Notice of Proposed Rulemaking to 

Include Chronic Lymphocytic Leukemia 

as a Covered Cancer under EEOICPA

James W. Neton, Ph.D., CHP

Associate Director for Science

Division of Compensation Analysis and Support

National Institute for Occupational Safety and Health

May 2011

St. Louis, MO
Background

 CLL is the only cancer assigned a probability of 

causation of zero under 42 CFR Part 81

 Rationale behind this decision was:

• Unavailability of existing epidemiological studies to 

demonstrate a link between radiation exposure and 

CLL

• Infeasibility of developing a quantitative risk model

 At the time of publication of the rule in 2002, 

NIOSH was committed to revisiting this decision 

as new scientific information became available
Summary of NIOSH Activities 

 Public meeting convened by NIOSH Office of 

Energy Research Programs

• Participants determined that current evidence is 

inconclusive

 NIOSH polled subject matter experts 

regarding radiogenicity of CLL

• Majority of reviewers supported the position that 

CLL should be considered radiogenic for 

compensation program purposes

 NIOSH conducts research into appropriate 

risk model for CLL
Summary of NIOSH Activities—cont.

 NIOSH polls subject matter experts on the 

etiology of CLL 

 NIOSH researches dosimetric target organ 

for CLL and develops approach to dose 

reconstruction

 Risk model and dose reconstruction 

approach completed

 Notice of proposed rulemaking published in 

the Federal Register
CLL Risk Model

 Conducted a comprehensive review of 

published papers on the epidemiological, 

molecular and clinical bases of CLL

 Compiled sex and age-specific incidence rates 

from the databases of the National Cancer 

Institute and the International Agency for 

Research on Cancer

 Critically evaluated epidemiologic data 

related to the issue of latency
CLL Risk Model—cont.

 Used existing multiple myeloma and lymphoma 

model as a starting point

• CLL is classified as a form of non-Hodgkin’s lymphoma

 Draft model set the latency period as 15 ± 5 

years

 As with other models risk is low at short latency 

periods and increases as a function of time
CLL Risk Model—cont.

 Draft model reviewed by four subject matter 

experts 

 Comments were reviewed and adjustments 

made as appropriate

 Resulted in one major modification to the risk 

model

• Revised model contains a shortened latency period of 

10 ± 5 years
Latency Adjustment

0.0

0.2

0.4

0.6

0.8

1.0

0 5 10 15 20 25 30

Latency adjustment (unitless)

Time after exposure (years)

CLL
Quantitative Evaluation of the Model

 Final model was quantitatively evaluated by 

calculating the probability of causation (PC) for 

certain exposure scenarios

• Calculated for males between 20 and 40 years of 

age

• Acutely exposed to 1 Sievert of high-energy 

gamma radiation

 Although analysis restricted to males, results 

should be similar for females

• Same risk coefficient is used for both

 PC results greater than 50% for some cases
Results of Quantitative Evaluation

Age at 

exposure 

(y)

PC

(percentile)

Time since exposure (y)

5 10 15 20 25 ≥30

20

50th 0.80 7.84 13.8 12.2 10.4 8.88

95th 16.7 48.4 54.2 50.1 45.4 41.3

99th 35.0 65.0 67.6 63.2 58.6 54.6

25

50th 0.46 4.88 9.07 8.16 6.99 6.99

95th 9.91 35.4 41.9 38.7 34.8 34.8

99th 22.5 51.0 55.3 51.3 47.2 47.2

30

50th 0.28 3.09 5.98 5.48 5.49 5.49

95th 6.04 24.9 31.2 28.9 28.9 28.9

99th 14.4 38.3 43.3 40.1 40.2 40.2

35

50th 0.23 2.56 5.10 5.48 5.49 5.49

95th 4.85 21.2 27.5 28.9 28.9 28.9

99th 11.5 33.4 38.6 40.1 40.2 40.2

40

50th 0.19 2.16 5.10 5.48 5.49 5.49

95th 4.01 18.4 27.5 28.9 28.9 28.9

99th 9.50 29.5 38.6 40.1 40.2 40.2
Dose Reconstruction Methodology

 CLL is a disease that originates from a population 

of mature B lymphocytes

 Lymphocytes could undergo transformation to 

CLL clones anywhere in the hematopoietic or 

lymphatic system

 Dose reconstructions for non-homogeneous 

exposures (e.g., internal dose) must account for 

this

 NIOSH proposes to use a probabalistic approach 

based on the weighted average of the doses to 

the various irradiated sites
Distribution of Lymphocytes in the Body

Compartments of the human lymphatic 

system

% of total B-CLL precursors

in human body

(95% C.I.)

Lymph nodes 27 (2.7−65)

Spleen 23 (2.1−59)

Peyer's patches (small intestinal 

wall) 3.7 (0.24−14)

Thymus 0.24 (0.010−1.1)

Red bone marrow 18 (1.5−52)

Tonsils (extrathoracic airways) 0.45 (0.018−1.9)

Blood (spleen) 2.3 (0.12−8.7)

Intestinal Mucosa 19 (1.5−56)

Respiratory Mucosa 3.4 (0.20−13)

Skin 0.064 (0.002−0.27)

Liver 0.50 (0.028−1.9)

Vermiform appendix 

(lower large intestinal wall) 0.036 (0.002−0.14)

Residual soft tissue 1.3 (0.079−4.8)
Example Dose Calculation Weighted dose components

Fraction of all pre-CLL 

cells Additional Sr-90 ingestion Sr-90 ingestion

Compartment in this tissue Fractions doses per unit intake per unit intake

[%] [Sv/Bq] [Sv/Bq]

Lymph Nodes 27

Extrathoracic 0.06 6.6E-10 1.1E-11

Thoracic 0.08 6.6E-10 1.4E-11

Remainder 0.86 6.6E-10 1.5E-10

Spleen 27 6.6E-10 1.8E-10

Peyer's Patches 2.8 8.0E-10 2.3E-11

Thymus 0.19 6.6E-10 1.3E-12

Red bone marrow 17.7 1.8E-07 3.2E-08

Tonsils 0.28 6.6E-10 1.9E-12

Blood 1.77 6.6E-10 1.2E-11

Intestinal mucosa 19.2

small intestinal wall 0.8 8.0E-10 1.2E-10

upper intestinal wall 0.1 1.3E-09 2.5E-11

lower large intestinal wall 0.1 1.8E-09 3.5E-11

Respiratory mucosa 2.93

extrathoracic airways 0.001 6.6E-10 1.9E-14

lung 0.999 6.6E-10 1.9E-11

Skin 0.051 6.6E-10 3.3E-13

Liver 0.425 6.6E-10 2.8E-12

Vermiform appendix 0.028 1.8E-09 5.1E-13

Residual soft tissue 1.06

adrenals, breast, esophagus, 

muscle, pancreas, thyroid, uterus, 

"remainder"

0.98 6.6E-10 6.9E-12

bladder wall 0.002 1.5E-09 3.2E-14

kidneys 0.009 6.6E-10 6.3E-14

ovaries 0.0003 6.6E-10 2.1E-15

stomach wall 0.005 9.0E-10 4.8E-14

testes 0.001 6.6E-10 7.0E-15

Total Dose 3.2E-08
Summary

 Proposed rule would rescind the 

designation of CLL as non-radiogenic

 New risk model would be added to allow 

for calculation of PC for CLL

 Dose reconstruction methodology would 

use a probabalistic approach to calculate 

the weighted average dose to the 

population of mature lymphocytes in the 

body
Additional Information

 Information used in NIOSH’s decision process is 

located in Regulatory docket #209 at:

http://www.cdc.gov/niosh/docket

 Includes NPRM, subject matter reviews, 

responses to reviews, proposed risk model, and 

dose reconstruction approach

 Public comment period closes June 20, 2011