Early and late effects of radiation in normal tissues and organs: threshold doses for tissue reactions and other non-cancer effects of radiation in a radiation protection context

British Institute of Radiology Response to ICRP Consultation on ‘Early & late effects of radiation in normal tissues and organs: threshold doses for tissue reactions and other non-cancer effects of radiation in a radiation protection context

Comments from BIR Radiation Protection Committee and the Radiation Cancer Biology Committee

Introduction

This response includes the individual responses from members of the Radiation Protection Committee of the British Institute of Radiology. We hope you find them both constructive and useful in producing the final version of what is undoubtedly an important contribution to knowledge underpinning radiation protection practice.

General Points

The Committee felt that this was a very useful, detailed compilation of evidence. The use of the 1% incidence of tissue reaction in providing an estimate of threshold dose initially appears to encourage unjustified economic penalties. However, when applied in practice to the various organs and tissues, it appears to avoid the problem with being too precautionary and at the same time accounting for evidenced risks and their uncertainties.

With regard to the eye, we agree there is strong evidence for risks being higher than previously thought. However, reduction in the threshold dose by an order of magnitude is a very significant reduction and any reduction in dose limits by that factor will need an extremely forceful case, as there may be unforeseen consequences of such a reduction to legal limits.

With regard to circulatory disease, we welcome the suggested threshold acute dose of ~0.5 Gy. Much work is already in progress assessing the risks of cardiovascular disease from radiotherapy with the ultimate aim of dose reduction. Any additional dissemination of these principles will be helpful in this area.

Specific Issues.

Infra-red radiation as a possible confounding factor for cataract

Studies of atomic bomb survivors are a major source of epidemiological information on risk of cataract from radiation.  However I am surprised not to see any mention in the ICRP draft that infra-red radiation from the bombs has been considered as a possible confounding factor.  The important 2007 paper on atomic bomb survivors by Neriishi et al (ref1) has one of the lowest estimates of threshold dose for cataract (at 0.1 Gray). In addition this paper “is the first to document clinically relevant visual disability many years after low dose radiation exposure” (paragraph 254). The authors of this paper list risk factors other than radiation as, diabetes myelitis, exposure to UV light, cortico-steroids and smoking.  They also showed no association of radiation dose with outdoor activity, medication use, smoking, white blood cell & neutrophil counts, serum-markers for inflammation or oxidative stress.  However there is no mention in this paper, or its review by ICRP, of the infra-red and heat radiation from the atomic bombs.

As a non-specialist on the causes of cataract I am sure there must be some reason why infra-red radiation from the bombs could not have caused cataract in these survivors, however it would be re-assuring to see this mentioned in the ICRP document, lest this query should likewise arise in the minds of other readers.  I mention this particularly as it is widely known that glass-blowers, blacksmiths etc are liable to cataract through looking into furnaces during their occupation.  Occupational exposure to infra-red radiation can increase cataract incidence by a factor of 5 times (ref2). It was known as long ago as the 18^th Century that those who gazed at the sun too long were liable to cataract (ref2).

One relevant question is whether cataracts caused by infra-red radiation differ to those cataracts caused by ionising radiation. The closest the ICRP draft comes to mentioning infra-red radiation is in paragraph 246 on p101 stating that “sunlight exposure is unlikely to be a contributory factor as such cataracts are generally associated with superficial cortical opacification”. According to Edbrooke and Edwards, infra-red radiation cataract develops as a “well-defined opacity in the outer layers of the posterior cortex of the crystalline lens” (ref2). There is an article on the internet (Occupational Vision Hazards: Infra-red radiation and the Eye, by Janet Voke) which states that “the subcapsular opacity typically seen as a result of infra-red radiation exposure is also exactly the same histologically as that seen as a result of other types of radiation induced cataracts such as those of X-ray, atomic bomb, and cyclotron radiation exposure” (ref3). In the Chernobyl study (ref4) it is said that “the radiogenic lens opacification initially manifests as defects in the transparency of the posterior superficial cortex in the lens tissue, which by virtue of its location is referred to as posterior subcapsule cataract”.  Edbrooke and Edwards speak of a characteristic golden sheen on the lens, the Chernobyl study speaks of a polychromatic sheen or beaten-brass looks to the posterior capsule.  In summary it may not be immediately apparent to the non-specialist how infra-red cataract is distinguished from ionising radiation cataract.

Moreover an earlier study of atomic bomb survivors found a radiation-dose response for both posterior-subcapsular cataracts, and for cortical cataracts. Finally the important study by Nerishii et al 2007 mentioned above, studies those bomb survivors who have had lensectomies; which I presume includes both posterior-subcapsular and cortical cataracts.

Given the importance of the atomic bomb survivor studies to this topic, it would be useful for the ICRP publication at least to mention infra-red as one of the causes of cataract (in paragraph 246) and if possible to confirm that the intense infra-red radiation from the atomic bombs could not have been a cause of cataract.  It might also be useful for them to clarify that the possibility of an interactive-effect has been considered and discounted; i.e. whether it is possible that exposure to infra-red radiation might act as a promoter for other causes of cataract for example from ionising radiation - and therefore whether exposure to ionising radiation and infra-red radiation simultaneously could have had a multiplicative effect. 

It has also been suggested that the mechanism of infra-red damage is due to absorption in the iris, and that the effect may be related to pigmentation, with those with a darker iris perhaps being at greater risk from infra-red, which could be relevant to the atomic bomb survivors.

Skin burns as a possible confounding factor for cataract

In the same vein as the above comment I have not seen any mention in the ICRP document, or in the 2007 paper by Nerishii et al (ref1) on atomic bomb survivors, of consideration of major skin burns as a possible confounding factor.  There are case reports in the literature of cataract formation after major skin burns, eg due to an explosion (ref 5). Likewise cataract formation can occur after lightning strike, or after high voltage electric shock (ref 6).  In the latter two scenarios the cataract might possibly be caused by the skin burns associated with these insults.  In the case reports I have read, cataract following skin burn, has occurred typically a few months or a few years after injury; however there is mention of a delayed cataract occurring many years after the event. 

Paragraph 246 summarising the non ionising-radiation insults that can cause cataract does not mention either infrared radiation or skin burn. Since studies of the atomic bomb survivors are of such great importance for the question of cataract formation and ionising-radiation risk, I feel that within the ICRP report, both paragraph 246, and the section on atomic bomb survivors and radiation cataract, would be strengthened substantially by mentioning infrared radiation, and skin burn, and confirming that these two topics have been considered and are not potential confounders.

Age at exposure

The possibility of a strong age at exposure effect is of great importance for the practical application of preventative measures against radiation cataract in occupational settings (eg for radiologists and cardiologists); and is also critical when considering protection of patients from diagnostic scans (eg CT scans). Paragraph 678 on page 280 mentions “the likely greater sensitivity of the lens in children compared to post adolescents” and I would have thought this possibility is of sufficient practical importance to have been given greater emphasis throughout the text; especially as there is a possible mechanistic difference between adults and children (see below*) due to the greater replication rate of cells in the lenses of children. I feel that the possibility of a difference in risk between adults and children should be mentioned earlier in the text to help the reader assess the individual studies in that light. Table 4.3 gives age ranges for the various studies, but it may be useful to distinguish adult from paediatric populations in the earlier summary table (Table 2.4), and to mention more clearly in wide age-range studies whether the effects were influenced significantly by exposures at young ages.

As an example of the difficulty which the reader currently faces in distinguishing paediatric from adult risks, in the Neriishi et al 2007 study of atomic bomb survivors (ref1) the excess risk at less than 2 Gray appears, at least by visual inspection of the raw data, to be limited to those under age 20 at the time of the bomb (see table below, which is adapted from that paper), but this point is not greatly emphasised in that paper, or mentioned in the ICRP draft. Should this point be clarified in regard to the ICRP summary of the atomic bomb survivor studies?

[*NB In terms of a possible mechanistic difference between adults and children, I believe the process of cell division is rare in the adult lens. Bone is another tissue where cell division may be infrequent in the adult (bone cell lifetime is about 20 years); and in the case of bone cancer there is a good model of radiation induced bone cancer where a cell division is required as part of the radiation-cancer induction process. If cell division were also an essential requirement for radiation induced cataract then it may be possible to consider separately scenarios where cell division is common, from those situations where it is rare. It is possible to suppose three potential scenarios where cell division might be common: 1) radiation doses above several Sieverts, if deterministic cell deaths from high radiation doses induce compensatory cell replacement; 2) exposure to high LET radiations (eg cosmic rays and astronauts) where the localised dose deposition could be many Sieverts(?) perhaps causing localised cell deaths and localised compensatory cell division in the vicinity of the radiation damage; and 3) in children at any dose level or radiation type. It might be of interest therefore to consider these three scenarios (doses above several Sieverts, exposure to high LET radiation, and exposures in children), separately to the case of lower dose low LET radiation in adults, especially where the question of thresholds is of interest. In other words is it possible that high LET exposures, and all exposures in children, might have no threshold due to the presence of cell division, but exposure to low LET radiation in adults might require cell death induced cell division, and therefore imply the presence of a threshold?]

Minor Typographical points

Page 102 first line states “radiation cataract is inversely related to dose”.  Perhaps dose rate is meant?

Page 105 Paragraphs 254-257 on the atomic bomb studies. The ordering of the material is confusing.   Paragraph 254 concerns the Neriishi et al 2007 study, where the best estimate threshold dose is unusually low at 0.1 Gray. The top of the next paragraph (255) claims these findings are comparable to and in support of earlier studies on atomic bomb survivors - yet the second part of paragraph 255 cites a sole study, presumably as an example of this support, where the dose threshold estimate was 1.5 to 2 Sieverts. Likewise Paragraph 257 details an atomic bomb study which revealed a threshold dose of around 0.7 Gray; and then immediately states that “A-bomb survivor studies provide epidemiological support for a low or zero threshold”.

Page 99 paragraph 238 mentions three studies that do not support a lower threshold for radiation cataract.  Hourihan et al 1999; Chemlevsky et al 1988; and Guskova 1999; however these studies don’t seem to appear in the summary section (e.g. the figure on page 276, or in table 4.3 page 278, or in appendix A which summarises the relevant studies of cataract and radiation).  Would it not be more balanced to include these negative studies in the summaries on page 276-278 and in Appendix A?

In the summary of studies in Appendix A (pages 290 and following) for the Nariishi et al 2007 study the “risk” at 1 Gy is tabulated - but the figure given is an odds ratio. Similarly in the Minnamoto et al 2004 and 2006 studies on page 307 the “prevalence” at 1Sv is tabulated -but again the figures are odds ratios. Likewise for the Hall et al 1999 study on page 295. 

In the Worgul et al 2007 study page 299 the comments section reads “so dose individual dose uncertainties were substantial”. Presumably there is an additional “dose” here.

References:

·         Reference 1: Neriishi et al 2007 Postoperative Cataract Cases among Atomic Bomb Survivors: Radiation Dose Response and Threshold. Radiation Research. Vol168 p404-408

·         Reference 2: Edbrooke and Edwards. 1967. Industrial Radiation Cataract: The Hazards and the Protective Measures. Ann. Occup. Hyg. Vol.10 pp293-304.

·         Reference 3: Janet Voke: Occupational Vision Hazards: Infrared Radiation and the Eye  (see intranet)

·         Reference 4: Worgul et al 2007: Cataracts among Chernobyl clean-up workers: Implications regarding permissible eye exposures. Radiation Research. Vol 167 p233-243.

·         Reference 5: Ozturk et al. 2002. Cataract formation after a major burn due to explosion: a case report. Burns vol 28 p276-278

·         Reference 6: Reddy 1999. Electric Cataract: a case report and review of the literature. European Journal of Ophthalmology vol 9 no2 pp134-136

Comments from BIR Radiation & Cancer Biology Committee

This is an extensive report, reviewing and evaluating the literature on the non-cancerous effects of ionising radiation on normal tissues, both in the context of high doses such as those received by cancer patients during radiotherapy and low doses sustained during occupational exposures. It builds on previous ICRP reports and pays particular attention to new information on radiation effects in the lens of the eye and in the cardiovascular system. It is a major step forward in bringing together the latest work and analysis of tissue effects and the Commission and the authors of the report are to be commended for producing a thorough analysis.

1.       In radiobiological terms, the clarification of the definition of tissue effects as “tissue reactions” and the move away from the older phrases of stochastic, non-stochastic and deterministic effects is to be commended.  The consistent use of Gy and Sv throughout the report and the realisation of the lack of applicability of the concept of a D₀ value in modern analysis of radiation response curves is also a step forward in clarifying terminology in this area.

2.       As part of the introduction (page 23 onwards), for clarity in introducing the concept of a threshold ED₁ dose, the authors should put this in the context of typical exposures observed in the human population broken down into environmental, occupational and medical exposures to put the risks of tissue damage into context. This would ensure a link to the discussion around the consequences of a 1% threshold risk when discussing annual exposures etc discussed in chapter 4.

3.       In the discussion of cell killing (Page 28, line 1066) mention is made of low dose hypersensitivity. Evidence of this has now been observed clinically in skin and should be referred to (see work of Turesson et al.). Under the immune responses section (page 51) mention is made of genomic instability and bystander effects but no definitions or mention of these are made elsewhere in the text.  A passing mention of “non-targeted” effects is required for completeness even if these have not yet manifested in terms of tissue responses.

4.       Radiation quality. The report discusses the concept of LET and this is mentioned at various places, but there are inconsistencies as to the value of this, particularly as previous ICRP reports have covered this. We suggest that it is defined early on in the report that only low LET external exposures will be considered to ensure clarity.

5.       The dose values used need to be standardised throughout.  Some sections talk about 0.5 Gy other 500 mGy and some 50 cGy. We suggest using mGy for less than 0.1 Gy,  Gy for 0.1 and above and refraining from using cGy.

6.       Some inconsistencies with ”x-ray” used instead of “X-ray”