August 19, 2005

CHRONIC LYMPHOCYTIC LEUKEMIA (CLL): RECONSIDERATION OF

EXCLUSION FROM ELIGIBILITY FOR COMPENSATION UNDER EEOICPA

I. Background

The Energy Employees Occupational Illn ess Compensation Program Act of 2000 (EEOICPA) provides a lump sum payment of $150,000 plus medical benefits to any covered former U.S. nuclear weapons worker diagnosed with cancer, if that cancer was judged to be “as least as likely as not” (a 50% or greater probability) caused by occupational exposure to ioni zing radiation. The Departme nt of Health and Human Services (HHS) is charged with developi ng and updating, as need ed, the scientific guidelines for assessing eligibility for compensation. The Office of Compensation Analysis and Support (OCAS) of the Nationa l Institute for Occupational Safety and Health (NIOSH) performs this function for HHS.

Each EEOICPA cancer claim is individuall y evaluated according to the claimant’s radiation dose, type of cancer, and other rele vant factors by means of a computerized set of quantitative risk assessment models. Th ese computerized models provide “probability of causation” estimates for radiation-exposed individuals. Probability of causation is defined as the likelihood, expressed as a perc entage, that a worker’s cancer was caused by occupational exposure to ionizing radiation.

The amount and type of radiation exposure incurred by a claimant is established by a process called “dose reconstruction.” Dose reco nstruction consists of systematic research and analysis leading to a quantitative estimat e of radiation exposure. The reconstructed radiation dose, type of cancer, and related factors determine proba bility of causation and, in turn, the success or failure of a claim. A probability of causati on of 50% or greater means that the cancer was at least as likely as not induced by radia tion and, thus, that it merits compensation.

II. Treatment of chronic lym phocytic leukemia under EEOICPA

Chronic lymphocytic leukemia (CLL) is curre ntly regarded as a non-radiogenic cancer under the regulations (DHHS, 2002) that esta blished the guidelines for determining probability of causation under EEOICPA. CLL is the only type of cancer assigned, a priori, a probability of causation of zero.

NIOSH excluded CLL from coverage primarily because no elevation in CLL incidence had been observed among the Japanese World War II atomic bomb survivors, the data

source from which most cancer risk models used under EEOICPA were derived. In addition, in NIOSH’s j udgment, other epidemiological ev idence available at the time the guidelines were promulgated did not convinc ingly demonstrate an association between2

ionizing radiation and increased risk of CLL. Moreover, the National Cancer Institute (NCI) had specifically excluded CLL from radia tion risk calculations in a set of radioepidemiologic tables used in adjudicating cancer claims filed by radiation-exposed military veterans. (NCI, 2000.) In addition, NIOSH observed that CLL was not covered by any other radiation compensation program.

III. Why NIOSH is reconsidering CLL

Although CLL was designated non-radiogenic fo r compensation purposes, other types of cancer lacking compelling evidence of ra diogenicity (e.g., prostate cancer, nonHodgkin’s lymphoma, hairy cell leukemia, etc. ) were not excluded from eligibility for compensation. For those cancers, NIOSH judge d that the evidence, even though in some instances marginal, was nonetheless sufficient to err on the side of e ligibility. Further, NIOSH’s cancer designations were consistent with NCI’s pos ition. NIOSH noted at the time, however, that the designation of CLL as non-radiogenic would be revisited in the future (NIOSH, 2002.) In the interim, this pe rceived disparity in th e treatment of cancers with questionable ev idence of radiogenicity has ge nerated concern among EEOICPA

claimants and other stakeholders.

Proponents of including CLL fo r compensation have advanced the following arguments:

1. There are hundreds of different types and sub-types of cancer, including many with sparse evidence of radiogenicity, yet only CLL is specifically excluded from compensation under EEOICPA. It is not plausible that CLL could be the only type of cancer that can not possibly be induced by r adiation. Moreover, there is no scientific evidence that convincingly demonstrat es it is non-radiogenic.

NIOSH comment: NIOSH did not assert that evidence proves CLL is nonradiogenic, only that evidence had no t supported the case for radiogenicity.

2. A major reason for excluding CLL wa s the apparent absence of excess risk among the Japanese A-bomb survivor cohort. However, the reported incidence of CLL varies widely among populations thr oughout the world. In fact, CLL is rare among the Japanese population and extremely rare among Japanese females (the majority of the A-bomb cohort) prior to age 70. Thus, the ability to detect excess CLL risk due to radiation exposure from atomic bombs is poor.

NIOSH comment: NIOSH agrees that the st atistical power to detect excess CLL risk among the Japanese surv ivor cohort was limited.

3. Hairy cell leukemia (HCL) is a slow ly progressing lymphocytic leukemia. Because its symptoms are similar to CLL, it has sometimes been misdiagnosed as CLL. In fact, it has been regarded by some as a sub-type of CLL. Misdiagnoses of cancers of the blood and bone marrow were more common when many EEOICPA claimants were diagnosed with cancer, before improvements in3

diagnostic techniques had been achieved. Thus, it’s likely that medical records for some claimants may contain inaccurate diagnoses. Despite the similarities between HCL and CLL and the diagnostic problems associated with those similarities, HCL is eligible for comp ensation under EEOICPA, but CLL is not. The disparity in treatment of these dise ases is neither fair nor justified.

NIOSH comment: NIOSH generally defe rs to NCI for expertise in the classification of cancers, and NCI has c onsistently regarded HCL and CLL as separate diseases. On th e other hand, this distinc tion is not universal; for example, the United Kingdom’s radia tion compensation program excludes both CLL and HCL from compensation eligibility.

4. NIOSH convened a public meeting in Washington, DC in July 2004 to seek input on gaps in CLL research. That meeting featured a panel discussion of experts from the fields of epidemiolo gy, medicine, radiobiology, and related

health sciences. A consensus seemed to emerge among this NIOSH-convened panel that scientific evidence is inconclusive with respect to CLL’s etiology and to its association with ionizing radiation. The intent of EEOICPA, and the often stated intention of NIOSH in carrying out its mandate under EEOICPA, is to err on the side of the claimant whenever scien tific evidence is lacking. The arbitrary exclusion of CLL, without regard to an individual’s degree of radiation exposure or to the stochastic nature of cancer risk , is clearly contrary to that intent.

NIOSH comment: The public meeting referre d to above was convened on July 21, 2004 by NIOSH’s Health-Related Energy Resear ch Branch (HERB) as part of an ongoing effort to investigate the possible relationship between ionizing radiation and CLL. HERB has not yet published a report of that meeting. However,

NIOSH/OCAS reaffirms its commitment to err on the side of the claimant whenever the state of scientific knowledge is lacking.

NIOSH is sensitive to the perception of disparate categorization of radiogenic cancers. Moreover, as noted earlier, it was stated when EEOICPA program guidelines were first published in 2002 that CLL would be revisite d at a later date. Thus, NIOSH/OCAS determined in 2004 that it would be appropria te to reconsider th e 2002 exclusion of CLL from eligibility for compensation.

IV. Solicitation of expert opinion

As part of the process of reconsidering CLL for EE OICPA compensation purposes,

NIOSH/OCAS in October-November 2004 solici ted the independent opinions of five experts otherwise unaffiliated with NIOSH, each of whom was selected based on his or her experience and expe rtise in the field of epidemio logy, medicine, and/or radiation carcinogenesis.

Each expert was asked, separately, to (1) re view a document outlining the CLL issue as it pertains to EEOICPA (NIOSH/OCAS, 2004) , (2) respond in writing to the question4

reprinted below, and (3) provide a rationale for his or her conclusion. In addition, each expert was provided with the program guide lines for determining compensation (DHHS, 2002) and a draft bibliography of relevant C LL literature, the latter prepared by NIOSH’s Health-related Energy Research Branch (N IOSH/HERB, 2004.) However, reviewers were invited to base their professional conclusions on any combination of personal expertise, NIOSH-provided documents, or re ference materials of their own choosing.

The question posed to each contributor was: “ In your expert judgment, is the evidence of an association, or lack thereof, between radi ation exposure and the risk of developing CLL sufficient to continue to regard CLL as a non-radiogenic cancer and to continue to exclude it, a priori, from eligibil ity for compensation under EEOICPA? ”

Note that the above question was intentiona lly framed within the narrow context of compensation policy. NIOSH/OCAS does not seek nor presume to resolve the scientific controversy surrounding CLL a nd radiation, nor should any policy decision that may

arise from the current reconsideration of C LL for compensation purposes be construed as NIOSH’s position on CLL’s radiogenic properties or lack thereof.

Given the above caveat, expert opinions were obtained from five individuals. They are listed below in alphabetical or der (titles and affiliations provided for information only), followed by their respective conclu sions and (capsu le) rationales.

1. John D. Boice, Jr., ScD

Scientific Director International Epidemiology Institute Rockville, MD

&

Professor of Medicine Vanderbilt University School of Medicine Nashville, TN

Boice’s conclusion: “...CLL should not be considered a radiation-inducible cancer.” Rationale given : (Excerpted) “The body of scientific evidence indicates that CLL is not caused by exposure to ionizing radiation at a ny level of dose. Not one of the major epidemiologic studies of (exposed patients or workers) has reported a statistically significant increase in CLL. Authoritative committees...have concluded that CLL is not caused by ionizing radiation. CLL appears etio logically and clinical ly a lymphoma and

differs from the other forms of leukemia. Lymphomas have also not been convincingly linked to ionizing radiation. In the same epidemiologic studies that find significant increases in myeloid leukemia, no increases in CLL are found despite CLL being the most frequent leukemia among adult Western populations. The etio logic factors that

cause CLL are not well defined but are differe nt from those factors that cause other forms of leukemia. (Note: Dr. Boice lists benzen e, cigarette smoking, and alkylating agents as examples of agents that cause myeloi d leukemia but not CLL.) Thus based on epidemiologic studies of radiation finding no evidence for an association with CLL, coupled with the etiologic and clinical diffe rences between CLL and the other forms of5

leukemia that are caused by radiation, CLL should not be considered a radiationinducible cancer.” (Boice, 2005)

2. Mark A. Crowther, MD, MSc, FRCPC

Associate Professor of Medicine Hematology Residency Program Director & Head of Service, Hematology McMaster University & St. Joseph’s Hospital Hamilton, Ontario, CA

Crowther’s conclusion: “...the available evid ence is insufficient to rule out an association between ionizing radiation and CLL; in this case my interpretation of the current standards is that comp ensation should be provided.” Rationale given : (Paraphrased/excerpted) Although an association betw een radiation and CLL has not been established through epidemiology, this can be explained by the low rates of CLL among Asian populations, the mi sclassification of hematological cancers prior to improved diagnostic techniques, the relatively short follo w-up periods of most studies, and a lack of randomized clinical tria ls. “CLL is clearly not different from other forms of cancer...it is caused by a deficit of programmed cell death, rather than excess proliferation. However, this characterist ic is shared with other cancers currently considered compensable. CLL is associated with (and likely due to) specific genetic mutations...specific genetic mutations are one of the consequences of exposure to radiation.” Given the lack of compelli ng evidence that CLL cannot be caused by radiation, it should be eligible fo r compensation. (Crowther, 2004)

3. David M. Ozonoff, MD, MPH

Professor of Environmental Health Boston University Schoo l of Public Health Boston, MA

Ozonoff’s conclusion: “In summary, my expe rt opinion supports including CLL as a radiogenic cancer and against the continuing, and it seems to me, arbitrary practice

of exclusion.” Rationale given : (Excerpted) “The arguments for c ontinued exclusion are not only weak, but lacking in foundation. Considering that all blood cells come from a common progenitor stem cell it has always seemed pl ausible to me that any cancer of the blood system could be radiation related. This is now generally accepted as true for benzene, which also affects progenitor stem cells. ... We tend to forget that the four ‘forms’ of leukemia (ALL, AML, CML and CLL) are desi gnations made on clinical grounds and are related to prognosis and management rather than etiology. Indeed if one wanted to employ cell surface markers, there could be hun dreds or even thousands of ‘different’ types of leukemia. ... Thus while the type of leukemia is very important if one wants to

treat the disease it is incorrect to assume this is related to etiology. Just as the difference between a fracture of the thigh bone and th e wrist bone is extremely important for treatment and management of a fracture, it sa ys nothing about the etiology of either.” (Ozonoff, 2004)6

4. David B. Richardson, PhD Assistant Professor of Epidemiology University of North Carolina School of Public Health Chapel Hill, NC

Richardson’s conclusion: “Available scient ific evidence does not provide sufficient grounds for continuing to regard chroni c lymphocytic leukemia (CLL) as a nonradiogenic form of cancer.” Rationale given : (Excerpted/paraphrased) “...conclusi ons regarding ionizing radiation as a cause of human cancer are based upon a s ynthesis of evidence from molecular and cytogenetic research, experime ntal studies in radiobiology, epidemiology, and theoretical

work on cancer causation.” W ith regard to CLL pathogenesis, NIOSH appears to have granted insufficient weight to mechanistic ev idence and too much weight to observational epidemiology. Epidemiological evidence for radiation-induced CLL is limited due to factors such as relatively l ong latency and unreliable case as certainment. “This is an inappropriate weighting of evidence for the evaluation of whether ionizing radiation exposure is a cause of CLL. ...the scient ific evidence pertaining to the molecular mechanisms of CLL induction weighs heavily towards the conclusion that CLL is similar to other hematological malignancies... The weight of this scientific evidence is in support

of the conclusion that the somatic mutations th at contribute to the genesis of CLL can be produced by ionizing radiation exposure. ... Av ailable scientific evidence suggests that CLL incidence will be increased by exposure to ionizing radiation. Scientific evidence does not provide a sufficient basis for rega rding CLL as non-radiogenic.” (Richardson, 2004)

5. Lydia B. Zablotska, MD, PhD Assistant Professor of Clinical Epidemiology Columbia University Sc hool of Public Health New York, NY

Zablotska’s conclusion: “...from an epidemiol ogical point of view it is not possible to prove that there is no risk of CLL due to occupational radiation exposure. It is only possible to say that currently we do not have solid scientific evidence to say that CLL is radiogenic.” Rationale given : (Excerpted) “...even after extended follow-up of the cohorts which were used by the BEIR V Committee as the basis for leukemia risk models, there appears to be no association between exposures to ionizing radiat ion and chronic lymphocytic leukemia either in Asian or Western populations. ... Fr om the scientific point of view, this (epidemiological) evidence could be inte rpreted as the absence of a convincing association between radiation exposure and s ubsequent CLL. ... CLL remains one of the

most controversial issues in radiation epidemiology. Though in the past it was thought to be definitely non-radiogenic, recent discoveri es, particularly from genetic and molecular studies, provide evidence that lymphatic can cers may differ to a gr eat degree from other types of leukemia. If risks are present, th ey are probably so small as to render them virtually undetectable in i ndividual studies under curre ntly available scientific epidemiological methods.” (Zablotska, 2004)7

V. Summary

Boice argues strongly that litt le if any evidence supports th e contention that CLL can be induced by ionizing radiation, even at mini mal exposure levels, a position supported by authoritative committees. In fact, numerous epidemiologic studies of varied populations have consistently demonstrated a lack of a ssociation between CLL a nd ionizing radiation. Further, he notes that signi ficant differences exist betw een CLL and other types of leukemia. CLL is etiologically and clinical ly more akin to a lymphoma, and evidence associating lymphomas with ionizi ng radiation is weak at best. Finally, the fact that other types of cancers weakly (if at a ll) associated with radiation are (mistakenly) eligible for compensation does not justify adding CLL. CL L presents the weakest case for radiation

induction of all cancers.

Zablotska seems to concur with Boice on mo st points, but she also notes that recent genetic and molecular evidence casts some doubt on the traditional notion that CLL is non-radiogenic. While thus conceding the possibility that CLL may be induced by radiation, she adds that the risk, if any, would likely be so small as to be undetectable by epidemiological studies. Her conclusion is much more cautious than Boice’s. While

evidence for an association between ionizi ng radiation and CLL is weak, it cannot be

demonstrated that the risk is zero.

Crowther, Ozonoff, and Richardson maintain that it is scientifically illogical to presume that CLL is not radiogenic, each citing various (and often similar) biologic and mechanistic constructs in suppor t of radiation induction. In fact, they maintain, cellular and other non-epidemiologic evidence tends to support the case for radiation induction; thus, it is much more plausible to assume that CLL, like other forms of cancer, is radiogenic. All agree that available scientific evidence does not s upport the continued exclusion of CLL from compensation. Moreove r, given that NIOSH’s stated policy is to

err on the side of claimants if scientific ev idence is inconclusive, it is thus arbitrary, inconsistent, and unfair to regard CLL as non-radiogenic.

VI. Recommendation

Three of the five expert consultants (Crowther, Ozono ff, Richardson) maintain unequivocally that CLL is radiogenic a nd that it should not be excluded from compensation. Only one (Boice) of the five experts concludes that CLL should absolutely not be regarded as a radiati on-inducible cancer unde r EEOICPA. Another (Zablotska) takes a position that could be categorized as cautious.

The issue hinges on how NIOSH should proceed in the absence of c onclusive scientific evidence. Although epidemiological eviden ce appears to offer little support for concluding that CLL is a ra diogenic cancer, a small positiv e risk cannot be excluded. Furthermore, objections have been raised w ith regard to the power and methodology used8

to address CLL in past epidemiologic studi es. The biological, mechanistic evidence lends somewhat more support for the plausibility of CLL as a radiogen ic cancer, but is far

from conclusive. The differences in the e xpert opinions solicited by NIOSH appear to stem from the relative weight given to the epidemiologic and mechanistic evidence. Given the direction, as set forth in EEOICPA, to side with the claimants in the face of scientific uncertainty, NIOSH proposes to (1 ) now regard CLL as a possibly radiogenic cancer for purposes of compensation e ligibility and to cease excluding it from compensation under EEOICPA, and (2) to create a new risk model for CLL, incorporating risk coefficients consistent with those assigned to other cancer risk models of similarly weak eviden ce for radiation induction.

NIOSH notes that this action should be regarded as a polic y decision which applies only to compensation eligibility under EEOICPA. It is not intended to apply, nor should it be construed as applying, to other compensation pr ograms or to regulator y issues outside of EEOICPA, nor should it be interpreted as offi cial NIOSH policy regarding the radiogenic

nature or lack thereof of chronic lymphocytic leukemia.

VII. References

Boice JD. Reconsideration of chronic lymphocytic leukemia for purposes of compensation. Report submitted to NIOSH, January 2005

Crowther MA. (untitled) CLL report submitted to NIOSH, November 2004

Department of Health and Human Services . 42 CFR Parts 81 and 82: Guidelines for Determining the Probability of Causat ion and Methods for Radiation Dose Reconstruction under the Employees Occupati onal Illness Compensation Program Act of 2000; Final Rules, May 2002

National Cancer Institute (NCI). Draft Repor t of the NCI-CDC Working Group to Revise the 1985 NIH Radioepidemi ological Tables. May 2000

National Institute for Occupational Safety and Health (NIOSH). NIOSH-Interactive RadioEpidemiological Program (NIOSH-IR EP) Technical Documentation, June 2002

National Institute for Occupational Safety a nd Health (NIOSH)/Hea lth-Related Energy Research Branch (HERB). Chronic Lymphoc ytic Leukemia: Annotated Bibliography (Draft), July 2004

National Institute for Occupational Safety and Health (NIOSH)/O ffice of Compensation Analysis and Support (OCAS). Chronic Lymp hocytic Leukemia: Reconsideration of Exclusion from Eligibility for Comp ensation under EEOICPA, October 2004

Ozonoff DM. Reconsideration of CLL. Report submitted to NIOSH, December 20049

Richardson DB. Chronic Lymphocytic Leukemi a: Reconsideration of Exclusion from Eligibility for Compensati on under EEOICPA. Report subm itted to NIOSH, November

2004

Zablotska LB. Comments on the arguments fo r covering chronic lymphocytic leukemia under the Energy Employees Occupational Il lness Compensation Program Act of 2000 (EEOICPA) advanced by its stakeholders in the “Chronic Lymphocytic Leukemia:

Reconsideration of Exclus ion from Eligibility for Compensation under EEOICPA.” Report submitted to NIOSH, December 2004