male




8.00E-03 6.00E-03 4.00E-03 2.00E-03 0.00E+00

1.00E-02


8.00E-03 6.00E-03 4.00E-03 2.00E-03 0.00E+00

c)

99m

Tc-tetrofosmin (rest) 18

Figure 2: Effective doses for a) F-FDG, b)

d)

123

I-ioflupane, c)

99m

Tc-tetrofosmin (rest) and d)

23

99m

99m


Tc-tetrofosmin (exercise) for the different adult male phantoms.

5.4 Total effective doses Table 6 shows the total effective doses if the maximum value of total administered activity is injected (based on literature value, see section 2.1). Asian males receive higher doses than the Caucasian male, but lower than the female and 15-year old. When activity is administered proportional by body weight Asian males receive lower effective doses. Table 6: Total effective doses and effective doses when activity is administered in proportion to body weight for Caucasians and adult Asian males.

Radiopharmaceutical

Adult male*

Caucasian Adult 15-year female old*

Asian (adult male) JapanChinese Indian ese

Korean

18

F-FDG

Effective Dose (mSv/370 MBq) Effective dose scaled by body weight ratio (mSv)

6.9

9.0

8.6

7.4

8.4

7.5

7.4

6.9

6.9

6.7

6.1

6.0

6.1

6.4

3.9

5.2

5.2

4.1

4.7

4.2

4.1

3.9

4.0

4.0

3.3

3.4

3.4

3.6

9.2

12.2

11.8

9.9

10.8

10.0

9.8

9.2

9.4

9.1

8.0

7.7

8.2

8.5

8.0

10.5

10.2

8.6

9.6

8.8

8.6

8.0

8.1

7.9

7.0

6.8

7.1

7.4

123

I-ioflupane

Effective Dose (mSv/185 MBq) Effective dose scaled by body weight ratio (mSv) 99m

Tc-tetrofosmin (rest)

Effective Dose (mSv/1221 MBq) Effective dose scaled by body weight ratio (mSv) 99m


Effective Dose (mSv/1221 MBq) Effective dose scaled by body weight ratio (mSv) *

Hermaphroditic

24

5.5 Phantom modelling Scaling the Caucasian adult female phantom instead of the adult male to create a Chinese male phantom resulted, in general, in greater absorbed doses. Organs with assigned normalised cumulated activities, i.e. self-irradiated, showed deviating absorbed doses up to 7% (lungs, 123Iioflupane). Cross-irradiation for hollow organs, i.e. organs where the contents irradiates the wall (e.g. urinary bladder, intestines, gallbladder) differed up to 29% (urinary bladder wall, 18F-FDG) and other cross-irradiated organs differed up to 42% (ovaries, 99mTc-tetrofosmin (rest)). Effective doses were 15%-30% higher.

5.6 Error estimates 5.6.1

18F-FDG

Figure 4 shows error estimates for the adult Caucasian male and female, adult Chinese male and adult Indian male for 18F-FDG. Uncertainties due to variations in organ masses and biodistribution are estimated for mean absorbed and effective doses. Absorbed doses overlap if biodistribution variations are considered, but not always if only organ mass variations are considered. Effective doses for Caucasian, Chinese and Indian male overlap whereas the adult Caucasian female is marginally higher than the adult Chinese male when only one of the parameters is considered.

5.6.2

123I-ioflupane

123

I-ioflupane showed variations very similar to those of Appendix 4.

25

18

F-FDG. These results are presented in

Adult Caucasian female Adult Indian male



Adult Caucasian male Adult Chinese male

2.50E-01 2.00E-01 1.50E-01 1.00E-01 5.00E-02 0.00E+00 UB Wall

Heart Wall

Kidneys

Brain

1.50E-01 1.00E-01 5.00E-02 0.00E+00

Liver

UB Wall

Heart Wall

Kidneys

Brain

Liver

b) Absorbed dose, biodistribution variations.


3.00E-02

2.50E-02





2.00E-01

a) Absorbed dose, anatomical variations. 3.00E-02


2.50E-01

2.00E-02 1.50E-02 1.00E-02 5.00E-03 0.00E+00



2.50E-02 2.00E-02 1.50E-02 1.00E-02 5.00E-03 0.00E+00

c) Effective dose, anatomical variations.

d) Effective dose, biodistribution variations. 18

Figure 3: Estimation of uncertainties in absorbed dose (figure a and b) and effective dose (figure c and d) due to variability in anatomy and biodistribution, respectively, for F-FDG. UB refers to Urinary Bladder.

26

6 DISCUSSION The purpose of this work was to evaluate the internal radiation dosimetry across Chinese, Indian, Japanese and Korean populations for 18F-FDG, 123I-iofluplane and 99mTc-tetrofosmin. In particular, it was to be determined whether a Caucasian female or 15-year old can, or should, be used as a surrogate for an Asian male.

6.1 Absorbed and effective doses As seen in Table 5, variations in mean absorbed dose to the critical organ across the male phantoms are low for 18F-FDG (9%) and 123I-ioflupane (15%), but greater for 99mTc-tetrofosmin (19%). The differences reflect inter-racial variations in critical organ mass, but are lower than uncertainties associated with variations in biodistributions. The Caucasian female receives higher absorbed doses than the male for all three radiopharmaceuticals. This is explained by smaller organs and shorter distances between source and target organs, resulting in greater absorbed fractions. The Indian male tends to receive slightly higher doses than the other Asian males for the same reason. Not all calculated mean absorbed doses and effective doses agreed with the literature, even when the same biodistribution was used. Small differences could be explained by use of different phantoms (e.g. the Cristy-Eckerman phantoms differ slightly from the ICRP Reference Man) and Sfactors, programs used for dose calculations and methods for calculating effective dose. For 18F-FDG, no good explanation for the much greater absorbed dose to kidneys compared to the ICRP’s value for 18F-FDG was found. For 123I-ioflupane, the greater absorbed dose to osteogenic cells compared to the value by Booij et al 1998a is explained by different calculation methods. Booij et al. used MIRDOSE, which uses an older bone model than OLINDA/EXM. Sydoff et al. 2011 used different biodistribution data, which could explain absorbed doses to brain, spleen and heart wall. The slightly different effective doses could be explained by the different biodistribution data and a different calculations method (value from OLINDA/EXM). For 99mTc-tetrofosmin, Nycomed Amersham plc 1999 used MIRDOSE and a slightly different phantom (Nycomed Amersham plc 1991), which could explain the (slight) differences in absorbed and effective dose. No explanation for the 20%-40% greater absorbed doses in the present work compared to ICRP Publication 106 (ICRP 2007) could be found.

6.2 Phantom modelling and choice of phantom Organs with observed uptake receive the greater part of the absorbed dose from self-irradiation or, for hollow organs, cross-irradiation from the contents (Table 4). These organs are also most influential on the total dosimetry profile. When a phantom’s organ masses are modified, the corresponding S-factors are scaled according to equations 3-4. The fact that these organs are most

27

influential on the dose profile supports the assumption that differences in cross-irradiation can be ignored when altering organ masses. It is, nevertheless, of interest to quantify these differences. When the Caucasian female phantom was modified to represent the adult Chinese male, it resulted in greater absorbed and effective doses. While some absorbed doses for cross-irradiated organs, such as ovaries, differed up to 42%, the self-irradiated organs differed with only 7%. The absorbed dose to the urinary bladder wall is often of interest (especially for 18F-FDG and 123I-ioflupane, where it is the critical organ), and these doses were up to 32% higher when the Caucasian female phantom was scaled. Effective doses increased by 15%-18%. These differences were surprisingly high, and therefore justify the question whether the Caucasian adult male or female should be modified to create an Asian phantom. A problem with modifying different Caucasian phantoms is, however, to determine which phantom to use. Should this be based primarily on similarities in body height, weight, body mass index or mass differences for key organs? How much can organs be scaled before the introduced error becomes unacceptably high? All calculations in this study are founded on the assumption that the scaling process in OLINDA/EXM is sufficiently accurate. While the above mentioned differences indicate possible underestimation of some absorbed and effective doses, these differences must be taken with a grain of salt, since this particular scaling process is associated with several assumptions:  



While body heights of the Asian male and Caucasian female agree better than the heights of the Asian and Caucasian male, many organ masses don’t; The mathematical description and placement of organs differ between the Caucasian male and female. For example, the urinary bladder, which is described as an ellipsoid, shows slightly different proportions in the two phantoms (Oakridge National Laboratory 2011); and, Many Asian male organ masses (e.g. urinary bladder wall) have, due to lack of data, been approximated by linear scaling of total body mass ratios. Many organ masses (e.g. brain, heart wall) are, however, not proportional to total body mass across the populations.

It must be recognised that this is a highly simplified, model-based method for radiation dose estimation for a Reference Man, where the S-factor scaling process introduces errors that may underestimate some absorbed doses (especially urinary bladder wall). Considering that these errors are well within the uncertainties associated with variation in biodistribution data, and the simpler method of always using the same phantom, it is concluded valid to use the adult Caucasian male for derivation of Asian phantoms. If the assumptions and approximations associated with OLINDA/EXM, and its S-factor scaling process, are considered sufficiently accurate, absorbed and effective doses for the Asian populations tend to agree better with the Caucasian male than female. This suggests that the Asian adult male is better modelled by scaling the Caucasian adult male rather than using the Caucasian adult female as a surrogate. The absorbed and effective dose differences are, however, so small across the different phantoms that it might even be acceptable to use an unmodified Caucasian phantom to predict radiation doses to an Asian population.

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6.3 Caucasian adult phantoms Absorbed and effective doses to the Caucasian adult male and female phantoms were included primarily for comparison, and it was noted that the Caucasian adult female received 31%-33% higher effective doses than the Caucasian adult male. Effective doses in the literature (e.g. ICRP) are, however, only presented for the adult, i.e. radiation dose differences between males and females are not mentioned. It would, from a radiation protection perspective, be useful if sex-specific absorbed and effective doses were presented.

6.4 Uncertainties Nuclear medicine dosimetry is an area of many assumptions and approximations. When dealing with biological systems, uncertainties and individual variations are great, and accurate dose calculations don’t come effortlessly! The absorbed doses in diagnostic nuclear medicine are low, which is why the requirements for precision can be relaxed compared to therapy. Below follows a discussion on uncertainties in nuclear medicine dosimetry, the approximations and assumptions in this work, and variations in absorbed doses across Caucasians and Asian populations. Stabin 2008b discusses the uncertainties associated with internal dose calculations for diagnostic radiopharmaceuticals by methodically going through each part of the dose equation. He concludes that the combined uncertainties typically will be a factor of at least 2 for model based estimates, whereas in therapy individualised calculations can reduce the uncertainties to ±10%-20%. The three parameters contributing the most are absorbed fractions, organs masses and biokinetic parameters (cumulated activities), while uncertainties from decay data terms and administered activity are negligible in comparison. ICRP publication 106 (ICRP 2007) also discusses uncertainties in absorbed dose calculations, claiming that experimental validations of estimated absorbed doses have indicated a 20%-60% agreement, and that for a reference person these uncertainties should be lower. Divioli et al. 2009 used Monte Carlo methods to calculate patient-specific S-factors from CT images of 9 patients. They compared mean absorbed doses from using the patient-specific S-factors and the standard S-factors from OLINDA/EXM and found differences up to 140%. These differences were reduced to less than 26% when the standard S-factors in OLINDA/EXM were scaled using organ mass ratios. This gives an idea of the magnitude of the uncertainties in nuclear medicine dosimetry, and clarifies that the kind of absorbed dose estimates carried out in this study apply only to the small percentage of individuals that truly are representative to their population. This study, however, deals with this small percentage, i.e. the Reference Man, which is associated with uncertainties as well (organ masses and biodistribution), but less so than the individual.

6.4.1 Asian Reference Populations Uncertainties associated with organ mass data include data collection, scaling by body mass ratios and definitions of age groups, where data collection probably dominates. The autopsies for organ mass data collection were carried out by different persons, which introduces uncertainties. Scaling

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by body mass ratio is an approximation since organ mass in many cases is not proportional to total body mass. Organ masses for some organs like liver, spleen and thymus vary in adulthood (Kawamura 1998), which is why different definitions of adult may introduce (slight) uncertainties. The Korean dataset used for this work was presented by Park et al. 2006, where data are founded on only 66 male and 55 female subjects. Hence, the calculated doses for the Koreans are less accurate than for the other Asian populations, whose data were based on several thousand autopsies. Some organ masses, especially the pancreas from the Korean dataset deviated unexpectedly much from the other Asian populations. A reason might be the different data collection methods (in vivo imaging and autopsies). It is likely that by using this value, the mass of the Korean pancreas was underestimated, which will, due to mass ratio scaling, overestimate the S-value and absorbed dose from self-irradiation. In the case of the Korean pancreas, this contribution to the effective dose should, however, be small due to the small weighting factor. The paediatric data are founded on less material; hence they are not as accurate as the adult data.

6.4.2 Radiopharmaceutical biodistribution data Due to lack of data, the assumption that biodistribution data apply equally well to all populations was made - an assumption previously been made by other authors (Jain et al. 1995c). While some metabolic differences can be seen across different populations, there is no reason to think that these differences would dominate over individual variations (which was also indicated by the 18FFDG data which covered Japanese and American subjects). It would, however, be interesting to quantify any differences in future studies. Where uncertainties for biodistribution data were presented, it was usually of the magnitude of tens of percent (smaller for remainder of body). The amount of injected activity is one of the least uncertain parameters (ICRP 1988), hence the uncertainties associated with cumulated activities come from the individual variations in uptake in different organs rather than the administered activity. The reason for variations in uptake is not necessarily due to variations in organ size. When error estimations were carried out, the assumption was made that increased organ uptake would come at a cost of decreased uptake in the remainder of body and vice versa. An approximation because organ uptake could come from other specified organs, and not only the remainder. However, this would be too complicated to model, and ignoring the fact would exaggerate the error estimates. For 99mTc-tetrofosmin, the normalised cumulated activity assessed to salivary glands was ignored. Had it been added to the remainder, changes in organ absorbed doses would be negligible (