DEPARTMENT OF HEALTH & HUMAN SERVICES i"&

Subject

To

Memorandum

August 28,2009

Mary Schubauer-Berigan, Ph.D.

Senior Research Epidemiologist,

Divi sion of Surveill ance. Hazar d

EPI II, Industrywide Studies Branch

Evaluations and Field Studies

Comments on "Development of a CLL Risk Model for NIOSH-IREP"

Trabalka and Apostoaei, Draft July 2009

James Neton, Ph.D.

Associate Director for Science, Office of Compensation Analysis and Support

General comments:

The document describes 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. nuclear workers. In general, I

believe that the proposed model to be used from the LSS cohort [non-Hodgkin lymphoma

(NHL) combined with Hodgkin lymphoma and multiple myelomal is appropriate. I also

concur with the dose metric to be used in estimating risk from the LSS cohort. A much

more difficult issue is the selection of the appropriate organ or tissue for which dose

should be calculated in consideration of the nuclear worker claimant's compensation case.

This issue, unfortunately, is not discussed adequately in the document; it is virtually

unmentioned outside 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 some firmer recommendations made on how to estimate an appropriate dose from

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 required to meet the benchmark of a 50Yo or greater assigned share at the upper 99olo

confidence limit). Because CLL is a form of NHL, it is not clear why a similar approach

could not be used to 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 recommend moving the very lengthy section 3 (Origins, Characteristics, and

Clinical Features of CLL) to an Appendix. Other comments and 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 The list of key references on p. 3 appears slightly outdated.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 related to the workshop on

CLL held earlier that year. These references, cited extensively later in this document,

formed part of the justification for the decisions made in producing risk models.
Page 2 - Associate Director for Science, OCAS

2. In formulating the arguments about the radiogenicity (or lack thereof) of CLL, it

may be of interest to note that the Intemational Agency for Research on Cancer recently

excluded CLL along with other non-Hodgkin lymphoma and multiple myeloma from its

list of cancer types having sufficient evidence of radiogenicity (El Ghissasi F, et al. 2009

Lancet Oncol l0:751-752). Consistent treatment of these three types of cancer within a

compensation program therefore makes sense 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 General Comments, 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 and the rest of 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 use the same models and assumptions? It would be good to have this 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 earliest events causing CLL.

6. The first paragraph on p. 11 misinterprets a 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 years does so. Considering CLL's long

pre-clinical and clinical phase, a latency of 10 years would be very short for CLL

mortality, which is what the study was based upon. Indeed, the research presented

elsewhere in the reviewed document also would lead to such a conclusion. Please correct

the misinterpretation of 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 diagnosis or some other meaningful fractile.

8. The first full paragraph on p. 13 contains some confusing information about CLL

coding in ICD-8. There is a unique code for CLL in that revision,204.l (the same as

ICD-9). I think the paragraph is trying to state that this code was lumped in with other

codes. This is not a problem stemming from the ICD coding per se, but rather with how

the investigators chose 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 otherwise directly 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 pooled estimate forNHL, Hodgkin lymphoma, and multiple myeloma is

described in the text (p. 14) but is not shown in Table 2. Please provide these estimates in

Table 2 or in the text.

1 1. The effects of attained age and age at exposure would be more easily

understandable if there were a verbal description of their net effect on p. 15.

12. I would not argue that there is much support for a risk transport model like that used

for breast cancer. The latter's departure from the standard risk transport model employed

for other cancers in IREP derives from the very comprehensive epidemiologic studies that

have been able to answer this question directly for breast cancer. Such evidence is simply

not available for CLL. Occupational studies have exposures that are too low to permit

discrimination between multiplicative and additive interaction with other risk factors

(which are not even generally understood for CLL). For this reason, I support the use of

the "uninformed" transport model.

13. The discussion of latency on p. 20 does not mention the recent paper by SchubauerBerigan et al. (2007), which explored the latency question through use of time windows.

An overall dose-response was seen for exposures less than 100 mSv. The time windows

analysis for this group suggested that a latency of 10 years was appropriate (no evidence

of risk was seen in shorter time windows). And, this was for a mortality study. Latency

for CLL incidence would be expected to be shorter still.

14. The sample results in Table 3 on p. 23 appear to be given as percentages, not

probabilities, though they are not labeled that way. Please clarify the labels on this table

so that the results are more easily comprehended.

15. The document ends rather abruptly onp.24, with no discussion of the very

important material in Appendix C. I suggest that this Appendix be incorporated into the

document, as the 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 are not really relevant for a discussion of CLL latency without

an appropriate denominator.

18. Appendix C, while providing a very useful discussion of the complex issues

involved, ultimately does not provide a firm recommendation on the target organ for

which dose should be estimated. It is not clear why this issue is substantively more

challenging for CLL than for other forms of NHL, for which a model and a dose

cc: Douglas Trout, M.D.