Choosing a Weighting Factor for Doses to Biota from Alpha Particles

Transcription

1 Choosing a Weighting Factor for Doses to Biota from Alpha Particles Dr. Douglas B. Chambers 1, Dr. Richard V. Osborne 2 and Amy Garva 1 1 SENES Consultants Limited, 121 Granton Drive, Unit 12, Richmond Hill, Ontario L4B 3N4, Canada dchambers@senes.ca 2 Ranasara Consultants Inc., P.O. Box 1116, 7 Pine Point Close, Deep River, Ontario K0J 1P0, Canada Abstract. The potential risks to non-human biota from exposure to ionizing radiation is an area of considerable current interest, both in Canada and internationally. It is well known that the effects of exposure to ionizing radiation depend not only on the physical quantity absorbed dose, appropriately averaged over a relevant target volume, but also on the type of radiation. It is common to multiply the absorbed dose of a particular type of radiation by a factor to account for the relative biological effectiveness (RBE) of the radiation type. For nonhuman biota, this factor has also been referred to as an ecodosimetric weighting factor or more simply, the radiation weighting factor. There have been many experimental studies of the RBE of doses from internally deposited alpha emitters for a variety of effects and organisms. Estimated values of RBE range over two orders of magnitude. Selection of the most appropriate value (or values) to apply as a radiation weighting factor is very judgmental and, not too surprisingly, different reviewers have made different selections. Currently recommended values range from 5 to 50. This paper reports on a review of relevant published literature discussing experimental RBE data for internally deposited alpha emitting radionuclides. However, rather than simply adding to that plethora of reviews, we first attempt here to lay out the questions that might be asked during an assessment of the data from experimental studies before coming to our own conclusions. In the end, some 66 relevant papers were identified and reviewed. Recommendations for alpha radiation weighting factors are provided. 1. Background Radiation effects on biota depend not only on absorbed dose, but also on the type or quality of the radiation. For example, alpha particles and neutrons can produce observable damage at much lower doses than beta or gamma radiation. Typically, the absorbed dose (in Gy) is multiplied by a modifying factor variously called the relative biological effectiveness (RBE), quality factor, radiation weighting factor, ecodosimetric weighting factor in order to account for the differences in the radiation s effectiveness in producing biological damage. At present, there is no universally accepted name for this factor in the context of dose to biota. For present purposes, we refer to this factor, derived from experimental data, as the radiation weighting factor with the understanding that we are actually referring to an ecological radiation weighting factor when we apply the factor in an ecological risk assessment. The concept of RBE is illustrated in the following equation and can be understood as the inverse ratio of absorbed doses of different quality radiations, delivered to the same locus of interest, that produce the same degree of a given biological effect in a given organism, organ or tissue all other factors being equal [1], namely: RBE = Dose of reference radiation needed to produce the same effect (1) Dose of the given radiation needed to produce (the same magnitude of) the same biological effect 1

2 D.B. Chambers, Richard Osborne, Amy Garva RBE depends on many factors among them, the type of cell or tissue irradiated, dose and dose-rate, the distribution of Linear Energy Transfer (LET) or lineal energy, the endpoint (effect) of interest, and other factors. Other than to note that the concept of RBE is complex and involves many considerations and sources of uncertainty, a full discussion of the factors influencing the use of experimental RBE data for application as (ecological) radiation weighting factors for non-human biota is beyond the scope of this paper. However, a few important issues are briefly noted below. Amongst many other factors, RBE depends on LET which is the amount of energy absorbed by the target tissue per unit path length. Low LET radiations such as x-rays, gamma rays or electrons of any energy have an average LET of about 3.5 kev/µm (of water) or less [1, 2]. Gamma rays from 137 Cs or 60 Co and 250 kvp x-rays have been used as the standard or reference radiations. It is important to understand, in looking at the literature, that 60 Co gamma rays are less effective than 250 kvp x-rays in producing radiobiological effects. At high doses, the difference is small (RBE = 0.86 for 60 Co relative to x-ray as the standard); however, the difference is larger at lower dose rates [3]. Overall, the difference in the relative effectiveness of 60 Co gamma rays and 250 kvp x-rays is about a factor of 2 [2, 3, 4]. In many systems, the RBE increases with increasing LET until the LET reaches about 100 kev/µm and then begins to decline. This phenomenon is shown for example in the impairment of regenerative capacity of cultured human cells inactivated by monoenergetic particles (Figure 2.3 [5]). The peaking of the RBE at an LET of about 100 kev/µm can perhaps be explained by noting that it only requires a few tens of kev of energy to break a single stand of DNA and that a single alpha particle with a LET of 100 kev/µm is sufficient to produce a double strand break which is prone to imperfect repair and may result in the death of the cell. Thus at LETs greater than about 100 kev/µm, there is sufficient energy to ensure a double strand break in target DNA and additional energy is simply wasted. Such behaviour is illustrated by data in [1] providing extensive discussions of radiation from internal emitters, including discussions of radiobiological mammalian RBE s for somatic effects and RBE data from dose-effect curves for a variety of radiological data (See Figure 1). In discussing these data, the National Council on Radiation Protection and Measurements (NCRP) notes that data for animals larger than mice are sparse and that even for a small animal, the physical dosimetry presents a severe problem. In discussing RBE, the authors of the NCRP report suggest that the increase in RBE with exposure reflects a relative lack of dependence of high LET radiation on dose rate for the life shortening effects, and a relative dependence of low-let radiation on dose rates. In commenting on radiological data for plants, mammalian organs and single cell populations, the authors comment that if dose-effect curves for two low LET radiation are compared, or if a comparison is made with a high LET radiation for the same effect, that the RBE will vary with the degree of effect (dose) and dose rate. The NCRP report [1] presents experimental curves of RBE versus LET for a wide variety of test organisms and endpoints including for example T1 bacteriophage in broth, haploid yeast survival in air, artemia eggs hatching or emerging, various mammalian tissues, broad leaf bean root effects on growth and survival and others suggest a maximum RBE of (about) 10, at an LET of (about) 300 kev/µm for human cells in culture. Notwithstanding experimental limitations, it seems remarkable that the RBE s for such a wide range of radionuclides, species and endpoints of these older experiments, are clustered within a quite narrow range. 2

3 D. B. Chambers, Richard Osborne, Amy Garva Adapted from NCRP [1] FIG. 1. Experimental curves of RBE versus LET (pre-1967). The dosimetry of internally deposited alpha emitters is the source of many questions. Consider for example, the studies shown in Table I. According to ACRP [6], in these studies it was assumed that the alpha emitting radionuclides were uniformly distributed throughout the organ of interest. However, in the dose ranges reported (0.1 to 10 mgy), only a few cells will receive very high doses; the vast majority of cells receive no dose at all. The effect of this inhomogeneity in dose is a distortion of the apparent RBE towards very high values. Table I. Summary of selected studies with alpha RBE values greater than 20*. RBE Author(s) Endpoint Comment 377 Samuels [7] Cell-killing in mouse oocytes Based on single point; author urged caution, suggested only Jiang, Lord & Fetal hemopoetic stem cell Assumed uniform dose distribution. A Hendry [8] deficit in mice repeat experiment gave Rao et al. [9] Spermhead abnormalities in Assumed uniform dose distribution. mice Poor statistics Brenner et al. For argon ions. Relevance to survival Lens opacification in rats [10] not clear. 65 Brooks et al. [11] Micronuclei in rat lung Conversion from WLM to mgy α fibroblasts dose was suspect Martin et al. [12] Transformation of Syrian hamster embryo cells Poor statistics *Adapted from ACRP [6] Consider for example, the paper by Samuel et al. [7] which reports an estimated dose to mice oocytes from the intake of 210 Po based on the number of alpha particles absorbed by a certain volume of tissue times the 5.3 MeV energy of 210 Po alpha particles. A major source of error lies in estimating the number of alpha particles originating and being absorbed in the specific tissue being assessed. This dose estimate relies on the results of a radiochemical assay. Samuels assumes a uniform gross 3

4 D.B. Chambers, Richard Osborne, Amy Garva distribution of 210 Po within the ovary (as opposed to microscopic localization in follicle cells) and further assumes that all the particles are absorbed within the ovary (track length for alpha particles is 37 µm). The large uncertainty in the dose estimate also reflects uncertainty in the radiochemical assay, which may be quite inaccurate at low dose rates. Samuels [7] used the results from his experiments on the effects of 210 Po on mice ovaries to estimate RBE values. His estimates suggest that in some cases the RBE for 210 Po alpha particles may be as high as 50 or more and provides error bars on the estimates as a function of the total radiation dose. As far as can be ascertained from the paper, the error bars reflect the uncertainty in the radiochemical analysis, but not the uncertainty in the assumption of uniform 210 Po distribution in the ovary. Removing this assumption and using a heterogeneous distribution (as actually observed) would imply higher doses to targeted tissues (in this case the follicle cells) and therefore would imply a much lower RBE. 2. Current Evaluations of RBE Over the past decade, a number of authors have reported evaluations of published data on RBE [e.g., ACRP [6], DOE [13], EC and HC [14], Copplestone et al. [15], UNSCEAR [16], FASSET [17], NCRP [18], Trivedi and Gentner [19], Tracy and Thomas and [20], Knowles [21] and others]. Nominal values for a radiation weighting factor from these reviews are summarized in Table II. In considering these values, it is important to understand that data are limited; that experimental RBE s are specific to the endpoint studied; the biological, environmental and exposure conditions (e.g. reference radiation, dose rate, dose, etc.) and other factors. Thus, as noted in a recent FASSET report [17], it is a challenge to develop a generally valid radiation weighting factor for use in environmental risk assessment. For such reasons, the ACRP [6] and FASSET [17] have proposed ranges of values for such general application. Coincidentally, the ACRP and FASSET both selected an alpha radiation weighting factor of 10, as a notional central value, in the case of the former ACRP, and in order to illustrate the impact of the radiation weighting factor for an internally deposited alpha emitter in the case of FASSET. Table II. Radiation weighting factors for internal alpha radiation for deterministic effects in nonhuman biota (relative to low LET radiation). Source Nominal Value Comment NRCP [18] 1 Built-in conservatism in dose model IAEA [22] 20 Keep same as for humans Barendsen [23] 2-10 Non-stochastic effect of neutrons and heavy-ions UNSCEAR [16] 5 Average for deterministic effects Trivedi & Gentner [19] 10 Deterministic population relevant endpoints UK Environment [24] 20 Likely to be conservative for deterministic effects EC and HC [14] 40 Includes studies with high RBEs ACRP [6] 5-20 (10) 5-10 deterministic effects (cell killing, reproductive) cancer, chromosome abnormalities 10, nominal central value FASSET [17] 5-50 (10) 10 to illustrate effect of α RBE There are also some new data entering the literature. Tracy and Thomas [20] measured the relative biological effectiveness (RBE) of 210 Po alpha particles versus 250 kvp x-rays in producing injury to bovine endothelial cells. Primary cultures of endothelial cells were harvested from bovine aortas. Cells were x-rayed at the Saskatoon Cancer Clinic and alpha irradiated by addition of 210 Po citrate to the culture medium. Radiation effects on cells were measured by a number of different assays; however, all of the measured RBEs fell in the range of 8 to 14. 4

5 D. B. Chambers, Richard Osborne, Amy Garva In addition, Knowles [21] reports on experimental studies of groups of zebra fish which were exposed from an early age to different dose rates of γ- and α- radiation ( 210 Po). Among the gamma irradiated fish, only those in the highest dose-rate group (7400 µgy/h) showed radiation related damage. No groups of alpha irradiated fish showed evidence of radiation induced reduction in egg production even though autoradiographs showed concentrations of 210 Po in testes and ovaries. Since the highest alpha dose rate (214 µgy/h) showed no effect, comparison with the γ- radiation dose rate of 7400 µgy/h which caused egg production to cease, resulted in only upper limits to the RBE calculated in the range of <7 to <20 based on ovary concentrations and <35 based on whole body concentrations. Knowles [2001] suggest the RBE s derived from their work provide the best available (upper bound) estimates of RBE for fish. 3. Review of Literature In total, 66 relevant papers providing experimental measurements of alpha RBE were identified and reviewed. For evaluation purposes, the RBE values extracted from the published literature were assigned to one of three broad categories, namely, Category A - population relevant deterministic endpoints such as cell mortality, oocyte mortality and sperm mortality; Category B - other deterministic endpoints such as haemopoiesis, spermhead abnormality and lens opacity (such effects are also potentially population relevant if a significant portion of the population were to be affected); and Category C - stochastic endpoints such as chromosomal aberration, double strand breaks and mutation. Detailed data extractions were carried out for all 66 papers. The RBE values extracted from these papers were then evaluated for application to non-human biota on the basis of four criteria. After much discussions, it was considered that these topics could be represented by the following four (4), admitedly subjective, criteria: 1. Are the dosimetric conditions sufficiently defined and not peculiar to the sources of radiation for the estimate of RBE to be an appropriate base for choosing a weighting factor for doses from alpha particles as such? 2. Are the dose-effect relationships well enough know that the results from the dose rates used experimentally can be applied to effects that may occur at environmental dose rates? 3. Are any uncertainties arising in the experiment that are not covered by criteria 1 and 2 adequately reflected in the quoted values for RBE? 4. Are the types of experimental radiations in the study relevant to the choice of a weighting factor for alpha particle doses from natural radioactivity? Each paper was evaluated according to the four criteria mentioned above. The process was to evaluate each of the papers by applying criteria #1 first and then applying criteria #2 to the remainder and criteria #3 and #4 after that. Two examples are provided to illustrate the evaluation process. In one reviewed paper [21], all of the criteria were met except for criteria #2. Criteria #2 requires that the dose-effect relationships are well enough known that the results from the dose rates used experimentally can be applied to effects that may occur at environmental dose rates. In the paper by Knowles [21], there was no dose-effect relationship for zebrafish to alpha radiation derived in this paper, since none of the alpha doses were sufficiently large enough to result in the desired endpoint of ceased egg production. Thus, no specific RBE can be determined from the paper [21], only an upper limit can be used as a conservative upper limit to the RBE and this value was not carried forward in our evaluation for consistency purposes. However, as discussed earlier, it is our opinion that even 5

6 D.B. Chambers, Richard Osborne, Amy Garva though this paper was unable to provide a specific RBE value, this paper nonetheless provides the best currently available estimate of RBE (upper range) for fish. Another example where criteria #2 was not met was in a paper by Kadhim et al. [25]. In this paper, the authors conclude that the alpha RBE approaches infinity due to the unique aberrations produced by the high-let radiations. However, the dose-effect relationship for bone marrow cells from mice to X-rays was not determined, some of the aberrations produced by alpha particles were not produced by the X- ray exposure. Therefore, it is likely that the alpha RBE for cytogenetic aberrations in bone marrow cells from mice is indeterminant due to the ineffectiveness of X-rays to produce the same type of cytogenetic aberrations as alpha radiation. Therefore, since Criteria #2 is not met, the RBE value reported in this paper is not included in our derived RBE range. Figure 2 shows the effect of applying the evaluation criteria to the RBE data for all types of endpoints Number of Results Eliminated by criterion #1 Eliminated by criterion #2 Eliminated by criterion #3 Final distribution 5 0 < >160 RBE Ranges FIG. 2. Application of criteria to distribution of RBEs (all types of endpoints). Table III provides a summary of the RBE data remaining after screening using the evaluation criteria. It is interesting to note that after the application of the screening criteria, there is very little difference among the categories and the median RBE for all categories is <5. Thus, a nominal value of about 5 is suggested. For purposes of a sensitivity analysis, a range of from 1 to 10 for the radiation weighting factor might be considered for population relevant deterministic endpoints and a range of from 1 to 30 might be considered for stochastic endpoints. Given the wide range of experimental data considered in this review, and the remarkably narrow range of RBE reported by the NCRP [1] (see Figure 1), it would seem reasonable that these values of radition weighting factors can be applied generically across all species and endpoints. 6

7 D. B. Chambers, Richard Osborne, Amy Garva Table III. RBE values after application of evaluation criteria. Values After SENES Evaluation Category Description Examples Median a of RBE Range a of RBE a Population Relevant Deterministic Endpoints Cell, Oocyte or Sperm Mortality, Egg Production b Other Deterministic Endpoints Haemopoiesis, Spermhead Abnormality, Lens Opacification c b Stochastic Endpoints Chromosomal Aberrations, Mutation, Sister Chromatid Exchange, DSB, Micronuclei 4.55 <1-26 a.) For purposes of caution, if the reference paper reported a range of RBEs, then the RBE used for the median and range was the maximum RBE value from that range. b.) A RBEm of 20 was reported by Miller [26], which wasn't included in the RBE median or range. Overall, recognizing the uncertainties in the data and the subjective nature of the evaluation of the data, a nominal radiation weighting factor of 5 is recommended for both population relevant deterministic endpoints and evaluation of stochastic endpoints. For purposes of sensitivity analysis, a range of radiation weighting factor of from 1 to 10 might be appropriate for population relevant deterministic endpoints and a range of from 1 to 30 might be considered for stochastic endpoints. 7

8 D.B. Chambers, Richard Osborne, Amy Garva REFERENCES [1] National Council on Radiation Protection and Measurements (NCRP), Dose-Effect Modifying Factors in Radiation Protection. Report of Subcommittee M-4 (Relative Biological Effectiveness) of the National Commission on Radiation Protection. BNL50073 (T-471). August. [2] National Council on Radiation Protection and Measurements (NCRP) The Relative Biological Effectiveness of Radiations of Different Quality. Report No [3] International Commission on Radiation Units and Measurements (ICRU) The QualityFactor in Radiation Protection. Report 40. April. [4] International Commission on Radiological Protection (ICRP) RBE for Deterministic Effects. Publication 58. Annals of the ICRP 40(4). Pergamon Press, Oxford. [5] Nikjoo, H., R.J. Munson and B.A. Bridges, RBE-LET relationships in mutagenesis by ionizing radiation. Journal of Radiation Research. Vol. 40, pages [6] Advisory Committee on Radiological Protection (ACRP22) Protection of Non- Human Biota from Ionizing Radiation Published by the Canadian Nuclear Safety Commission (CNSC) INFO-0703, March. [7] Samuels, L.D Effects of Polonium-210 on Mouse Ovaries. Int. J.Radiat.Biol. 11: [8] Jiang, T.N., B.I. Lord and J.H. Hendry Alpha Particles are Extremely Damaging to Developing Hemopoesis Compared to Gamma Radiation. Radiat. Res. 137: [9] Rao, D.V., V.R. Narra, R.W. Howell, V.K. Lanka and K.S.R. Sastry Induction of Spermhead Abnormalities by Incorporated Radionuclides. Radiat.Res.125: [10] Brenner, D.J., C. Medvedovsky, Y.Huang, G.R. Marian and B.V. Worgul Accelerated Heavy Particles and the Lens: VI.RBE Studies at Low Doses. Radiat.Res.128: [11] Brooks, A.L., R. Miick, R.L. Buschbom, M.K. Murphy and M.A. Khan The Role of Dose Rate in the Induction of Micronuclei in Deep-Lung Fibroblasts in vivo after Exposure to Cobalt-60 Gamma Rays. Radiat.Res.144: [12] Martin S.G., R.C. Miller, C.R. Geard and E.J. Hall The Biological Effectiveness of Radon Progency Alpha Particles: IV. Morphological Transformation of Syrian Hamster Embryo Cells at Low Doses. Radiat. Res.142: [13] US Department of Energy (DOE) DOE Standard, A Graded Approach for Evaluating Radiation Doses to Aquatic and Terrestrial Biota. DOE-STD YR, July. [14] Environment Canada (EC), Health Canada (HC) (PSL2), 2001 Canadian Environmental Protection Act, 1999, Priority Substances List Assessment Report, Releases of Radionuclides from Nuclear Facilities (Impact on Non-Human Biota) July. [15] Copplestone D. et al Impact Assessment of Ionizing Radiation on Wildlife U.K. Environment Agency, R&D Publication 128, June. [16] United Nations Scientific Committee on the Effects of Atomic Radiation, Sources and Effects of Ionising Radiation, United Nations Scientific Committee on the Effects of Atomic Radiation 1996 Report to the General Assembly, Fifty-first Sessions, Supplement No. 46 (A/51/46), Annexes: Effects of Radiation on the Environment, United Nations Sales No. E96.IX.3. [17] FASSET Deliverable 4: Radiation Effects on Plants and Animals. June. [18] National Council on Radiation Protection and Measurements Effects of Ionizing Radiation on Aquatic Organisms. NCRP Report No. 109, Bethesda MD. [19] Trivedi, A. and Gentner N.E., Ecodosimetry Weighting Factor for Non-Human Biota in Harmonization of Radiation, Human life and the Ecosystem, Proceedings of the International Radiation Protection Association (IRPA-10), 2000 May 14-19, Hiroshima, Japan, CD Rom (2002). [20] Tracy, B.L. and A. Thomas An Appropriate Weighting Factor for the Effects of Alpha Radiation on Non-Human Species. Presented at International Conference on Radioactivity in the Environment. Monoco

9 D. B. Chambers, Richard Osborne, Amy Garva [21] Knowles, J.F An Investigation into the Effects of Chronic Radiation in Fish, U.K. Environmental Agency R & D Technical Report p3-053/jr. [22] International Atomic Energy Agency (IAEA) Effects of Ionizing Radiation on Plants and Animals at Levels Implied by Current Radiation Protection Standards. Technical Report Series No.332, Vienna. [23] Barendsen, G.W., RBE for Non-Stochastic Effects Adv. Space Research, Vol. 12, No. 2-3, pp (2) 385 (2) 392. [24] United Kingdom (UK) Environmental Agency. Copplestone, D., S. Bielby, S.R. Jones, D. Patton, P. Daniel and I. Gize Impact Assessment of Ionizing Radiation on Wildlife. R&D Publication 128, Bristol, U.K. [25] Kadhim, M.A., D.A. MacDonald, D.T. Goodhead, S.A. Lorimore, S.J. Marsden and E.G. Wright, Transmission of Chromosomal Instability After Plutonium α-particle Irradiation. Nature, Vol. 355, Pages [26] Miller, Richard C., Stephen A. Marino, David J. Brenner, Stewart G. Martin, Marcia Richards, Gerhard Randers-Pehrson and Eric J. Hall, The Biological Effectiveness of Radon-Progeny Alpha Particles II Oncogenic Transformation as a Function of Linear Energy Transfer. Radiation Research, Vol. 142, Pages