DEPARTMENT OF HEALTH& HUMANSERVICES 

# i"&

Subject

To 

# Memorandum

August 28,2009 Mary Schubauer-Berigan, Ph.D. Senior Research Epidemiologist, Divi sionof Surveill

ance. Hazar d EPI II, Industrywide

Studies Branch Evaluations

andField Studies
Comments

on "Development

of a CLL Risk Model for NIOSH-IREP" Trabalka and Apostoaei, Draft July 2009
James Neton, Ph.D. Associate

Directorfor Science,

Office of Compensation Analysisand Support General comments:
The documentdescribes the development

of a risk model from the Japanese Life Span Study (LSS) cohort of atomic bomb survivors to be applied to the compensation of cases of chronic lymphocytic leukemia (CLL) among U.S. nuclearworkers. In general, I believe that the proposedmodel to be usedfrom the LSS cohort [non-Hodgkin lymphoma (NHL) combinedwith Hodgkin lymphoma and multiple myelomal is appropriate.I also concur with the dosemetric to be used in estimating risk from the LSS cohort. A much more difficult issue is the selectionof the appropriate organ or tissuefor which dose should be calculatedin consideration of the nuclearworker claimant's compensation case. This issue,unfortunately, is not discussed adequately

in the document; it is virtually unmentionedoutside of Appendix C, and no ultimate recommendation is given. This very important topic should be moved from the Appendix to the main body of the document and somefirmer recommendations made on how to estimate an appropriate

dosefrom internal exposure.

With no accounting

for the contribution to risk from internal dose,it is unlikely that claims for compensation will be successful

(since a very high extemal dose is requiredto meet the benchmarkof a 50Yo or greaterassigned

shareat the upper 99olo confidence limit). Because CLL is a form of NHL, it is not clear why a similar approach could not be usedto estimate a target organ for CLL. Lastly, to reduce the main body length as a result of this change and to increase

overall clarity and focus for the document, I recommendmoving the very lengthy section3 (Origins, Characteristics, and Clinical Features

of CLL) to an Appendix. Other commentsand suggestions are detailed below. Specific comments: 1. The list of key references on p. 3 appears

slightly outdated.I suggest adding Silver et al. (2007) and the publications in the 2007 Br J Haematol relatedto the workshop on CLL held earlier that year. Thesereferences, cited extensively later in this document, formed part of thejustification for the decisionsmade in producing risk models.Page 2 - Associate Director for Science, OCAS
2. In formulating the arguments aboutthe radiogenicity (or lack thereof) of CLL, it may be of interestto note that the Intemational Agency for Research on Cancerrecently excluded CLL along with other non-Hodgkin lymphoma and multiple myeloma from its list of cancer

types having sufficient evidenceof radiogenicity (El GhissasiF, et al. 2009 Lancet Oncol l0:751-752). Consistent treatmentof these

threetypes of cancerwithin a compensation

program thereforemakessense from a scientific and epidemiologic perspective,

if the sole barrier to the inclusion of CLL has been lack of an available doseresponse

model from the LSS cohort.
3. As indicated in the GeneralComments,I suggest moving Section 3 to an appendix and only briefly summarizing it in the main body of the text. While it is important information to illustrate the complexity of the natural history of CLL and its relation to NHL, the material is described in far too much detail for this document,and the important information is not readily extractable by the reader.
4. Section

3 andthe restof the document describe B-lymphocyte

CLL very well, but I saw no mention of T-lymphocyte CLL, which comprises 5% of all CLL. Will all forms of CLL usethe samemodels and assumptions? It would be good to havethis mentioned explicitly.
5. The implications of the lengthy exposition on B-lymphocyte maturation on p. 7 could be made more explicit. For example, the second

paragraph

mentions germinal cell division in lymph node follicles, but doesn't state that this implies lymph node could be a target organ for the development of the earliesteventscausingCLL. 6. The first paragraph on p. 11 misinterpretsa statement by Schubauer-Berigan et al. (2007). This statement was not that an extended latency period suggests radiation is a promoter for CLL, but rather that a latency of 10 yearsdoesso. Considering CLL's long pre-clinical and clinical phase, a latency of 10 yearswould be very short for CLL mortality, which is what the study was based upon. Indeed,

the research

presented elsewhere

in the reviewed documentalso would lead to such a conclusion. Please correct the misinterpretationof the reference.
7

. The second

full paragraph

on p. I I is repetitive and confusing. What does "75oh diagnosed

at an average

age of 60" mean? If this sentence is retained it should be rewritten to indicate the median age at diagnosisor someother meaningful fractile. 8. The first full paragraph on p. 13 containssome confusing information about CLL coding in ICD-8. There is a unique code for CLL in that revision,204.l (the sameas ICD-9). I think the paragraph is trying to state

that this code was lumped in with other codes. This is not a problem stemmingfrom the ICD coding per se, but rather with how the investigatorschose to group CLL. 9. The relevance

of the first full paragraph on p. 14 is unclear. I would retain it only if it sheds light on the appropriate target organ for CLL or is otherwisedirectly relevant to the questions

at hand about deriving an appropriate risk assessment

model for compensation.Page 3 - Associate

Director for Science,

OCAS
10. Use of a pooledestimate forNHL, Hodgkin lymphoma, and multiple myeloma is described

in the text (p. 14) but is not shown in Table 2. Please provide theseestimates in Table 2 or in the text.
11. The effects of attainedage and ageat exposure would be more easily understandable

if there were a verbal description of their net effect on p. 15.
12. I would not arguethat there is much supportfor a risk transportmodel like that used for breastcancer.

The latter's departure

from the standard

risk transport model employed for other cancers

in IREP derivesfrom the very comprehensive epidemiologic studies

that have been able to answer this questiondirectly for breastcancer.Such evidenceis simply not available for CLL. Occupationalstudieshave exposures that aretoo low to permit discrimination betweenmultiplicative and additive interactionwith other risk factors (which are not even generally understood for CLL). For this reason,I supportthe use of the "uninformed" transport model. 13. The discussion

of latency on p. 20 does not mention the recentpaper by SchubauerBerigan et al. (2007), which exploredthe latency questionthrough use of time windows. An overall dose-response was seen

for exposures

lessthan 100 mSv. The time windows analysisfor this group suggested that a latency of 10 yearswas appropriate(no evidence of risk was seenin shortertime windows). And, this was for a mortality study. Latency for CLL incidencewould be expected to be shorterstill.
14. The sampleresults in Table 3 on p. 23 appear to be given as percentages, not probabilities, though they are not labeledthat way. Please clarify the labels on this table so that the results are more easily comprehended. 15. The documentendsrather abruptly onp.24, with no discussion of the very important material in Appendix C. I suggest that this Appendix be incorporatedinto the document,asthe target organ for which doses should be estimated

is very important for compensation

purposes. 16. Appendix B, p. 39: suggest incorporating information from the third column of Table III of Schubauer-Berigan et al. (2007), as mentioned in comment 13 above.
17. Tables

B.9 and B.10 arenot really relevant for a discussion

of CLL latency

without an appropriate denominator. 18. Appendix C, while providing a very usefuldiscussion of the complex issues involved, ultimately does not provide a firm recommendation on the target organ for which doseshould be estimated.It is not clear why this issue is substantivelymore challenging for CLL than for other forms of NHL, for which a model and a dose

cc: Douglas

Trout, M.D.