Review of the report “Development of a CLL Risk Model for

NIOSH-IREP” by John R. Trabalka and A. Iulian Apostoaei. 

Draft dated December 21, 2007; amended January 30, 2009 

(reformatted June 30, 2009).

Overview

The lymphomas (Hodgkin’s lymphoma and non-Hodgkin’s lymphoma) and 

multiple myeloma are considered together in NIOSH-IREP, using the 

Radiation Effects Research Foundation (RERF) incidence data for 1950-1987 

for the Japanese atomic bomb survivors, as reported by Preston et al. (1994). 

Thus, the data upon which the current NIOSH-IREP lymphoma-multiple 

myeloma model is based was published 15 years ago. The incidence data for 

solid tumours among the Japanese atomic bomb survivors has recently been 

updated by Preston et al. (2007), covering the period 1958-1998, and an 

update of the incidence data for lymphatic and haematopoietic cancers (i.e. 

cancers other than solid tumours) is expected soon. It may be prudent to 

enquire of RERF as to when this latter update might be expected to be 

published since

o It would be of value to know what impact (if any) the recent 

lymphoma and multiple myeloma incidence data for the Japanese 

atomic bomb survivors have upon the current NIOSH-IREP 

lymphoma-multiple myeloma risk model, and

o It would be of value to know whether the recent incidence data for 

haematopoietic cancers shed any light upon the risk of chronic 

lymphocytic leukaemia (CLL) among the Japanese atomic bomb 

survivors
Should publication of the RERF update of lymphatic and haematopoietic 

cancers incidence among the Japanese atomic bomb survivors be within an 

acceptable timescale, it may be advisable to await these latest findings before 

making any decisions about CLL and the applicability of the current 

lymphoma-multiple myeloma risk model. This is particularly so if radiationinduced lymphatic and haematopoietic cancers other than the acute 

leukaemias and chronic myeloid leukaemia have characteristically long latent 

periods (as discussed by Trabalka and Apostoaei). Further, the authors from 

the RERF published risk models in their update of solid tumours incidence 

among the Japanese atomic bomb survivors, and these models were 

somewhat different from, for example, those published in the BEIR VII Report

(2006). Again, it might be advisable to assess what the RERF researchers 

have to say about relevant risk models for lymphatic and haematopoietic 

cancers before finalising any model for CLL. However, since CLL is rare 

among the Japanese population it may well be that the next update of the 

incidence of CLL among the Japanese atomic bomb survivors will not add 

significantly to the information currently available. Nonetheless, the additional 

information on the lymphomas and multiple myeloma could indirectly 

illuminate the question of how to deal with CLL.

It would seem to be the case that chronic lymphocytic leukaemia (CLL) is 

more akin to a lymphoma (specifically, non-Hodgkin’s lymphoma) than to an 

acute leukaemia or chronic myeloid leukaemia. Since NIOSH-IREP has a risk 

model for the lymphomas and multiple myeloma – in fact, just one risk model 

covering all the lymphatic and haematopoietic cancers other than the 

leukaemias – then it is arguable that CLL should be included in the NIOSHIREP programme, since CLL is the only malignant neoplastic disease 

currently omitted from this programme. The evidence for CLL being capable 

of induction by ionising radiation is weak. However, the evidence for ionising 

radiation increasing the subsequent risk of lymphoma/multiple myeloma, 

particularly Hodgkin’s lymphoma, cannot be considered strong, and it is not 

obvious that these cancers should be considered capable of induction through 

exposure to ionising radiation and therefore included in a radiation worker 

compensation program – the UK Compensation Scheme for Radiation-linked 
Diseases, for example, does not consider Hodgkin’s lymphoma to be sensitive 

to induction by radiation. However, if the lymphomas and multiple myeloma, 

particularly Hodgkin’s lymphoma, are included among the cancers that are 

compensatable in the NIOSH-IREP programme then it is reasonable that CLL 

should be evaluated for inclusion, even in the absence of persuasive evidence

of radiation-induction. Had EEOICPA excluded cancers such as Hodgkin’s 

lymphoma (as in the UK Compensation Scheme) for which the evidence for 

radiation induction is also weak then the position with respect to CLL would be 

a different matter, but it is only CLL that is currently excluded.

The NRRW-3 Study

The third analysis of data from the UK National Registry for Radiation 

Workers (NRRW) was published earlier this year (Muirhead et al., 2009). This 

is the most statistically powerful study of radiation workers to be published to 

date, and is of particular relevance to the circumstances of radiation workers 

in the USA. The authors found no evidence of an association between CLL 

and radiation exposure, even with a 10-year lag – the trends of CLL mortality 

and incidence with cumulative radiation dose were negative (but were not 

statistically significant). Muirhead et al. also reported positive trends with 

dose for non-Hodgkin’s lymphoma and multiple myeloma mortality and 

incidence, and negative trends with dose for Hodgkin’s lymphoma mortality 

and incidence – the positive trend with dose for multiple myeloma incidence 

was statistically significant, but the other trends were not statistically 

significant.

So, the NRRW-3 study does not support CLL being capable of induction by 

ionising radiation (although results for lags greater than 10 years are not 

reported); but then the study also does not support Hodgkin’s lymphoma 

being capable of induction by ionising radiation and this cancer is included as 

compensatable in the NIOSH-IREP programme. The NRRW-3 study does 

add weight to the inference that CLL and Hodgkin’s lymphoma are not 

capable of induction by radiation (a position adopted by the UK Compensation 
Scheme). However, I suspect that it is unlikely that Hodgkin’s lymphoma will 

be removed from the category of compensatable diseases in NIOSH-IREP, 

and the position of CLL must be viewed in this context.

The Trabalka and Apostoaei Report

Given the above background, the approach of Trabalka and Apostoaei is a 

reasonable one. CLL is a cancer that is more like a non-Hodgkin’s lymphoma 

than an acute leukaemia or chronic myeloid leukaemia, and the lymphomamultiple myeloma risk model currently adopted in NIOSH-IREP would seem to 

be the model most appropriate for application to CLL. The central point is 

this: if the lymphomas and multiple myeloma, especially Hodgkin’s lymphoma,

are considered to be compensatable on the basis of the available evidence, is 

it acceptable to exclude CLL from NIOSH-IREP (the only type of cancer not to 

be included in the NIOSH-IREP programme)? Given the evidence forming 

the basis for the inclusion of Hodgkin’s lymphoma in the NIOSH-IREP 

programme, the exclusion of CLL might not be thought acceptable. Under 

these circumstances, the solution adopted by Trabalka and Apostoaei –

basically, considering CLL to be covered by the current lymphoma-multiple 

myeloma risk model – is logical. The authors highlight the uncertainties, 

which are substantial, but then the uncertainties surrounding the application of 

the current lymphoma-multiple myeloma risk model in NIOSH-IREP are also 

substantial.

Summary

The issues can be summarised thus:

o The evidence for chronic lymphocytic leukaemia (CLL) being 

capable of induction by ionising radiation is weak

o The evidence for the acute leukaemias and chronic myeloid 

leukaemia being capable of induction by ionising radiation is strong
o CLL is more like a non-Hodgkin’s lymphoma than an acute 

leukaemia or chronic myeloid leukaemia

o The evidence for Hodgkin’s lymphoma, non-Hodgkin’s lymphoma 

and multiple myeloma being capable of induction by ionising 

radiation is weak, especially the evidence for Hodgkin’s lymphoma

o However, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma and 

multiple myeloma are considered compensatable diseases under 

NIOSH-IREP

o The evidence for Hodgkin’s lymphoma being capable of induction 

by ionising radiation is not materially greater than that for CLL, but 

Hodgkin’s lymphoma is included in the current lymphoma-multiple 

myeloma risk model in NIOSH-IREP

o Given this, can the continued exclusion of CLL from NIOSH-IREP 

be justified?

o If the answer to this question is no, then it is reasonable to treat 

CLL in the same way as the lymphomas and multiple myeloma are 

currently treated in NIOSH-IREP

o Presently, the lymphomas and multiple myeloma are considered 

together by one risk model and this could be extended to CLL

o Consideration should be given to the implications of the anticipated 

publication of the results of the analysis of the updated incidence 

data for lymphatic and haematopoietic cancers among the 

Japanese atomic bomb survivors

o The results of this update could affect the approach taken by 

NIOSH-IREP to the lymphomas and multiple myeloma (currently 

considered together), and also to how CLL should be included in 

the programme (if at all).

Conclusion

The approach of Trabalka and Apostoaei to the treatment of CLL in NIOSHIREP is reasonable, given the inclusion of some other cancers as 

compensatable in the programme for which the evidence for induction by 
radiation is weak, as is that for CLL. The crux of the matter is this: if 

Hodgkin’s lymphoma is considered as compensatable, given the evidence for 

induction by radiation, is it acceptable to consider CLL as non-compensatable, 

given the evidence for induction by radiation? If the answer to this question is 

no, then the approach of Trabalka and Apostoaei is logical.

Richard WAKEFORD

25 August 2009