NIOSH-IREP technical documentation June 18, 2002

background risk (caused primarily by exposure of susceptible skin to UV radiation;

UNSCEAR 2000b, p. 200), if melanin is not similarly protective of its effects. However, some
studies have suggested that melanin provides protection from radiation-induced skin cancer as
well (Harley et al. 1983, Shore et al. 1984, Davis et al. 1989). Unfortunately, few studies have
evaluated formally the interaction of ionizing radiation exposure with skin pigmentation. A
meta-analysis of twelve epidemiologic studies of UV and ionizing radiation exposed individuals
could not distinguish between an additive and multiplicative interaction, due to the lack of
controls with ionizing radiation exposure alone (Shore 1990; UNSCEAR 2000b). Without the
capability to formally test for the form of interaction within a study, the United Nations Scientific
Committee on the Effects of Atomic Radiation (UNSCEAR) recommends careful comparison
of the relative risks among different populations in comparable studies (UNSCEAR 2000e, p.
310). The ICRP evaluated existing studies, and, given the findings of several studies that
excess absolute risk from ionizing radiation exposure is greatest among white populations (and
is still higher in areas of the skin usually exposed to greater UV radiation), suggested an
interaction that is more than additive (Harley et al. 1983, Shore et al. 1984; ICRP 1991a, pp.
75-78). However, a recent analysis of non-melanoma skin cancer among the Japanese atomic
bomb survivors found excess relative risks per unit dose nearly ten times higher for areas of the
body unexposed to UV radiation (Ron et al. 1998). This finding strongly suggests a

submultiplicative interaction between ionizing and UV radiation exposures. An authoritative

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NIOSH-IREP technical documentation June 18, 2002

Cc.

Large changes in cancer incidence over time exist for many cancers (e.g., breast, lung,
prostate); however, the background rates have been fixed at a single point in time (usually,
1990). Failing to incorporate these changes could lead to an overestimation or
underestimation of a claimant’s probability of causation.

Some of the source models for risk coefficients have unquantified uncertainty related to the
latency between exposure and cancer incidence. For example, the excess relative risk of
leukemia between 2 and 5 years following exposure is unknown, because the follow-up
time for the Japanese atomic bomb survivors began 5 years after the exposure. Excess
relative risks between 2 and 5 years after exposure may be different than those 5 or more
years after exposure. This limitation is less likely to exist for other cancer types because of
the generally longer latency for most cancers.

The assumed form of interaction between UV radiation exposure or susceptibility (as
reflected by racial and ethnic differences in background skin cancer risk) and radiation
exposure is highly uncertain, and has not been evaluated formally through a thorough
assessment (or meta-analysis) of the relevant literature. Similarly, formal evaluations of the
risk factor interactions for many cancers (e.g., breast and stomach) could further elucidate
the appropriate form of risk transfer between the Japanese and U.S. populations.

The uncertainty distribution of the adjustment factor for low-dose, low dose-rate exposure
(i.e., the DDREF) used in NCI’s and NIOSH’s IREP currently has a large influence on the

calculated probability of causation values. This factor merits further attention with respect

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NIOSH-IREP technical documentation June 18, 2002

never, rare or highly infrequent smokers (e.g., Rogot and Murray 1980, McLaughlin et al. 1995). This
quantitative classification is currently in use by the CDC in several national surveys of smoking behavior
(Anonymous 1994). A “former smoker” is an individual who ceased smoking cigarettes at least five
years before the date of primary lung cancer diagnosis. This definition is adopted from the original NIH
radioepidemiological tables, and is based on the observation that lung cancer background risks are not

reduced for the first five years following smoking cessation (Rogot and Murray 1980).

III. Cancer model selection

The model to be used in NIOSH-IREP for each primary cancer is given in Table 4. For some
cancers (e.g., certain leukemias) more than one IREP model will be employed. In this case, the model
producing the highest probability of causation at the upper 99% credibility limit is to be used as a basis
for the compensation decision,

IREP models do not specifically include cancers as defined in their early stages: carcinoma in situ
(CIS). These neoplasms are becoming more frequently diagnosed, as the use of cancer screening
tools, such as mammography, has increased in the general population. Thus, many cancers of epithelial
origin are now being detected before they have spread to the basement membrane of the affected
tissue. The risk factors and treatment for CIS are frequently similar to those for malignant neoplasms.
While controversial, there is growing evidence that CIS represents the earliest detectable phase of
malignancy (Correa 1996, Kerlikowske et al. 1997, Grippo and Sandgren 2000), and they have been

included in some evaluations of radiation-related cancer risks (Ron et al. 1998). It is uncertain what

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NIOSH-IREP technical documentation June 18, 2002

Figure 4. Draft and final DDREF distribution used in NIOSH-IREP for (a) all solid cancers
except breast and thyroid and (b) breast and thyroid cancer.

(@) 0.40

0.35 ¢- ---------~-~~----------~-~~-------------
0.30 4. -------~----— ~~ gue — - gy - - --- -----------

0.25 ¢- ----~---------- -- 4 ----------------
0.20 + ---~------ --4 - - 4 ----------------
0.15 f+ ---------- ~~ --- ----------------
0.10 4---~~------~ -- a --- ---ye -----------
0.05 4 ------——-- -- 3 --@ ------__------
000 a UU

0.50 0.70 1.00 1.50 2.00 3.00 4.00 §.00
DDREF, Solid cancers (except breast and thyroid)

Probability

® 0.40

Probability

0.50 0.70 1.00 1.50 2.00 3.00 4,00 5.00
DDREF, Breast and thyroid cancers

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B. Cancers added to NIOSH-IREP

The final NCI-IREP program (NCI 2002) includes more cancer models than the draft NCI-
TREP program reviewed by the NAS panel (NCI 2000). Cancer models for squamous cell carcinoma
of skin and basal cell carcinoma of skin have been added, based on new analyses conducted by
researchers at the Radiation Effects Research Foundation (RERF), in Japan (see discussion of “skin
cancer models” in Sec. II.B.2, below). Certain cancer models have been added to NIOSH-IREP.

These include malignant melanoma of skin, and cancers of the male breast, bone, connective tissue,
eye, and endocrine glands other than thyroid. The NCI version of IREP includes the last four of these
in a general “miscellaneous” cancer model, but they are explicitly separated in NIOSH-IREP. The
scientific basis of these models and their implementation in NIOSH-IREP are described below.

In summary, NIOSH-IREP incorporates three different models for skin cancer. For non-
melanoma skin cancer, basal cell and squamous cell carcinoma models are based on different sets of
tisk coefficients. In claims for which the non-melanoma skin cancer type is indeterminate, the model for
basal cell carcinoma is to be used in estimating the probability of causation. Both basal cell and non-
basal cell carcinoma models are modified by race-specific background incidence rates for combined
non-melanoma skin cancers. A third skin cancer model, for malignant melanoma, uses basal cell
carcinoma risk coefficients, modified by background incidence rates for malignant melanoma. All three
skin cancer models use the “general” risk transfer uncertainty distribution (developed for all solid

cancers save breast and thyroid), For other cancer types, the sites used to produce excess relative risk

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NIOSH-IREP technical documentation

Appendix I (continued): NIOSH-IREP program output

Results of NIOSH-IREP
Probability of Causation:

1* percentile 0.0%
5" percentile 0.0%
50" percentile 0.81%
95" percentile 5.29%
99" percentile 10.22%

June 18, 2002

Name of Analyst:
Title:

Signature:
Date:

Name of Reviewer:
Title:

Signature:
Date:

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NIOSH-IREP technical documentation June 18, 2002

Table 4 (continued). Cancer models to be used in calculation of probability of causation.
Derivation of NIOSH-IREP models is described in Section II-B. Abbreviations: MN
(malignant neoplasm), CIS (carcinoma in situ), NUB (neoplasm of uncertain behavior), NUM
(neoplasm of unspecified nature).

Primary neoplasm ICD-9 code NIOSH-IREP model for
calculating PC

NUB of breast 238.3 Breast

NUB of other lymphatic and 238,5-238.7 Lymphoma and multiple myeloma

hematopoietic

NUB of other specified and unspecified] 238.8, 238.9 Other and ill-defined sites
sites

Neoplasm of unspecified nature (NUN) 239.0 All digestive

of digestive system

NUN of respiratory system 239.1 Lung AND Other respiratory

NUN of bone and soft tissue 239.2 Bone

NUN of skin 239.2 Non-melanoma skin-Basal cell

NUN of breast 239.3 Breast

NUN of bladder 239.4 Bladder

NUN of other genitourinary organs 239.5 Female genital less ovary AND
Ovary AND All urinary organs (if
female)

All male genital AND All urinary
organs (if male)

NUN of brain and other parts of 239.6, 239.7 Nervous system

nervous system

NUN of endocrine glands 239.7 Thyroid AND Other endocrine
glands

NUN of other specified or unspecified | 239.8, 239.9 Other and ill-defined sites
sites

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NIOSH-IREP technical documentation

June 18, 2002

Table 4 (continued). Cancer models to be used in calculation of probability of causation.
Derivation of NIOSH-IREP models is described in Section II-B. Abbreviations: MN
(malignant neoplasm), CIS (carcinoma in situ), NUB (neoplasm of uncertain behavior),
NUM (neoplasm of unspecified nature).

Primary neoplasm ICD-9 code NIOSH-IREP model for
calculating PC
CIS of larynx and other respiratory 231.0, 231.8, Other respiratory
231.9
CIS of lung 231.1, 231.2 Lung
CIS of skin 232 Malignant melanoma AND non-
melanoma skin
CIS of breast 233.0 Breast
CIS of cervix uteri or other and 233.1, 233.2 Female genitalia, less ovary
unspecified parts of uterus
CIS of other and unspecified female 233.3 Female genitalia, less ovary AND
genital organs Ovary
CIS of prostate, penis or other and 233.4 All male genitalia
unspecified male genital organs
CIS of bladder 233.7 Bladder
CIS of other and unspecified urinary | 233.9 Urinary organs less bladder
organs
CIS of eye 234.0 Eye
CIS of other and unspecified sites 234.8, 234.9 Other and ill-defined sites
Neoplasm of uncertain behavior (NUB)| 235.0, 235.1 Oral cavity and pharynx
of salivary gland, lip, oral cavity or
pharynx
NUB of stomach 235.2 Stomach
NUB of colon 235.2 Colon
NUB of rectum and anus 235.2 Rectum

Page 50 of 73


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NIOSH-IREP technical documentation June 18, 2002

V. References

Altman A, Rosen T, Tschen JA, Hoffmann T, Bruce S, Siegel DM, Levy ML, Schaefer D, Goldberg
LH. Basal cell epithelioma in black patients. J. Am. Acad. Dermatol. 17:741-745, 1987.

Andersson, M, Carstensen B, Visfeldt J. Leukemia and other related hematological disorders among
Danish patients exposed to Thorotrast. Radiat Res. 134:224-233, 1993.

Anonymous. Leads from the Morbidity and Mortality Weekly Report, Atlanta, GA: Cigarette smoking
among adults—United States, 1992, and changes in definition of smoking. J. Am. Med. Assoc. 272:14-
16, 1994.

Austin DF, Reynolds PJ. Investigation of an excess of melanoma among employees of the Lawrence
Livermore National Laboratory. Am. J. Epidemiol. 145:524-531, 1997.

Austin DF, Reynolds PJ, Snyder MA, Biggs MW, Stubbs HA. Malignant melanoma among employees
of Lawrence Livermore National Laboratory. Lancet 1981:712-716, 1981.

Baron JA, Rohan TE. The causes of cancer: Tobacco. Chapter 14 in Cancer Epidemiology and
Prevention, 2" Edition, D Schottenfeld and JF Fraumeni Jr, eds. New York: Oxford University
Press, 1996.

Bernstein L, Ross RK, Pike MC, Casagrande JT, Henderson BE. Urinary estrogens and male-to-
female breast cancer ratios. Int. J. Cancer 44:954-956, 1989.

Boice Jr JD, Land CE, Preston DL. Ionizing Radiation. Ch 16 in Cancer Epidemiology and
Prevention, 2" Edition, Schottenfeld D, Fraumeni Jr JF, eds. New York: Oxford University Press.
1996, 1521 pp.

Brenner DJ, Miller RC, Marino SA, Geard CR, Randers-Pehrson G, Hall EJ. Inverse dose rate effects
for neutrons: general features and biophysical consequences. Radiat. Protect. Dosim. 44:45-48, 1992.

Brenner DJ, Hall EJ, Randers-Pehrson G, Miller RC. Mechanistic considerations on the dose-rate/LET
dependence of oncogenic transformation by ionizing radiations. Radiat. Res. 133:365-369, 1993.

Cardarelli JC. A potential consequence of excluding work-required x-ray exposures when computing

cumulative occupational radiation dose at a uranium enrichment plant. University of Cincinnati, PhD
Dissertation, 2000.

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NIOSH-IREP technical documentation

June 18, 2002

Table 4 (continued). Cancer models to be used in calculation of probability of causation.
Derivation of NIOSH-IREP models is described in Section II-B. Abbreviations: NM
(malignant neoplasm), CIS (carcinoma in situ), NUB (neoplasm of uncertain behavior),
NUN (neoplasm of unspecified nature.

Primary neoplasm ICD-9 code NIOSH-IREP model for
calculating PC

Malignant melanoma 172 Malignant melanoma

Basal cell carcinoma of skin 173 Non-melanoma skin-Basal cell

Other (non-basal cell, non-melanoma) | 173 Non-melanoma skin-Squamous cell

carcinoma of skin

MN of breast 174, 175 Breast

MN of uterus or uterine cervix

179, 180, 182

Female genitalia less ovary

leukemia

MN of ovary 183 Ovary

MN of other female genital 181, 184 Female genitalia less ovary

MN of male genital 185-187 All male genitalia

MN of urinary bladder 188 Bladder

MN of kidney and other urinary organs | 189 Urinary organs less bladder

MN of eye 190 Eye

MN of brain and other nervous system | 191, 192 Nervous system

MN of thyroid gland 193 Thyroid

MN of other endocrine glands 194 Other endocrine glands

MN of other and ill-defined sites 195 Other and ill-defined sites
Non-Hodgkin’s lymphoma and other | 200-202 Lymphoma and muitiple myeloma
lymphoid tissue, Hodgkin’s disease

Multiple myeloma and other 203 Lymphoma and multiple myeloma
immunoproliferative diseases

Acute and unspecified lymphocytic 204.0, 204.9 Acute lymphoid leukemia

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NIOSH-IREP technical documentation June 18, 2002

IREP includes separate risk coefficients for BCC and other non-melanoma skin cancers (mainly
SCC), based on new analyses of skin cancer incidence among atomic bomb survivors
conducted by researchers at the Radiation Effects Research Foundation in Japan (NCI 2002,
p. 34), The method used to develop risk coefficients for these separate models is quite
consistent with that for other cancers. The results of this modeling effort support the use of
substantially different risk coefficients for the two non-melanoma skin cancer types. However,
it should be noted that ICD-9 (and its revision, ICD-10) does not distinguish between SCC
and BCC within the non-melanoma skin cancer category. In cases where it is not possible to
determine which cancer cell type applies to a given claimant, DOL is instructed to use the risk
models for basal cell carcinoma.

The risk coefficients developed for non-melanoma skin cancer in the finalized NCI-
IREP were incorporated into the final NIOSH-IREP. The excess relative risk coefficients for
BCC vary by age at exposure but not by gender or attained age, and are linear in dose. The
coefficients for SCC do not vary by gender, age at exposure, or attained age. No adjustment is
made for time since exposure (except the latency adjustment used for all other cancers between
0 and 5 years after exposure). This is supported by evidence from several studies which
indicate that radiation-related skin cancer risks remain elevated for many years following

exposure (van Daal et al. 1983; Ron et al. 1998).

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NIOSH-IREP technical documentation June 18, 2002

to the appropriate weighting to use for various values (including less than one), for low-
dose, chronic photon exposures, and to the incorporation of uncertainty associated with the

quadratic term of the dose-response relationship for leukemia.

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NIOSH-IREP technical documentation

Appendix I (continued): NIOSH-IREP program output

GENERAL EXPOSURE INFORMATION:

June 18, 2002

Exposure # | Exposure | Organ Dose (cSv) | Exposure Radiation Type
Year Rate
1 1955 Lognormal (0.5,1.8) | acute photons E=30-250keV
2 1955 Lognormal (0.7,1.8) | acute photons E>250keV
3 1956 Lognormal (0.1,1.8) | chronic neutrons E=100keV-2MeV
4 1956 Lognormal (0.4,2.5) | acute photons E>250keV
5 1957 Uniform (0.1,4) chronic alpha
6 1957 Lognormal (1.3,1.8) | acute photons E>250keV
7 1958 Uniform (0.05,5.6) | chronic alpha
8 1958 Lognormal (0.2,1.8)} acute photons E>250keV
9 1959 Lognormal (0.5,2.5) | chronic neutrons E=100keV-2MeV
10 1959 Lognormal (0.1,1.8) | acute photons E>250keV
11 1960 Lognormalt (0.5,1.8) | acute photons E>250keV
12 1960 Lognormal (0.1,2.5) | chronic neutrons E=100keV-2MeV
13 1961 Lognormal (0.3,1.8) | acute photons E>250keV
14 1961 Lognormal (0.2,2.5) | chronic neutrons E=100keV-2MeV
15 1962 Lognormal (0.1,1.8) | acute photons E>250keV

Radon Exposure Information:

N/A (applies only to cases of Lung Cancer with Radon Exposures)

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NIOSH-IREP technical documentation June 18, 2002

I. Background

Under the Energy Employees’ Occupational Illness Compensation Program Act of 2000
(EEOICPA), the National Institute for Occupational Safety and Health (NIOSH) is charged with the
development of guidelines to determine whether a claimant’s cancer meets the criterion for causation by
workplace exposure to ionizing radiation (i.¢., a 50% or greater probability of causation).

The basis for this determination, as specified in EEOICPA, is the set of radioepidemiological
tables developed by a National Institutes of Health Ad Hoc working group in 1985 (NIH 1985), as
they are updated periodically. These radioepidemiological tables serve as a reference tool providing
probability of causation estimates for individuals with cancer who were exposed to ionizing radiation.
Use of the tables requires information about the person’s dose, gender, age of exposure, date of cancer
diagnosis and other relevant factors. The tables are used by the Department of Veterans Affairs
(DVA) to make compensation decisions for veterans with cancer who were exposed in the line of duty
to radiation from atomic weapon detonations. The primary source of data for the 1985 tables is
research on the occurrence of cancer-related deaths among Japanese atomic bomb survivors from
World War II.

The 1985 tables have recently been updated by the National Cancer Institute (NCI) and the
Centers for Disease Control and Prevention (CDC) to incorporate progress in research on the
relationship between radiation and cancer risk, including the assessment of associated uncertainties.
The draft update (NCI 2000) has been reviewed by the National Research Council (NAS/NRC

2000). The finalized update (NCI 2002) will be available soon for public release. HHS/NIOSH has

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Appendix II (continued): Glossary of ICD-9 codes and their cancer descriptions

ICD-9 code Cancer description

160 Malignant neoplasm of nasal cavities, middle ear, an accessory sinuses

161 Malignant neoplasm of larynx

162 Malignant neoplasm of trachea, bronchus an lung

163 Malignant neoplasm of pleura

164 Malignant neoplasm of thymus, heart, and mediastinum

165 Malignant neoplasm of other and ill-defined sites within the respiratory
system and intrathoracic organs

170 Malignant neoplasm of bone and articular cartilage

171 Malignant neoplasm of connective and other soft tissue

172 Malignant melanoma of skin

173 Other malignant neoplasm of skin

174 Malignant neoplasm of female breast

175 Malignant neoplasm of male breast

179 Malignant neoplasm of uterus, not otherwise specified

180 Malignant neoplasm of uterine cervix

181 Malignant neoplasm of placenta

182 Malignant neoplasm of uterine corpus (body of uterus)

183 Malignant neoplasm of ovary and other uterine adnexa

184 Malignant neoplasm of other and unspecified female genital organs

185 Malignant neoplasm of prostate

186 Malignant neoplasm of testis

187 Malignant neoplasm of penis and other male genital organs

188 Malignant neoplasm of urinary bladder

189 Malignant neoplasm of kidney and other and unspecified urinary organs

190 Malignant neoplasm of eye

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NIOSH-IREP technical documentation June 18, 2002

Appendix II: Glossary of ICD-9 codes and their cancer descriptions!

ICD-9 code Cancer description

140 Malignant neoplasm of lip

141 Malignant neoplasm of tongue

142 Malignant neoplasm of major salivary glands

143 Malignant neoplasm of gum

144 Malignant neoplasm of floor of mouth

145 Malignant neoplasm of other and unspecified parts of mouth

146 Malignant of neoplasm of oropharynx

147 Malignant neoplasm of nasopharynx

148 Malignant of neoplasm of hypopharynx

149 Malignant of neoplasm other and ill-defined sites within the lip, oral cavity,
and pharynx

150 Malignant of neoplasm of esophagus

151 Malignant of neoplasm of stomach

152 Malignant of neoplasm of small intestine, including duodenum

153 Malignant of neoplasm of colon

154 Malignant of neoplasm of rectum, rectosigmoid junction, and anus

155 Malignant neoplasm of liver and intrahepatic bile ducts

156 Malignant neoplasm of gall bladder and extrahepatic bile ducts

157 Malignant neoplasm of pancreas

158 Malignant neoplasm of retroperitoneum and peritoneum

159 Malignant neoplasm of other and ill-defined sites within the digestive organs
and peritoneum

'The International Classification of Diseases Clinical Modification (9" Revision) Volumes I&II.
[1991] Department of Health and Human Services Publication No. (PHS) 91-1260, U.S. Government
Printing Office, Washington, D.C.

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NIOSH-IREP technical documentation June 18, 2002

summary, the approach used to estimate the REF for each type of radiation was to review the relevant
literature comparing the REF for the specific exposure type as compared to high-dose, high-energy
photon radiation (i.e., the same exposure type as experienced by the Japanese atomic bomb survivors).
Evidence from neoplastic endpoints was preferentially considered.

The REF was assumed to be unity for photons of energy greater than 250 keV, as this is the
primary exposure in the Japanese atomic bomb survivors studies, upon which the majority of the risk
estimates are based. Two sets of distributions, having an increased REF compared to >250 keV
photons, were established for photons of lower energy, based on reviews of the relevant radiobiological
literature. The REF distributions assumed for electrons are also based on values obtained from review
of the relevant literature (Kocher et al. 2002; Table 5A). For alpha radiation, the estimated REF for
chronic alpha exposure compared to low-dose-rate, low-LET exposure was also much greater than
one (Kocher et al. 2002, Table 5B).

For neutrons, the REF distribution was estimated first for fission neutrons (those of energy
between 100 keV and 2 MeV). For neutrons of higher or lower energy, an REF reduction factor was
applied (Table 5, ICRP 1991b). The neutron REFs include an adjustment for a possible inverse dose-
rate relationship for chronic exposures (Kocher et al. 2002; Table 5C). This factor increases the effect
of a given dose for a chronic relative to an acute exposure. A direct adjustment is also made within
NIOSH-IREP for a possible inverse dose rate relationship for all alpha radiation exposure except
radon (as discussed below). The inverse dose-rate phenomenon has been observed for many in vitro

and animal studies, but it is thought to apply to a rather narrow range of LET and total dose (Brenner et

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NIOSH-IREP technical documentation June 18, 2002

UNSCEAR report (UNSCEAR 2000b) suggests that a sub-multiplicative model should be
employed for risk modeling, based on the totality of evidence.

The uncertainty in the appropriate form of interaction between UV and ionizing
radiation exposure is expected to be most critical in determining the role of race or ethnicity in
modifying the excess relative risk estimates produced from the Japanese atomic bomb survivor
study. Because of this large uncertainty, the method of risk transfer from the Japanese to the
USS. racial/ethnic groups, built into the NIOSH-IREP program, should incorporate the
possibility of an additive or multiplicative interaction (or a mixture of these). Given the
conflicting evidence regarding the appropriateness of any specific interaction model between
UV and ionizing radiation exposure, the IREP program uses the same uncertainty distribution
for risk transfer as was used for all other solid cancers (except breast and stomach cancer).
This distribution is trapezoidal, equally weighting the probabilities for an additive and
multiplicative interaction, with slight probabilities of sub-additive or super-multiplicative
interactions.

In order to apply the risk transfer function referenced above, background cancer
incidence rates in Japan and the U.S. (by race/ethnicity categories) are required. Incidence
rates for non-melanoma skin cancer are available for Japan, but not for the U.S., as this is not a
reportable cancer among U.S. registries. However, a survey of non-melanoma skin cancer
rates was carried out by researchers at the National Cancer Institute in the early 1980s,

reflecting rates across a wide area within the U.S. for 1977-1980 (Scotto et al. 1983), In

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NIOSH-IREP technical documentation June 18, 2002

Both the basal cell carcinoma and the miscellaneous cancer models have higher
ERR/Sv estimates than the squamous cell carcinoma model (NCI 2002). Of these two, the
basal cell carcinoma model produces higher ERR/Sv estimates for men at all combinations of
age at exposure and attained age, and for women at younger ages of exposure (Fig. 2). At
ages of exposure above about 35, the miscellaneous cancer model produces slightly greater
ERR/Sv estimates (but these are both quite low, considering typical exposure patterns at DOE
facilities). Therefore, it would in general be most favorable to the claimant to use the basal cell
carcinoma model to provide excess relative risk estimates for malignant melanoma. These
estimates should be applied to the background incidence rates for malignant melanoma in Japan
and the U.S., and the same risk transfer model as for other skin cancers, as discussed earlier
(e., the distribution favoring neither the additive nor the multiplicative interaction model).

For these reasons, the ERR per Sv estimates for basal cell carcinoma were used to
evaluate probability of causation for malignant melanoma. The sources of background
incidence rates used in NIOSH-IREP for malignant melanoma of the skin are the same as for
other cancers: Japanese incidence data were obtained from Parkin et al. (1997), and U.S. rates
(race- and ethnicity-specific) were obtained from the U.S. Surveillance Epidemiology and End

Results (SEER) program.

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NIOSH-IREP technical documentation June 18, 2002

occurring since the worker began employment at a facility (i.c., a time period extending from
the 1940s through the present day).

While many studies have found an association between ionizing radiation exposure and
skin cancer, the appropriate form of dose-response model for skin cancer is highly uncertain
(ICRP 1991a, p. 52). Some researchers advocate the use of a threshold model, on the basis
of observations about dose-response relationships for such deterministic endpoints as skin
dermatitis, desquamation and erythema, and upon evidence for a nonlinear dose-response
relationship observed in some animal studies (reviewed in ICRP 1991a, pp 52-55). However,
no evidence of a dose threshold was observed in a meta-analysis of twelve UV and ionizing
radiation-exposed groups (Shore 1990, UNSCEAR 2000b). A recent study evaluated various
forms of the dose-response relationship for the atomic bomb survivors, and concluded that the
best-fitting model for non-melanoma skin cancer is proportional to the fourth power of dose
(Little and Charles 1997). However, a more recent analysis found no significant model
improvement (over linearity) using a linear-quadratic model (Ron et al. 1998). A linear dose-
response relationship for non-melanoma skin cancer has been advocated by others as well
(e.g., Scotto et al. 1996). The mechanisms in skin carcinogenesis that might lead to a threshold,
not observed for most other organs in these studies, are unclear (ICRP 1991a, pp. 54-55).

Skin doses are poorly estimated in most studies of risks associated with ionizing
radiation exposure, making quantitative dose-response analysis difficult. As for other cancer

sites, an exception is the Japanese atomic bomb survivors study. The final version of NCI-

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al. 1992, 1993). An inverse dose-rate effect has also been observed in studies of radon-exposed
workers (Hornung and Meinhardt 1987, Xuan et al. 1993, Tomasek et al. 1994); however, it has not
been observed at doses below approximately 50 working level months (Lubin et al. 1995), nor has it
been adopted in expert panel assessments of low-dose radon risk (NAS/NRC 1999). Such an inverse
dose-rate effect was not incorporated for models of lung cancer risk from radon exposure, because it is

implicitly included in the form of the dose-response relationship for that exposure.

F. Definitions of smoking categories for lung cancer claims

The NCI IREP program includes an adjustment to the probability of causation estimate for
primary lung cancer, based on an assumed submultiplicative relationship between smoking and lung
cancer (NCI 2000, pp. 48-50). There are seven smoking categories included in the NCI model (Table
6). No adjustments were made to this model for NIOSH-IREP; however, the definitions of the cancer
categories require clarification for use under EEOICPA. The first clarification needed is that only
cigarette smoking history is considered. This is a result of precedent established in the first NIH
Radioepidemiological Tables (NIH 1985), based on the strong, unambiguous, and quantifiable
relationship between cigarette smoking and lung cancer (Baron and Rohan 1996). In addition, all
smoking categories are defined as of the date of the primary cancer diagnosis. Lastly, additional
clarification is given for the definitions of “never smoker” and “former smoker.” For EEOICPA, a
“never smoker” is defined as a person who has smoked fewer than 100 cigarettes throughout his or her

lifetime (prior to cancer diagnosis). Most epidemiologic studies define the “never smoker” category as

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for use at this time in the bone cancer models is the miscellaneous cancer model from NCI-
IREP. As is the case for other cancers in this category, the risk coefficients are modified by the

background incidence rates for the specific cancer.

2. Non-melanoma skin cancer:

Some expert groups consider skin cancer risk in establishing low-level skin radiation
exposure limits (ICRP 1991a), as several studies have provided evidence that non-melanoma
skin cancers, particularly basal cell carcinoma (BCC), are related to exposure to ionizing
radiation (Shore 2001). These include studies of radiologists, uranium miners, and patients
exposed during treatment for medical conditions, as well as the Japanese atomic bomb
survivors (Sevcova et al. 1978, van Daal et al. 1983, Hildreth et al. 1985, Thompson et al.
1994, Ron et al 1998). Many studies suggest that, of the two types comprising non-melanoma
skin cancer, BCC is much more radiosensitive than squamous cell carcinoma and other non-
melanoma skin cancers (SCC; van Daal et al. 1983, Ron et al. 1998, Shore 2001); however,
others do not specify the relative radiosensitivity of these two skin cancer types (Hildreth et al.
1985), or found similar radiosensitivity of the two types (Lichter et al. 2000).

Within NIOSH-IREP, only skin cancer has an adjustment for race and/or ethnicity in
determining the probability of causation. Unlike other cancers, the biological justification for
this adjustment is very strong: skin cancer incidence rates vary by a factor of 20 or more for

individuals of different racial or ethnic groups, while most other cancers that show racial

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Appendix II (continued): Glossary of ICD-9 codes and their cancer descriptions

ICD-9 code Cancer description

191 Malignant neoplasm of brain

192 Malignant neoplasm of other an unspecified parts of nervous system
193 Malignant neopiasm of thyroid gland

194 Malignant neoplasm of other endocrine glands and related structures
195 Malignant neoplasm of other and ill-defined sites

196 Secondary and unspecified neoplasms of the lymph nodes

197 Secondary neoplasms of the respiratory and digestive organs

198 Secondary neoplasms of other tissue and organs

199 Malignant neoplasm without specification of site

200 Lymphosarcoma and reticulosarcoma

201 Hodgkin's disease

202 Other malignant neoplasms of lymphoid and histiocytic tissue

203 Multiple myeloma and other immunoproliferative diseases

204 Lymphoid leukemia

205 Myeloid feukemia

206 Monocytic leukemia

207 Other specified leukemia

208 Leukemia of unspecified cell type

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Table 7. Primary cancers (ICD-9 codes‘) for which probability of causation is to be calculated, if only a
secondary cancer site is known. “M” indicates cancer site should be used for males only, and “F” indicates
cancer site should be used for females only. Whenever “173" is indicated, the “non-melanoma skin-basal

cell” model should be used.

Secondary cancer

ICD-9 code of likely primary cancers

Lymph nodes of head, face and neck (196.0)

141, 142 (M), 146 (M), 149 (F), 161 (M), 162, 172, 173, 174
(F), 193 (F)

Intrathoracic lymph nodes (196.1)

150 (M), 162, 174 (F)

Intra-abdominal lymph nodes (196.2)

150 (M), 151 (M), 153, 157 (F), 162, 174 (F), 180 (F), 185
(M), 189, 202 (F)

Lymph nodes of axilla and upper limb (196.3)

162, 172, 174 (F)

Inguinal and lower limb lymph nodes (196.5)

154 (M), 162, 172, 173 (F), 187 (M)

Intrapelvic lymph nodes (196.6)

153 (M), 154 (F), 162 (IM), 180 (F), 182 (F), 185 (M), 188

Lymph nodes of multiple sites (196.8)

150 (M), 151 (M), 153 (M), 162, 174 (F)

Lymph nodes, site unspecified (196.9)

150 (M), 151, 153, 162, 172, 174 (F), 185 (M)

Lung (197.0)

153, 162, 172 (M), 174 (F), 185 (M), 188 (M), 189

Mediastinum (197.1)

150 (M), 162, 174 (F)

Pleura (197.2)

150 (M), 153 (M), 162, 174 (F), 183 (F), 185 (M), 189 (M)

Other respiratory organs (197.3)

150, 153 (M), 161, 162, 173 (M), 174 (F), 185 (M), 193 (F)

Small intestine, including duodenum (197.4)

152, 153, 157, 162, 171, 172 (M), 174 (F), 183 (F), 189 (M)

Large intestine and rectum (197.5)

153, 154, 162, 174 (F), 183 (F), 185 (M)

Retroperitoneum and peritoneum (197.6)

151, 153, 154 (M), 157, 162 (MD), 171, 174 (F), 182 (F), 183
®)

Liver, specified as secondary (197.7)

151 (M), 153, 154 (MN), 157, 162, 174 (F)

'The International Classification of Diseases Clinical Modification (9" Revision) Volumes I&II.
[1991] Department of Health and Human Services Publication No. (PHS) 91-1260, U.S. Government

Printing Office, Washington, D.C.

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using site-specific estimates, and generally decrease with increasing age at exposure. For the skin
cancer model, a log-linear term is used to decrease risks for increasing ages at exposure between 10
and 40. Ideally, this model would include only adult exposures (as for other solid cancers); however,
the data were not modeled in this way for NCI-IREP, and the data were not available to NIOSH
researchers. Data were modeled categorically for a given age at exposure, and risk coefficients for
intermediate ages at exposure were obtained through interpolation from values at surrounding age
categories (Table IV.D.9 of NCI 2002).

For radon exposures and lung cancer, there is no direct adjustment for exposure age; risks are
dependent on time since last exposure and on age at diagnosis. The effect of this adjustment is that, at a
constant “time since last exposure”, the risk decreases for increasing age at last exposure; however, for
constant “age at diagnosis”, the risk increases for increasing age at last exposure. For all other cancers,
the NCI models incorporate a trend of decreasing risk per unit dose for exposure ages between 15 and
30, and assumes constancy thereafter.

These changes are detailed in the NCI IREP documentation being finalized by the NCI (NCI
2002), [It must be noted, however, that the NCI IREP is not finalized at the time of this writing. (May
2002) Any changes or modifications which occur as part of the finalization of the NCI-IREP which are
not notes here must be evaluated for scientific merit and applicability under EEIOCPA.] Changes in the
NCI IREP that are relevant to the evaluation of compensation claims under EEOICPA may be

incorporated into future versions of NIOSH-IREP.

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change, reflecting a preference for the use of epidemiological data to estimate low-dose effects, is the
latest analyses of the Japanese atomic bomb survivor data (Pierce and Preston 2000), upon which the
majority of IREP models are based. This analysis strongly supports a linear over a sublinear (e.g.,
linear-quadratic) model, even within the lowest dose categories. The A-bomb survivor study (the
epidemiological study deemed most informative in the development of other risk modifiers, such as
gender and age at exposure) does not support the use of a DDREF of much larger than one, for low-
dose acute exposures. [The DDREF in NCI-IREP is phased-in at acute doses lower than 0.2 Sv — well
above levels found to be linear in studies of incidence (Pierce and Preston 2000) and mortality (Pierce
et al. 1996) in the A-bomb survivor cohort].

The recent strong evidence for a linear (or, more weakly, for a supralinear) dose-response
relationship for all solid incident cancers in the dose range of 0.05 to 0.1 Sv in the A-bomb study is
made more compelling because it avoids the potential biases for which the finding in the mortality series
has been criticized. On the other hand, there is substantial evidence from animal studies supporting a
DDREF of greater than two (summarized on pp. 60-66 of NCRP 1997 and on p 23 in BEIR V 1990)
for low-LET exposures. Moreover, most expert committees, including the NCRP, the ICRP, and
UNSCEAR, recommend a DDREF of about 2 (NCRP 1997, p 66; ICRP 1991b; UNSCEAR
20000, p 358).

However, in light of the new analysis of cancer incidence in low-dose ranges of the Japanese
A-bomb study referenced above, the NCI has shifted the DDREF distribution for all solid cancers in

IREP to more heavily weight a DDREF of one, and to include a small probability for a DDREF of less

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NIOSH-IREP technical documentation June 18, 2002

National Cancer Institute (NCI). Draft Report of the NCI-CDC Working Group to Revise the 1985
NIH Radioepidemiological Tables, May 17, 2002, 109 pp.

National Council on Radiation Protection and Measurements (NCRP) . Uncertainties in fatal cancer
risk estimates used in radiation protection. Recommendations of the National Council on Radiation
Protection and Measurement. NCRP Report No. 126, 1997, 112 pp.

National Institutes of Health (NIH). Report of the National Institutes of Health Ad Hoc Working
Group to Develop Radioepidemiological Tables. NIH Publication No. 85-2748. 355 pp, 1985.

Olsson H, Ranstam J. Head trauma and exposure to prolactin-elevating drugs as risk factors for male
breast cancer. J. Natl. Canc. Inst. 80:679-683, 1988.

Parkin DM, Whelan SL, Ferlay J, Raymond L, Young J. Cancer Incidence in Five Continents,
Volume VII. International Agency for Research on Cancer (IARC). IARC Scientific Publications No.
143. Lyon: IARC press, 1240 pp, 1997.

Pierce DA, Mendelsohn ML, A model for radiation-related cancer suggested by atomic bomb survivor
data. Radiat. Res. 152:642-654, 1996.

Pierce DA, Preston DL, Joint analysis of site-specific cancer risks for the A-bomb survivors. Radiat.
Res. 137:134-142, 1993.

Pierce DA, Preston DL Radiation-related cancer risks at low doses among atomic bomb survivors.
Radiat, Res. 154:178-186, 2000.

Pierce DA, Shimizu Y, Preston DL, Vaeth M, Mabuchi K. Studies of the mortality of atomic bomb
survivors. Report 12, Part I. Cancer: 1950-1990. Radiat. Res. 146:1-27, 1996.

Preston DL, Kusumi S$, Tomonaga M, Izumi S, Ron E, Kuramoto A, Kamada N, Dohy H, Matsui T,
Nonaka H, Thompson DE, Soda M, Mabuchi K. Cancer incidence in atomic bomb survivors. Part III:
Leukemia, lymphoma and multiple myeloma, 1950-1987. Radiat. Res. 137:S68-S97, 1994.

Radiation Exposure Compensation Act (RECA) Committee. Final Report of the Radiation Exposure
Compensation Act Committee. Submitted to the Human Radiation Interagency Working Group, July
1996.

Rogot E, Murray JL. Smoking and causes of death among U.S. veterans: 16 years of observation.
Public Health Rep. 95:213-222, 1980.

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United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR). Sources,
Effects and Risks of Ionizing Radiation, No. E.94.LX.2, United Nations, New York, 1993.

United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR). Biological
effects at low radiation doses. Annex G in: Sources and Effects of Ionizing Radiation. Vol. Il. Effects.
75-175, 2000a.

United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR). Combined
effects of radiation and other agents. Annex H in: Sources and Effects of Ionizing Radiation. Vol. II.
Effects. 177-295, 2000b.

United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR). Epidemiological
evaluation of radiation-induced cancer. Annex I in: Sources and Effects of Ionizing Radiation. Vol. Il.
Effects. 297-450, 2000c.

United States Environmental Protection Agency (USEPA). Estimating Radiogenic Cancer Risks. EPA
Report 402-R-00-003, Washington, DC, May 1999.

van Daal WA, Goslings BM, Hermans J, Ruiter DJ, Sepmeyer CF, Vink M, van Vloten WA, Thomas
P. Radiation-induced head and neck tumours: is the skin as sensitive as the thyroid gland? Eur. J.

Cancer Clin. Oncol. 19:1081-1086, 1983.

Xuan XZ, Lubin JH, Li JY, Blot WJ. A cohort study in southern China of workers exposed to radon
and radon decay products. Health Phys. 64:120-131, 1993.

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Appendix I: NIOSH-IREP program output

NIOSH-Interactive RadioEpidemiological Program
Probability of Causation Results

Date of Run: 06/12/2002 DOL District Office: DE
Time of Run: 12:00:05 PM NIOSH-IREP version: 5.2
NIOSH ID# 123456 Claimant SSN: 123-45-6789

Claimant Name: John Q. Doe

Claimant Cancer Diagnoses:

Primary Cancer #1: Prostate (ICD-9 185) Date of Diagnosis: 10/20/1988
Primary Cancer #2: N/A Date of Diagnosis: N/A
Primary Cancer #3: N/A Date of Diagnosis: N/A
Secondary Cancer #1: Lung (ICD-9 197.0) Date of Diagnosis: 03/13/1994
Secondary Cancer #2: N/A Date of Diagnosis: N/A
Secondary Cancer #3: N/A Date of Diagnosis: N/A

Claimant Information Used In Probability of Causation Calculation:

Gender: Male Race (skin cancer only): N/A
Birth Year: 1920 Year of Diagnosis: 1988
Cancer Model: All Male Genitalia (185-187)

Should alternate cancer model be run?: No

Smoking history (trachea, bronchus, or lung cancer only): N/A

NIOSH-IREP Assumptions and Settings:

User Defined Uncertainty Distribution: _Lognormal (1,1)
Number of Iterations: 2000
Random Number Seed: 99

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5. Connective tissue cancer, eye cancer, other endocrine cancer, and other and ill-defined
sites

There is very little specific information about the radiogenicity of the following cancer
groups:

(1) connective and other soft tissue cancers (ICD-9 171),

(2) cancer of the eye (ICD-9 190),

(3) cancer of the endocrine glands other than thyroid (ICD-9 194), or

(4) cancers of other, ill-defined and unspecified sites (ICD-9 196 and 199).

The NCI-IREP program contains a set of “miscellaneous” ERR per Sv coefficients
derived from analysis of these and a few other sites, namely bone cancer and male breast
cancer. To implement probability of causation models for the four groups above, the
miscellaneous-site ERR per Sv model was applied to the background cancer incidence rates
(U.S. and Japan) for each of the four groupings defined above, using data from Parkin et al.
(1997). Thus, there are four additional models within NIOSH-IREP, for each of the four

groupings described above (Table 2, 4).

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The software program, named the Interactive RadioEpidemiological Program (IREP), allows
the user to apply the NCI risk models directly to data on an individual claimant. This makes it possible
to calculate probability of causation using better quantitative methods than could be incorporated into
printed tables. In particular, IREP allows the user to take into account uncertainty concerning the
information being used to calculate probability of causation. There typically is uncertainty about the
radiation dose levels to which a person has been exposed, as well as uncertainty in the science relating
levels of dose received to levels of cancer risk observed in study populations.

Accounting for uncertainty is important because it can have a large effect on the probability of
causation estimates. DVA, in its use of the 1985 radioepidemiological tables, employs the value found
in the tables at the upper 99 percentile of the probability of causation estimate. Similarly, as required by
EEOICPA, the U.S. Department of Labor (DOL) will use the upper 99 percent credibility limit to
determine whether the cancers of employees are at least as likely as not caused by their radiation
doses. This will help minimize the possibility of denying compensation to claimants under EEOICPA
for those employees with cancers likely to have been caused by radiation exposures.

The risk models developed by NCI and CDC for IREP (NCI 2002) provide the primary basis
for developing guidelines for estimating probability of causation under EEOICPA. They directly
address most cancers and most types of radiation exposure relevant to employees covered by
EEOICPA. These models take into account the employee’s cancer type, year of birth, year of cancer
diagnosis, and exposure information such as years of exposure, as well as the dose received from

gamma radiation, x rays, alpha radiation, beta radiation, and neutrons during each year. The risk model

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employed the finalized version of the NCI update, with certain modifications important to claims under
EEOICPA, as a basis for determining probability of causation for employees covered under
EEOICPA.

A scientific change achieved by the NCI update is the use of risk models developed from data
on the occurrence of cancers (cases of illness) rather than the occurrence of cancer deaths among
Japanese atomic bomb survivors. The risk models are based on more current data as well. Many
more cancers have been modeled in the revised report. The new risk models also take into account
factors that modify the effect of radiation on cancer, related to the type of radiation dose, the amount of
dose, and the timing of the dose.

A major technological change accompanying this update, which represents a scientific as well
as practical improvement, is the development of a computer software program for calculating assigned
share. The assigned share is a term recommended in the NCI update of the radioepidemiological
tables, instead of probability of causation, to properly reflect that these estimates are properties of
groups of similar people, not of the individual. In other words, it is not possible to determine, for a
given individual, whether his or her cancer resulted from a workplace exposure to ionizing radiation.
The assigned share is used to estimate the probability of causation needed for determining eligibility for
an award under EEOICPA, and these terms are used interchangeably in this document. It should also
be noted that this software does not predict an individual’s chances of getting cancer from workplace

radiation exposure. Rather, it estimates (from epidemiological models combined with information on

the individual’s past exposure) the likelihood that an existing cancer resulted from that exposure.

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variation in incidence differ by a factor of two or less (Fig. 1). For malignant melanoma,
incidence rates are 18-20 times greater among non-Hispanic U.S. whites than among A frican-
Americans. Skin cancer incidence rates for Asian-Americans and Native Americans are similar
to African-Americans (Miller and Gaudette 1996), and rates for Hispanic whites are
intermediate between those of African-Americans and whites (Scotto et al. 1996). For most
cancers, the reasons for disparity in incidence by race are not known, but probably include
factors such as differences in tobacco use, dietary factors, and access to health care. In
contrast, the reasons for racial and ethnic differences in skin cancer incidence rates appear
strongly related to the damage produced by exposure to ultraviolet radiation (UV) in
susceptible individuals, Non-whites are thought to be at less risk of cancer from exposure to
UV through the protective effect of melanin, which absorbs harmful UV radiation in the skin
(Kaidbey et al. 1979, Altman et al. 1987, Kollias et al. 1991). The net effect of incorporating
the background incidence rate of skin cancer is to properly reflect the increased probability of
causation for radiation-induced skin cancer for non-white claimants, compared to whites
exposed to the same doses under the same conditions, if a sub-multiplicative relationship exists
between radiation exposure and sensitivity to UV radiation exposure. Not incorporating the
ethnic differences in background risk would have the effect of underestimating the probability of
causation of radiation-induced skin cancers among non-whites.

The true form of the interaction between ionizing and UV radiation exposure is unclear.

On theoretical grounds, ionizing radiation might be expected to interact additively with

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site-specific models, unless there was a statistically-significant difference between these risk modifiers
for the site-specific and general model. This approach has been recommended by an international
expert committee (Pierce and Preston 1993; UNSCEAR 2000b, p. 208). The models show higher
sensitivity (in general) for females compared to males. The general coefficients also show reductions in
tisk per unit dose between ages-at-exposure of 15 and 30 (if attained age is held constant). The ERR
per Sv estimates do not change after age-at-exposure of 30. Thus, for most cancers NIOSH-IREP

relies on direct evidence from the A-bomb survivors exposed as adults rather than as young children.
This modulates the strong decline in risk with increasing age that is observed among those exposed as
children in that study, and thus is more appropriate for modeling risks among those exposed as adults.

The modeling of risk from exposures as young as age 15 is a result of the Poisson regression
procedure used to analyze the atomic bomb survivor cohort. This is a grouped data method; data are
available for modeling within 5-year age-at-exposure categories; therefore, the modeled exposure
classes for adults must begin at either age 15 or age 20. Because DOE employees may have begun.
working and accrued workplace radiation exposures before age 20, for EEOICPA it is necessary to
model exposure categories beginning at age 15.

No age-at-exposure effect has been incorporated for acute myeloid leukemia, chronic myeloid
leukemia, lung cancer (non-radon exposures), and female genital cancers other than ovary. The NCI
models incorporate a trend of decreasing risk per unit dose with increasing age at exposure for acute
lymphocytic leukemia, all leukemia other than chronic lymphocytic, basal cell carcinoma, and cancers of

thyroid, For thyroid and non-melanoma skin cancer models, the age at exposure effects were modeled

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3. Malignant melanoma

The association between malignant melanoma and radiation is not clear. Few studies
have been conducted with sufficient power to detect increases in the relative risk of melanoma.
This problem is exacerbated by the fact that background incidence rates are very low for some
populations in which radiation-related risks have been evaluated. For example, the point
estimate of radiation excess relative risk among atomic bomb survivors is high, but with a wide
confidence interval, due to the very small number of cases (Ron et al. 1998). No significant
excess of malignant melanoma was observed among the primarily African and Asian cohort of
children exposed to radiation for the treatment of tinea capitis (scalp ringworm) in Israel (Ron et
al. 1991). However, a small study of Israeli children exposed to x rays during cardiac
catheterization showed elevated incidence of malignant melanoma (Modan et al. 2000). The
radiation-related relative risk point estimate for melanomas was very similar to that for non-
melanoma skin cancer in an irradiated North American population; however, the melanoma
estimate was based on sparse data (Hildreth et al. 1985).

Most studies of DOE workers have shown no association between malignant
melanoma and radiation exposure. However, early studies of workers at the Lawrence
Livermore National Laboratory showed elevated incidence of malignant melanoma compared
to the adjacent community, although risk was not associated with recorded doses to ionizing
radiation (Austin et al. 1981). This finding has been attributed by some to potentially increased

surveillance among this population, and to important related factors, such as skin pigmentation

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NIOSH-Interactive RadioEpidemiological Program (NIOSH-IREP)
Technical Documentation

Final Report
National Institute for Occupational Safety and Health
Office of Compensation Analysis and Support

4676 Columbia Parkway, MS-R45
Cincinnati, OH 45226

June 18, 2002


NIOSH-IREP technical documentation

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Table 2. Cancer sites as source for excess relative risk (ERR) per Sv coefficients for risk
models in NIOSH-IREP, and cancer group to which model should be applied.

Cancer models in NIOSH-IREP

Cancer site used as

ICD - codes of

source of ERR/SV background rates
(ICD-9 code)
Oral Cavity and Pharynx (140-149) 140-149 140-149
Esophagus (150) 150 150
Stomach (151) 151 151
Colon (153) 153 153
Rectum (154) 154 154
All digestive (150-159) 150-159 150-159
Liver (155.0) 155.0 155.0
Gallbladder (155.1, 156) . 155.1, 156 155.1, 156
Pancreas (157) 157 157
Trachea, Bronchus and Lung (162) 162 162

Other respiratory (nasal cavity, larynx and
other, 160, 161, 163-165)

160, 161, 163-165

160, 161, 163-165

Bone (170) 170, 171, 175, 190, 170
194, 195
Connective tissue (171) 170, 171, 175, 190, 171
194, 195
Malignant melanoma (172) 173 (basal cell 172
carcinoma only)
Non-melanoma skin (173) -basal cell 173 (basal cell 173 (all combined)
carcinoma carcinoma only)
Non-melanoma skin (173)-non basal cell | 173 (non-basal cell 173 (all combined)
carcinoma carcinoma only)
Breast-female (174) 174 174
Breast-male (175) 174 175

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particles. The exposure units used in NIOSH-IREP are working level months (WLM) for radon, and
cSv (rem) for all other radiation types.

For each type of exposure, the dose used in NIOSH-IREP will be based on the individual organ
or tissue in which the primary cancer occurred, or, if unavailable, in the nearest relevant organ or tissue.
For bone cancer, dose to the endosteal cells (the cells of the outer bone surface) will be calculated.

For skin cancer, a more site-specific approach will be used. Because studies of medically-exposed
persons have shown that radiation-induced skin cancers tend to occur within the field of radiation
exposure (van Daal et al. 1983, Shore et al. 1984, Hildreth et al. 1985, Lichter et al. 2000), skin dose
will be calculated only for the location where the cancer occurred, as reflected in the 9"" Revision of the
International Classification of Diseases (ICD-9) 4-digit nosology code (i.e., lip, eyelid, ear, other parts
of face, scalp and neck, trunk, upper limb, lower limb). If the body location is unspecified, the
maximum skin dose at any location will be calculated as input to NIOSH-IREP.

In determining the dose rate (i.e., acute or chronic) that should be assumed for use in NCI-
IREP, the NCI working group referenced the definition used by the UNSCEAR (UNSCEAR 1993),
which is that an acute dose is delivered at a dose rate of 6 mGy per hour or greater (NCI 2002, p. 37),
averaged over several hours. This is equivalent to a dose rate of 0.1 mGy (10 mrem) per minute.
Lower exposure rates should be considered chronic, according to this definition.

Work-related medical x-ray exposures are clearly acute, by this definition. Although likely to
have been chronic, the true dose rate of these gamma and neutron exposures is unknown for any given

worker within the badging period. Therefore, the approach used in the NIOSH Dose

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II, NIOSH-IREP and its implementation under EEOICPA
A. Dosimetry Issues

NIOSH-IREP includes twelve types of radiation exposure. For this purpose, radon is
considered an exposure that may contribute to risk of lung cancer only, and the remaining eleven types
of exposure, considered for any cancer type, are described in Table 1. These types of exposures are
differentiated by the assumed radiation weighting factor (termed here the radiation effectiveness factors
or REF) and in some cases, a factor accounting for reduced or enhanced effectiveness in producing
cancers resulting from dose protraction (dose and dose rate effectiveness factor, or DDREF). The
distributions assumed for these factors are described in Section H.D below. There are two classes of
electron (beta particle) exposure within NIOSH-IREP: one class associated with exposure to tritium,
and a second class for all other electrons. Three different photon energy classes exist within NIOSH-
IREP: photons of energy greater than 250 keV (exemplified by high-energy gamma radiation that was
the primary exposure of the Japanese atomic bomb survivors), photons of energy between 30 and 250
keV, which includes photofluorographic x rays used during the 1940s and 1950s at some Department
of Energy (DOE) facilities (Cardarelli 2000), and photons of energy less than 30 keV, which includes
photons emitted by certain transuranic radionuclides. There are five classes of neutrons differentiated
by energy type. The most commonly encountered type of neutron exposure within the DOE workforce
is fission neutrons, composed primarily of neutrons with energy between 100 keV and 2 MeV.
However, neutrons of higher and lower energy are included because these exposures are relevant for

certain DOE workers. Finally, a single class of radiation exposure is included for non-radon alpha

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NIOSH-IREP technical documentation June 18, 2002

Table 6. Smoking category definitions for lung cancer claims under NIOSH-IREP

Smoking category

Definition

Never Smoked fewer than 100 cigarettes (throughout lifetime) prior to cancer diagnosis
Former Quit smoking five years or more before date of cancer diagnosis
Current (? cig/day) Smoked at time of cancer diagnosis (or quit fewer than 5 years before),
quantity unknown
Current (<10 cig/day) Smoked at time of cancer diagnosis (or quit fewer than 5 years before), average of

fewer than 10 cigarettes per day

Current (10-19 cig/day)

Smoked at time of cancer diagnosis (or quit fewer than 5 years before), average of
10-19 cigarettes per day

Current (20-39 cig/day)

Smoked at time of cancer diagnosis (or quit fewer than 5 years before), average of
20-39 cigarettes per day

Current (40+ cig/day)

Smoked at time of cancer diagnosis (or quit fewer than 5 years before), average of
40 or more cigarettes per day

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NIOSH-IREP technical documentation

June 18, 2002

Figure 2. ERR/Sv estimates (at the upper 99" percentile of the credibility distribution) for
basal cell carcinoma (triangle) and for miscellaneous cancer (X) models, from NCI (2002), for

(a) males and (b) females.

(a) Males

100.0 J —*— BCC, Exposure age=20 —<— Misc, Exposure ag
—a’ —BCC, Exposure age=30 —X = Misc, Exposure age=30
= & - BCC, Exposure age=40 —X — Misc, Exp. age=40

i “ie "he i “ik x x _¥

Upper 99th percentile of ERR/Sv

=20

10.0 4
bet te
coe Se ee ae
7 ~~ Se

25 30 35 40 45 50 55 60 65
Age at diagnosis

(b) Females

——&— BCC, Exposure age=20 —< Misc, Exposure age=20
100.0 —A- ‘BCC, Exposure age=30 —>< ‘Misc, Exposure age>=30

10.0 +

;
ta Se ee See |
donk - ee -
1.0 + + + + + + + +

Upper 99th percentile of ERR/Sv

- A ~ BCC, Exposure age=35 =A - BCC, Exposure age=40

25 30 35 40 45 50 55 60 65
Age at diagnosis

Page 40 of 73

70

70


NIOSH-IREP technical documentation June 18, 2002

In addition to these individual studies, most expert committees have listed CLL as a
cancer that appears non-radiogenic. The BEIR V Committee report (NAS/NRC 1990)
excluded CLL from the group of leukemias for which risk models were produced, based on the
lack of an association found among the studies reviewed. The UNSCEAR 2000 report states
that CLL appears to be non-inducible by radiation exposure (UNSCEAR 2000c, p. 308). In
summary, chronic lymphocytic leukemia is strongly associated with attained age. No evidence
has been found in published studies that ionizing radiation is associated with increased risk of
CLL. This approach will be revisited in future versions of NIOSH-IREP, as new scientific

information becomes available.

D. Dose and dose-rate effectiveness factors

As indicated in Section I of this report, changes in the DDREF and REF distributions adopted
in the final NCI program were used in NIOSH-IREP. These changes include substantial modifications
of the uncertainty distributions for the REF, described in detail in the accompanying document (Kocher
et al. 2002).

For DDREF, the NCI-IREP program has modified an uncertainty distribution used by Grogan
et al. (2000), p. 6-23, for low linear energy transfer (LET) radiation (NCI 2002). The uncertainty
distribution is similar to that recommended in NCRP (1997), except that it is discrete, more heavily
weights a DDREF of one, and it incorporates a small probability of a DDREF less than one (i.e., it

allows the possibility of an inverse dose-rate effect for low-LET radiation). The justification for this

Page 28 of 73


NIOSH-IREP technical documentation June 18, 2002

Table 2 (continued). Cancer sites as source for excess relative risk (ERR) per Sv coefficients
for risk models in NIOSH-IREP, and Cancer group to which model should be applied.

Cancer models in NIOSH-IREP Cancer site used as ICD-9 codes of
source of ERR/SV background rates
(IcD-9)
Ovary (183) 183 183
Female genitalia less ovary (179-182, 184)} 179-182, 184 179-182, 184
All male genitalia (185-187) 185-187 185-187
Bladder (188) 188 188
Kidney and other urinary organs (188-189) 188-189 189
Eye (190) 170, 171, 175, 190, 190
194, 195
Nervous system (191, 192) 191, 192 191, 192
Thyroid (193) 193 193
Other endocrine glands (194) 170, 171, 175, 190, 194
194, 195
Other and ill-defined sites (195, 199) 170, 171, 175, 190, 195
194, 195
Lymphoma and Multiple Myeloma (200- | 200-203 200-203
203)
Leukemia, less chronic lymphocytic 204-208, less 204.1 204-208, less 204.1
leukemia (204-208, less 204.1)
Acute lymphocytic leukemia (204.0) 204.0 204.0
Acute myelogenous leukemia (205.0) 205.0 205.0
Chronic myelogenous leukemia (205.1) | 205.1 205.1

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NIOSH-IREP technical documentation June 18, 2002

C. Cancers excluded from NIOSH-IREP
1. Chronic lymphocytic leukemia (ICD-9 204.1).

No dose-response model was developed for chronic lymphocytic leukemia (CLL) by
either the NIH Working Group (NIH 1985) or the NCI/CDC working group to update these
tables (NCI 2000). This is because no elevation of CLL incidence was observed among
Japanese atomic bomb survivors (Preston et al 1994). Because CLL is very rare among non-
Western populations (implying, therefore, that the power to detect small excess relative risks is
poor in the atomic bomb survivors study), it is necessary to evaluate the relationship observed
between radiation and CLL in other populations. No association of radiation exposure with
CLL was observed among 14,000 British ankylosing spondylitis patients treated with x rays (a
total of 2 CLL deaths; Darby et al. 1987). No elevation of CLL risk has been observed
among U.S., Canadian and European women exposed to radiation during treatment for uterine
cancer (a total of 57 CLL deaths; Curtis et al. 1994), nor has a relationship been observed in a
large study of over 124,000 nuclear workers in the U.K. (Muirhead et al. 1999). Finally, no
relationship was observed between extemal radiation dose and CLL in the first combined
international nuclear workers study (a total of 27 CLL deaths; Cardis et al 1995). Studies of
people exposed to internal sources of radiation have also not shown increased risks of CLL.
For example, no increased risk was found for CLL among patients in Denmark exposed to

Thorotrast, a “’Th-containing contrast medium (Andersson et al. 1993, [ARC 2001)

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NIOSH-IREP technical documentation June 18, 2002

McLaughlin JK, Hrubec Z, Blot WJ, Fraumeni Jr JF, Smoking and cancer mortality among U.S.
veterans: a 26-year follow-up. Int. J. Cancer 60:190-193, 1995,

Miller AB, Gaudette LA. Cancers of skin, bone, connective tissues, brain, eye, thyroid and other
specified and unspecified sites in Inuit. Acta Oncologica. 35:617-616, 1996.

Miller DL, Weinstock MA. Nonmelanoma skin cancer in the United States: Incidence. J. Am. Acad.
Dermatol. 30:774-778, 1994.

Modan B, Keinan L, Blumstein T, Sadetzki S. Cancer following cardiac catheterization in childhood.
Int. J. Epidemiol. 29:424-428, 2000.

Moore II DH, Patterson HW, Hatch F, Discher D, Schneider JS, Bennett D, Mendelsohn ML. Case-
control study of malignant melanoma among employees of the Lawrence Livermore National
Laboratory, Am. J. Ind. Med. 32:377-391, 1997.

Muir C, Waterhouse J, Mack T, Powell J, Whelan S,. Cancer Incidence in Five Continents, Vol. V.
International Agency for Research on Cancer (IARC). IARC Scientific Publications No. 88. Lyon:
IARC press, 970 pp, 1987.

Muirhead CR, Goodill AA, Haylock RGE, Vokes J, Little MP, Jackson DA, O’Hagan JA, Thomas
JM, Kendall GM, Silk TJ, Bingham D, and Berridge GLC. Occupational radiation exposure and
mortality second analysis of the National Registry for Radiation Workers. J Radiol Prot 19:3-26, 1999.

National Academy of Sciences/National Research Council. Health Risks of Radon and Other
Internally Deposited Alpha-Emitters, BEIR IV. Washington, DC: National Academy Press. 602 pp,
1988.

National Academy of Sciences/National Research Council (NAS/NRC). Health Effects of Exposure to
Low Levels of Ionizing Radiation (BEIR V). Washington DC: National Academy Press, 421 pp, 1990.

National Academy of Sciences/National Research Council (NAS/NRC). Health Effects of Exposure to
Radon (BEIR VI). Washington DC: National Academy Press, 500 pp, 1999.

National Academy of Sciences/National Research Council (NAS/NRC). A Review of the Draft
Report of the NCI-CDC Working Group to Revise the “1985 Radioepidemiological Tables”, 2000.

National Cancer Institute (NCI). Draft Report of the NCI-CDC Working Group to Revise the 1985
NIH Radioepidemiological Tables, May 31, 2000.

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NIOSH-IREP technical documentation June 18, 2002

for lung cancer takes into account smoking history as well. None of the risk models explicitly accounts
for exposure to other occupational, environmental, or dietary carcinogens. Models accounting for these
factors have not been developed and may not be possible to develop based on existing research.
Moreover, DOL could not consistently or efficiently obtain the data required to make use of such
models.

As stated above, the final draft of the National Cancer Institute’s IREP software (NCI 2002)
has formed the basis of the NIOSH-IREP software. The NCI’s final draft has been updated from the
version reviewed by the National Research Council in several ways. The updated draft includes a
model for lung cancer resulting from radon exposure, developed from an analysis of U.S. uranium miner
cohorts (RECA Committee, 1996), the development of models for non-melanoma skin cancer, the
incorporation of a “miscellaneous cancer model”, which they suggest should be used for bone cancer
and male breast cancer, and the inclusion of models for non-melanoma skin cancer (squamous cell and
basal cell carcinoma ). Other changes include the incorporation of an uncertainty distribution for the
latency of solid cancers, and the development of statistical distributions for the radiation effectiveness
factors (REF) and dose and dose-rate effectiveness factor (DDREF) of different energies of photons,
neutrons, and alpha particles (Kocher et al. 2002).

One important change in the NCI’s methodology (which also constitutes the basis of NIOSH-
TREP) is in the method of modeling solid cancer risk from the Japanese atomic bomb survivor study
(NCI 2002, pp 27-31). Effects of gender, age at exposure and attained age were modeled for all

solid cancers as a group. The risk modifications from these general models were then applied to the

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NIOSH-IREP technical documentation June 18, 2002

Japan, non-melanoma skin cancers are reportable, and incidence rates are available both for
1990 (Parkin et al. 1977) and for 1978-1982 (Muir et al, 1987). Therefore, to more
accurately reflect comparative rates in both countries, incidence rates for the late 1970s (age-
adjusted to the 1970 U.S. standard population) were used from both countries for NIOSH-
TREP. For the U.S. population of non-Hispanic whites, these data were obtained from Tables
5 (males) and 6 (females) of Scotto et al. (1983). For Hispanic whites and African-Americans
(Hispanic and non-Hispanic), these data were obtained from Scotto et al. (1996). The age-
adjusted background incidence rates used in NIOSH-IREP are shown here in Table 3.
Incidence rates for Asian or Native Americans have not been estimated in the special surveys
of non-melanoma skin cancer incidence (Scotto et al. 1983, 1996). Based on literature
reporting low rates of non-melanoma skin cancer risk among these groups (Miller and Gaudette
1996), as well as the similarity in malignant melanoma incidence among Native Americans,
Asian-Americans and African-Americans (Table 3), the non-melanoma skin cancer incidence
for the former two ethnic groups is assumed to be the same as for African-Americans, for
purposes of NIOSH-IREP. While the background incidence rates for most cancers are based
on relatively current rates (i.e., circa 1990), the rates for non-melanoma skin cancer for both
the Japanese and U.S. populations are based on data from the late 1970s. More recent studies
show that incidence rates have likely increased since that time (Miller and Weinstock 1994).
This is not likely to be an unacceptable source of error for calculation of probability of

causation within the DOE workforce, since claims are to be considered for any cancer

Page 18 of 73


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NIOSH-IREP technical documentation June 18, 2002

radioactivity. In: Epidemiology applied to health physics. Proceedings of the 16" meeting of the Health
Physics Society. Albuquerque, NM: 1983:125-142.

Henderson BE, Pike MC, Bernstein L, Ross RK. Breast Cancer. Ch 47 in Cancer Epidemiology
and Prevention, 2" Edition, Schottenfeld D, Fraumeni Jr JF, eds. New York: Oxford University
Press. 1996, 1521 pp.

Hiatt RA, Fireman B. The possible effect of increased surveillance on the incidence of malignant
melanoma. Preventive Med. 15:652-660, 1986.

Hiatt RA, Krieger N, Sagebiel RW, Clark Jr WH, Mihm Jr MC. Surveillance bias and the excess risk
of malignant melanoma among employees f the Lawrence Livermore National Laboratory. Epidemiol.
4:43-47, 1993.

Hildreth NG, Shore RE, Hempelmann LH, Rosenstein M. Risk of extrathyroid tumors following
radiation treatment in infancy for thymic enlargement. Radiat. Res. 102, 378-391, 1985.

Hornung RW, Meinhardt TJ. Quantitative risk assessment of lung cancer in U.S. uranium miners.
Health Phys. 52:417-430, 1987.

Hsing AW, McLaughlin JK, Cocco P, Co Chien HT, Fraumeni JF. Risk factors for male breast cancer
(United States). Cancer Causes Control 9:269-275, 1998.

International Agency for Research on Cancer (IARC). [ARC Monographs on the Evaluation of
Carcinogenic Risks to Humans. Vol. 75. Ionizing Radiation, Part 1: X- and Gamma (y)-Radiation, and
Neutrons. Lyon, France: IARC press. 491 pp, 2000.

International Agency for Research on Cancer (IARC). IARC Monographs on the Evaluation of
Carcinogenic Risks to Humans. Vol. 78. Ionizing Radiation, Part 2: Some Internally Deposited
Radionuclides. Lyon, France: LARC press. 595 pp, 2001.

International Commission on Radiological Protection (ICRP). The biological basis for dose limitation in
the skin, Annals of the ICRP, vol 22, No. 2, ICRP Publication 59, 104 pp, 1991a.

International Commission on Radiological Protection (ICRP). 1990 Recommendations of the
International Commission on Radiological Protection. Annals of the ICRP, Vol 21, No. 1-2. ICRP
Publication 60, 1991b.

International Commission on Radiological Protection (ICRP). Human respiratory model for radiological
protection. Annals of the ICRP, vol 24 No.1-4. ICRP Publication 66, 482 pp., 1994.

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NIOSH-IREP technical documentation June 18, 2002

separately; Table 7). Therefore, for secondary cancers with unknown primary site, this table will be
consulted to select likely primary sites, which will each then be evaluated using NIOSH-IREP.

Ifno primary or secondary cancer site is specified (i.e., the cancer is identified as ICD-9 199,
with no secondary cancer site specified), then the model for “Other and ill-defined sites” should be used

(Table 2, 4),

IV. Limitations of NIOSH-IREP

As stated previously, the basis of NIOSH-IREP is the set of methods and models developed by
the National Cancer Institute, which updated the 1985 Radioepidemiological Tables developed by a
National Institutes of Health working group. The National Research Council (NAS/NRC 2000)
identified some limitations to the methods used in the first draft of NCI-IREP (NCI 2000), many of
which were addressed by NCI in the version that is the basis of NIOSH-IREP (NCI 2002). The
revised NCI report (NCI 2002) considers the current IREP software to be an interim product that may
require substantial revision after the publication of the consensus of the BEIR VII committee.

Several limitations existing in the revised NCI methods could not be addressed in NIOSH-IREP,
due to the very short time frame established by EEOICPA. The following list describes some of these
limitations, It is anticipated that these and other limitations will be remedied in future versions of
NIOSH-IREP.

A. For EEOICPA, the ideal source population from which to develop risk estimates for

probability of causation calculation is the DOE workforce itself, particularly for exposures

Page 35 of 73


NIOSH-IREP technical documentation June 18, 2002

to alpha radiation. Despite the finding of excess cancers among some DOE populations, at
present it is difficult to use these findings in a quantitative risk assessment, because of
uncertainties about confounding exposures (like chemical exposures), complex patterns and
timings of exposure and disparate findings among different populations. It is likely that
current research studies underway and future research will provide a better basis for
quantitative risk assessment using data that relates directly to the DOE workforce,
particularly for cancers found to be weakly associated with radiation exposure in the
Japanese atomic bomb survivor cohort (or not at all associated, such as chronic
lymphocytic leukemia).

B. Consideration of the appropriateness of various methods of incorporating the modification
of cancer risk from radiation exposure by time-dependent factors such as age at exposure,
time since exposure and attained age. The NCI-IREP modeling approach, in particular,
requires further evaluation in future versions of NIOSH-IREP, as there are alternative ways
of modeling the data. For example, a recent re-analysis of the A-bomb survivors suggests
that, excluding the hormonally-related cancers (such as breast and thyroid), no variation by
age-at-exposure is indicated for remaining cancers after accounting for attained age (Pierce
and Mendelsohn 1996). Models that provide equivalent fit to the source data (e.g., the
Japanese atomic bomb survivor cohort) could produce quite different estimates of assigned
share for a given claimant; however, the current NCI models (adopted for NIOSH-IREP)

use a fixed modeling approach to incorporate these factors.

Page 36 of 73


NIOSH-IREP technical documentation

June 18, 2002

Table 4 (continued). Cancer models to be used in calculation of probability of causation.
Derivation of NIOSH-IREP models is described in Section II-B. Abbreviations: MN
{malignant neoplasm), CIS (carcinoma in situ), NUB (neoplasm of uncertain behavior),
NUM (neoplasm of unspecified nature).

Primary neoplasm ICD-9 code NIOSH-IREP model for
calculating PC
NUB of liver and biliary passages 235.3 Liver
NUB of retroperitoneum and 235.4, 235.5 All digestive
peritoneum, and other and unspecified
digestive organs
NUB of larynx, pleura, thymus, 235.6, 235.8, Other respiratory
mediastinum, and other and unspecified] 235.9
respiratory organs
NUB of trachea, bronchus and lung 235.7 Lung
NUB of uterus, and other and 236.0, 236.1, Female genitalia, less ovary
unspecified female genital organs 236.3
NUB of ovary 236.2 Ovary
NUB of prostate, testis and other male | 236.4, 236.5, All male genitalia
genital 236.6
NUB of bladder 236.7 Bladder
NUB of other and unspecified urinary | 236.9, 237.2 Urinary organs less bladder
tract, and suprarenal gland
NUB of pituitary, pineal and other and | 237.0, 237.1, Thyroid
unspecified endocrine glands 237.4
NUB of paraganglia, brain and spinal j 237.3, 237.5, Nervous system
cord, and other nervous system 237.6, 237.7,
237.9
NUB of bone and articular cartilage 238.0 Bone
NUB of connective and other soft tissug 238.1 Connective tissue
NUB of skin 238.2 Malignant melanoma AND Non-

melanoma skin-Basal cell

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NIOSH-IREP technical documentation June 18, 2002

4. Male breast cancer

Breast cancer is extremely rare among men: the age-adjusted incidence is 0.7 per
100,000 among white males, compared to 90.7 per 100,000 for white females in the U.S.
(Parkin et al. 1997). As a result, this cancer is very difficult to study directly in men, and little
is known about risk factors for male breast cancer, with the exception of Klinefelter syndrome,
a known major risk factor (Hultborn et al. 1997). A few sporadic cases among men given
medical radiation treatment have been reported (Greene et al. 1983, Olsson and Ranstam
1988). However, the following lines of evidence (summarized in Henderson et al. 1996)
suggest that male breast cancer may have similar hormonally-related cancer promotion risk
factors as female breast cancer: 1) Breast cancer in males, as in females, increases greatly with
age 2) Male breast cancer is associated with overweight in early adulthood, a finding that is
true for post-menopausal women as well. 3) Gynecomastia (a factor related to excess
estrogen) is a risk factor for breast cancer in men 4) Evidence from mathematical modeling of
breast tissue aging in men and women suggests that differences in predicted tissue
concentrations of estrogen are sufficient to explain the differences in breast cancer incidence
among the sexes (Casagrande et al. 1988, Bernstein et al. 1989, Thomas et al. 1992, Hsing et
al. 1998). Hormonally-related risk factors have been found to interact multiplicatively with
radiation, in studies of female Japanese atomic bomb survivors (Land et al. 1994, NCI 2002).
Thus, the excess relative risk of radiation-induced male breast cancer (applied to the

background rates of males) may be similar to that of female breast cancer. An alternative

Page 24 of 73


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NIOSH-IREP technical documentation June 18, 2002

Kaidbey KH, Agin PP, Sayre RM, Kligman AM. Photoprotection by melanin~a comparison of black
and Caucasian skin. J. Amer. Acad, Dermatol. 1:249-260, 1979.

Karagas MR, McDonald JA, Greenberg ER, Stukel TA, Weiss JE, Baron JA, Stevens MM. Risk of
basal cell and squamous cell skin cancers after ionizing radiation therapy. J. Natl. Canc. Inst. 88:1848-
1853, 1996.

Kerlikowske, K, Barclay J, Grady D, Sickles EA, Ernster V. Comparison of risk factors for ductal
carcinoma in situ and invasive breast cancer. J. Natl. Canc. Inst. 89:76-82, 1997.

Hultborn R, Hanson C, Kopf I, Verbiene I, Warnhammar E, Weimarck A. Prevalence of Klinefelter’s
syndrome in male breast cancer patients. Anticancer Res. 17:4293-4297, 1997.

Kocher DC, Apostoaei AI, Hoffman FO, Proposed radiation effectiveness factors for use in calculating
probability of causation of cancers. SENES Oak Ridge, Center for Risk Analysis. Final Internal
Report, May 2002.

Kollias N, Sayre RM, Zeise L, Chedekel MR. Photoprotection by melanin. J. Photochem. Photobiol.
B-Biol. 9:135-160, 1991.

Koshurnikova NA, Gilbert ES, Sokolnikov M, Khokhryakov VF, Miller S, Preston DL, Romanov SA,
Shilnikova NS, Suslova KG, Vostrotin VV. Bone cancers in Mayak workers. Radiat. Res. 154:237-
245, 2000.

Land CE, Hayakawa N, Machado S, Yamada Y, Pike MC, Akiba S, Tokunaga M. A case-control
interview study of breast cancer among Japanese A-bomb survivors. II. Interactions between
epidemiologic factors and radiation dose, Cancer Causes Control 5:167-176, 1994.

Leong GK, Stone JL, Farmer ER, Scotto J, Reizner GT, Burnett TS, Elpern DJ. Nonmelanoma skin
cancer in Japanese residents of Kauai, Hawaii. J. Am. Acad. Dermatol. 17:233-238, 1987.

Lichter MD, Karagas MR, Mott LA, Spencer SK, Stukel TA, Greenberg ER. Therapeutic ionizing
radiation and the incidence of basal cell carcinoma and squamous cell carcinoma. Arch. Dermatol.

136:1007-1011, 2000.

Little MP, Charles MW. The risk of non-melanoma skin cancer incidence in the Japanese atomic bomb
survivors, Int. J. Radiat. Biol. 71:589-602, 1997.

Lubin JH, Boice JD Jr, Edling C, et al. Lung cancer risk in radon-exposed miners and estimation of risk
from indoor exposure. J. Natl. Canc. Inst. 87:817-827, 1995.

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NIOSH-IREP technical documentation June 18, 2002

List of Tables
Table 1. Radiation exposure types in NIOSH-IREP. ........6. 6000s e cece cece ence eens 43
Table 2. Cancer sites as source for excess relative risk (ERR) per Sv coefficients for risk models in
NIOSH-IREP, and cancer group to which model should be applied. ............... 44
Table 3. U.S. skin cancer incidence rates used in NIOSH-IREP. «oe eee eee ee eee 46

Table 4. Cancer models to be used in calculation of probability of causation. Derivation of NIOSH-
IREP models is described in Section II-B. 0.0... 6.6 c cece ccc eee eee eee 47

Table 5A. Photons and electrons: Probability distributions of radiation effectiveness factors (REFs) to
be used in estimating risks and probability of causation of cancers. ............005 53

Table 5B. Alpha particles: Probability distributions of radiation effectiveness factors (REFs) to be used
in estimating risks and probability of causation of cancers. 6... 0... ce eee eee eee 54

Table 5C. Neutrons: Probability distributions of radiation effectiveness factors (REFs) to be used in
estimating risks and probability of causation of cancers. 0.6... cece cece eee eee 55

Table 6. Smoking category definitions for lung cancer claims under NIOSH-IREP ......... 57

Table 7. Primary cancers (ICD-9 codes) for which probability of causation is to be calculated, if only a
secondary cancer site is KNOWN. ©... 66.6. cece eee e teen ete 58


NIOSH-IREP technical documentation June 18, 2002

Table 1. Radiation exposure types in NIOSH-IREP

Exposure type | Energy range Typical exposure scenario

Radon (lung All Exposure occurs near large sources of radium-bearing material such as the
cancer only) K-65 material at Fernald, or storage of radium in drums.

Electron > 14 keV Exposure typically results from processing and/or handling of fission
(source other products, such as Sr-90, or activation products, such as Co-60. Exposure
than tritium) can also result from uranium handling or processing operations.

Electron Epimax = 14 keV_ | Exposure typically occurs around tritium production facilities such as
(tritium) Savannah River and Mound, but can also result from nuclear reactor

operations or nuclear weapons assembly or research.

Photon <30 keV Low-energy x rays from transuranic isotopes such as plutonium.

Photon 30-250 keV Medium-energy photons are typically encountered from scatter of higher
energy photons. These photons can also result from gamma emissions of
certain transuranic isotopes such as americium, and are the primary energy
found in early stereoscopic x rays.

Photon >250 keV High-energy photons are the most common of the three categories listed.
These are typically encountered from work with the nuclear fuel cycle
from fuel manufacturing, reactor operations, spent nuclear fuel processing,
decontamination and decommissioning activities and waste monitoring
and storage.

Neutron <10 keV Low-energy neutrons exposures include thermal neutrons commonly
found around nuclear reactors.

Neutron 10-100 keV Intermediate-energy neutron exposure can occur around nuclear reactors
as neutrons are moderated from high energy to thermal energies.

Neutron 100 keV-2 MeV | Neutron exposure typically encountered during the operation of a nuclear
(fission) reactor. This energy of neutron exposure can also be encountered from
work with californium neutron sources.

Neutron 2-20 MeV Reactions between alpha particles from materials such as plutonium or
polonium and light materials such as beryllium resulting the production of
neutrons. These reactions are commonly called («,n) reactions, This
range also includes 14 MeV neutrons from fusion reactions.

Neutron >20 MeV Exposure to neutrons greater than 20 MeV can result from work around
accelerators.
Alpha All Primary exposure hazard is internal radiation following the inhalation or

ingestion of an alpha emitting radionuclides such as plutonium, uranium,
americium, polonium, actinium, and thorium.

Page 43 of 73


NIOSH-IREP technical documentation June 18, 2002

Figure 3. ERR/Svy estimates (at the upper 99" percentile of the credibility distribution) for
female breast cancer (FBC, triangle) and for male miscellaneous cancer (M Misc, X) models,
from NCI (2002).

100.0 7
—t-— FBC, Exp age=15

—<~ M Misc, Exp age=15
—4A- ‘FBC, Exp age=20
—>< 'M Misc, Exp age=20
- -& - FBC, Exp age>=30

- -< - M Misc, Exp age>=30

10.0

Upper 99th percentile of ERR/Sv

SN
4 ye
a SAE SR Sk
T gene Cy Oey rey
OK
pe aD Cn ao
4.0 ttt ttt tt tt ttt ttt
25 35 45 55 65

Age at diagnosis

Page 41 of 73


NIOSH-IREP technical documentation June 18, 2002

Ron E, Modan B, Preston D, et al. Radiation-induced skin carcinomas of the head and neck. Radiat.
Res. 125:318-325, 1991.

Ron E, Preston DL, Kishikawa M, Kobuke T, Iseki M, Tokuoka S, Tokunaga M, Mabuchi K. Skin
tumor risk among atomic-bomb survivors in Japan. Cancer Causes and Control 9:393-401, 1998.

Schwartzbaum JA, Setzer RW, Kupper LL. Exposure to ionizing radiation and risk of cutaneous
malignant melanoma: search for error and bias. Ann. Epidemiol. 4:487-496, 1994,

Scotto J, Fears TR, Fraumeni Jr JF. Incidence of nonmelanoma skin cancer in the United States. US
Department of Health and Human Services (DHHS) Publ]. No. 83-2433. Washington, DC: US Gov’t
Printing Office, 113 pp, 1983.

Scotto J, Fears TR, Kraemer KH, Fraumeni Jr JF, Nonmelanoma skin cancer. Chapter 60 in Cancer
Epidemiology and Prevention, 2nd Edition, Schottenfeld D, Fraumeni Jr JF, eds. New York:
Oxford University Press, 1521 pp, 1996.

Sevcova M, Seve J, Thomas J. Alpha irradiation of the skin and the possibility of late effects. Health
Phys. 35:803-806, 1978.

Shore R, Albert R, Reed M, Harley N, Pasternack B. Skin cancer incidence among children irradiated
for ringworm of the scalp. Radiat. Res. 100:192-204, 1984.

Shore RE. Overview of radiation-induced skin cancer in humans. Int. J. Radiat. Biol. 57:809-827,
1990.

Shore RE. Radiation-induced skin cancer in humans. Med. Pediat. Oncol. 36:549-554, 2001.

Thomas DB, Jimenez LM, McTiernan A, Rosenblatt K, Stalsberg H, Stemhagan A, Thompson WD,
Curnen MG, Satariano W, Austin DF. Breast cancer risk in men: risk factors with hormonal
implications. Am. J. Epidemiol. 135:734-748, 1992.

Thompson DE, Mabuchi K, Ron E, Soda M, Tokunaga M, Ochikubo S, Sugimoto S, Ikeda T,
Terasaki M, Izumi S, Preston DL, Cancer incidence in atomic bomb survivors. Part I: Solid Tumors,
1958-1987, Radiat. Res. 137:S17-S67, 1994.

Tomasek L, Darby SC, Fearn T, Swerdlow AJ, Placek V, Kunz E. Patterns of hing cancer mortality

among uranium miners in West Bohemia with varying rates of exposure to radon and its progeny.
Radiat. Res. 137:251-261, 1994.

Page 66 of 73


NIOSH-IREP technica! documentation June 18, 2002

(ERR) per Sv estimates for each risk model, and the cancer groupings to which these models were
applied, are given in Table 2.
1. Bone cancer:

Exposure to plutonium has been found in numerous animal studies to cause bone cancer
(NAS 1988). There is also a large body of literature regarding the induction of bone cancer
from occupational exposure to radium, in the form of Thorotrast (see NAS/NRC 1988 and
IARC 2001, for summary). Most U.S. worker studies are based on relatively low exposures
and small numbers of workers exposed to plutonium, and have thus been inconclusive with
respect to bone cancer induction. However, a recent study of the Russian Mayak facility
(Koshurnikova et al. 2000) found elevated rates of bone cancer among workers with positive
plutonium body burdens, after adjusting for cumulative external dose (RR = 7.9; 95%
confidence interval = 1.6-32). Unfortunately, this study cannot be used for quantitative
assessment of risk, because of serious limitations in the plutonium dosimetry for these workers
(Koshurnikova et al. 2000); however, it does provide strong qualitative evidence for an
association between plutonium exposure and bone cancer in humans.

For the purposes of NIOSH-IREP, two sources of risk coefficients were considered:
data from the risk analysis conducted for plutonium exposures among Rocky Flats workers
(Grogan et al. 2000, 2001), and the miscellaneous cancer model used in NCI-IREP. The risk
coefficients from Grogan and colleagues’ analysis are based on three sources: mortality data

from the Japanese atomic bomb survivors studies (modified by the uncertain radiation

Page 11 of 73


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NIOSH-IREP technical documentation June 18, 2002

Table 7 (continued). Primary cancers (ICD-9 codes) for which probability of causation is to be calculated, if on
a secondary cancer site is known. “M” indicates cancer site should be used for males only, and “F” indicates
cancer site should be used for females only. Whenever “173" is indicated, the “non-melanoma skin-basal cell”

model should be used.

Secondary cancer

ICD-9 code of likely primary cancers

Other digestive organs (197.8)

150 (M), 151, 153, 157, 162, 174 (F), 185 (M)

Kidney (198.0)

153, 162, 174 (F), 180 (F), 185 (M), 188, 189, 202 (F)

Other urinary organs (198.1)

153, 174 (F), 180 (F), 183 (F), 185 (M), 188, 189 (F)

Skin (198.2)

153, 162, 171 (M), 172, 173 (M), 174 (F), 189 (M)

Brain and spinal cord (198.3)

162, 172 (M), 174 (F)

Other parts of nervous system (198.4)

162, 172 (M), 174 (F), 185 (M), 202

Bone and bone marrow (198.5)

162, 174 (F), 185 (M)

Ovary (198.6)

153 (F), 174 (F), 183 (F)

Suprarenal gland (198.7)

153 (F), 162, 174 (F)

Other specified sites (198.8)

153, 162, 172 (M), 174 (F), 183 (F), 185 (M), 188 (M)

Page 59 of 73



NIOSH-IREP technical documentation June 18, 2002

obtained from Japanese atomic bomb survivors, modified by relevant distributions of REF and
DDREF for different types of radiation. Use of this approach is also consistent with that
adopted by NCI for other tissues in which transuranic radionuclides tend to accumulate (e.g.,
liver).

The study of cancer incidence among atomic bomb survivors (Thompson et al, 1994)
does not quantify bone cancer risks; however, the Grogan model uses excess risk estimates
from the latest mortality study (Pierce et al. 1996) for its cancer incidence model. This model
was not deemed appropriate by NCI for IREP because the extreme rarity of this cancer,
particularly in the exposed group, would have resulted in a model that was inconsistent with the
methods used for other cancers (which were based on risk coefficients for groups of similar
cancers that numbered at least 50 in the population exposed to 0.5 cSv or greater).

The final NCI-IREP program includes bone cancer among the grouping of
miscellaneous cancers includes bone cancer (NCI 2002). The primary argument against the
use of the miscellaneous cancer risk coefficients for bone cancer claims is that the model
includes many disparate types of cancers, including those of bone, connective tissue, eye, male
breast cancer, non-thyroid endocrine glands, and ill-defined sites. The alternative, however, of
using highly uncertain risk coefficients (from the bone cancer mortality series) without
modification from other information sources, seems less defensible, and inconsistent with the
approach used for other cancers in this class. The point estimates for the two models are quite

similar. Therefore, we concur with the NCI that the most appropriate source of risk coefficients

Page 13 of 73


NIOSH-IREP technical documentation June 18, 2002

List of Figures

Figure 1. U.S. White and African-American cancer excess incidence ratio ..............46 39

Figure 2. ERR/Sv estimates (at the upper 99" percentile of the credibility distribution) for basal cell
carcinoma (triangle) and for miscellaneous cancer (X) models, from NCI (2002), for (a) males
and (b) females, 6.0... cece cette eee een ttt e ents eee beeen 40

Figure 3. ERR/Sy estimates (at the upper 99" percentile of the credibility distribution) for female breast
cancer (FBC, triangle) and for male miscellaneous cancer (M Misc, X) models, from NCI
(0X00) a 4

Figure 4. Draft and final DDREF distribution used in NIOSH-IREP for (a) all solid cancers except
breast and thyroid and (b) breast and thyroid cancer. 0.2.0... 0c c cece eee e eee ee 42

iii


NIOSH-IREP technical documentation June 18, 2002

proportion of these would proceed to invasive malignant neoplasms without intervention, and it is
impossible to determine this at the level of the individual claimant. A policy consistently used in
NIOSH-IREP is to provide the benefit of doubt to the claimant, and to assume that a carcinoma in situ
is a malignant neoplasm. No distinction is made among the sites at which the CIS might develop with
regard to this policy. Therefore, within NIOSH-IREP, CIS will be treated as a malignant neoplasm of
the specified site.

Cancers identified by their secondary sites (sites to which a malignant cancer has spread), when
the primary site is unknown, raise another issue for the application of IREP. This situation will most
commonly arise when death certificate information is the primary source of a cancer diagnosis. It is
accepted in medicine that cancer-causing agents such as ionizing radiation produce primary cancers.
This means, in a case in which the primary site of cancer is unknown, the primary site must be
established by inference to estimate probability of causation.

An evaluation of the relationship between primary and secondary cancer sites using the National
Center for Health Statistics (NCHS) Mortality Database for years 1995-1997 was used to infer the
primary site when only the site of metastasis is known. Because national cancer incidence databases
(e.g., the National Cancer Institute’s Surveillance, Epidemiology and End Results program) do not
contain information about sites of metastasis, the NCHS database was considered the best available
data source to assign the primary site(s) most likely to have caused the spread of cancer to a known
secondary site. For each secondary cancer, the set of primary cancers producing approximately 75%

of that secondary cancer among the U.S. population was identified (males and females were considered

Page 34 of 73


NIOSH-IREP technical documentation June 18, 2002

and sunlight exposure patterns, which were not considered in the initial study (Hiatt et al. 1986,
Moore et al. 1997). Other recent studies have concluded that, while surveillance bias may
have partially contributed to the observed excess in malignant melanoma, an association with
employment exposures including ionizing radiation persists after adjusting for confounding
factors (Hiatt et al. 1993, Schwartzbaum et al. 1994, Austin and Reynolds 1997). Among
other nuclear worker cohorts, skin cancer mortality (predominantly malignant melanoma) was
found to be associated with external ionizing radiation dose in the U.K. National Registry of
Radiation Workers cohort (Carpenter et al. 1994), although that finding was not significant in a
later study of that cohort (Muirhead et al. 1999),

Direct quantitative estimates of radiation risk for malignant melanoma are not generally
available. The risk estimates from the Japanese atomic bomb survivor data have very wide
confidence intervals, as they are based on only ten cases; however, they are consistent with the
rates for basal cell carcinoma (Ron et al. 1998). There is great need for future studies of
malignant melanoma in radiation-exposed populations, in order to better estimate risk
coefficients for this cancer. However, in the absence of direct information, three reasonable
potential sources of risk coefficients are those developed in IREP for non-melanoma skin
cancer (one model each for basal cell and squamous cell carcinoma) and the miscellaneous site
cancer model. Using the model producing the highest ERR/Sv risk coefficients would be
consistent with HHS policy decisions about selecting the most claimant-favorable among

equally-valid alternatives in determining probability of causation in EEOICPA.

Page 22 of 73


NIOSH-IREP technical documentation June 18, 2002

Table of Contents

IL Background 6.0.0... ccc eee eee eee tenner n eben nate tren eee ens 1
Il. NIOSH-IREP and its implementation under EEOICPA ..... 2.0... cece eee e eee ee eee 7
A. Dosimetry Issues ..... 0. 0c cece ccc eee n nee nen e eee tee ene ees 7

B. Cancers added to NIOSH-IREP ...... 0... c cece c cee eee e eee teen ene eee 10

1, Bone cancer... eee eee ene e nent eens 11

2. Non-melanoma skin cancer .......0 6.0 c cece cece cere tenes 14

3. Malignant melanoma ........ 0.00 c ec c eee ee eee eee nee ees 21

4. Male breast cancer... 6... cece cece cece ence teen een eee 24

5. Connective tissue cancer, eye cancer, other endocrine cancer, and other and ill-

defined sites 06. c tence ne ene e ene aee 26
C. Cancers excluded from NIOSH-IREP ........ 0. c cece eee e eect nen eee 27
1. Chronic lymphocytic leukemia .......... 00. cece cece eee eee eee

D. Dose and dose-rate effectiveness factors
E. Radiation (type) effectiveness factors (REFS) ......... 00 cee cece eee eee e nee 30
F. Definitions of smoking categories for lung cancer claims ............0..0.0005 32
TIL Cancer model selection 60.0.0... ccc cence cnet eee r eee e eben eens 33
IV. Limitations of NIOSH-IREP .... 2... 60. cece cece eect teen eee en enenees 35
V. References . 6... cic nee e een n teen e nee e bene neee 60
Appendix I: NIOSH-IREP program output .....0 000. ccc cece cece nent een eens 68
Appendix II: Glossary of ICD-9 codes and their cancer descriptions .................0.05 71

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NIOSH-IREP technical documentation June 18, 2002

than one (i.¢., a supralinear effect at low doses). This distribution, more similar to that used by the U.S.
EPA (USEPA 1999), and the recent report by Grogan and colleagues (Grogan et al. 2000), is also the
basis for the revised NIOSH-IREP (Fig. 4a). To make the DDREF distribution consistent for breast
and thyroid cancers, NCI has added a small probability of supralinear effects at low doses (i.e., a
DDREF of less than one; Fig. 4b). This has also been adopted for use in NIOSH-IREP.

The uncertainty distribution used in both NCI’s and NIOSH’s IREP is consistent with the large
body of laboratory studies that demonstrate a reduced effect with dose protraction for most cancers
(IARC 2000, pp 301-304; UNSCEAR 2000a, pp 116-119), together with the latest analysis of the
Japanese atomic bomb survivors, which suggests no reduction (and possibly, an enhancement) of
carcinogenic effects at low doses, This DDREF distribution is used for chronic exposures, and is
invoked for acute exposures below 0.2 Sv, according to the probability distribution used in NCI’s
original IREP methodology (NCI 2000).

It should be noted that at present IREP (both NCI and NIOSH versions) assumes the
quadratic term in the leukemia dose-response relationship is fixed. Ideally, this term should have some
uncertainty associated with it (this was also mentioned by the NAS panel reviewing the draft NCI-

IREP); however, it is not clear what that uncertainty distribution should be.

E. Radiation (type) effectiveness factors (REFs)
The REF distributions used in IREP vary for each different type of radiation (Tables 5A, 5B,

and 5C). The assumptions underlying these distributions are detailed in Kocher et al. (2002). In

Page 30 of 73


NIOSH-IREP technical documentation June 18, 2002

Figure 1. U.S. White and African-American cancer excess incidence ratio (calculated as
higher rate divided by lower rate, minus 1), for cancers showing heterogeneity by race (data
from Parkin et al. 1997). Bars extending to the left indicate cancers that have higher
incidence rates among African-Americans, and bars extending to the right indicate cancers
with higher incidence rates among whites.

Leukemia
Multiple myeloma
Non-Hodgkin's |
Thyroid |

Brain

Bladder

Testis

Prostate

Ovary

Uterus

Cervix 0 Females

Breast mTM Males
Melanoma

Bone

Lung
Pancreas
Liver

Small intestine
Stomach
Esophagus
Mouth

Tongue

- T , T r r

3 6 9 12 15 18
Cancer Excess Incidence Ratio

wo
°

Page 39 of 73


NIOSH-IREP technical documentation June 18, 2002

approach that was considered was the use of the miscellaneous cancer model, which includes
male breast cancer incident cases from the Japanese atomic bomb survivor cohort. In the
absence of scientific information to determine which of two or more alternative methods should
be used, a consistent policy throughout the development of the HHS methods for determining
probability of causation under EEOICPA has been to use the approach that is most favorable
to the claimant. The female breast is considered among the most radiosensitive tissues in the
body (Boice et al. 1996); however, sensitivity of the breast decreases greatly with increasing
age at exposure. Therefore, it is not immediately clear which source of risk coefficients
provides the most claimant-favorable estimate of probability of causation. Examination of the
upper 99" percentile ERR/Sv estimates for both models (Fig. 3) shows that the use of the
female breast cancer model provides the most claimant-favorable estimates, at most
combinations of exposure and diagnosis ages.

Within NIOSH-IREP, therefore, for the male breast cancer model, ERR per Sv
coefficients from female breast cancer models were modified by the background incidence
rates for male breast cancer in the U.S. and Japan (Parkin et al. 1997; NCI 2000, 2002).

There is no data to support the use of any particular risk transfer model between the Japanese
and U.S. populations. In the absence of such information, the approach developed for all
cancers other than female breast and stomach was employed in NIOSH-IREP. This transfer
function is trapezoidal, which equally weights additive and multiplicative transfer models (with

small probabilities of sub-additive and super-multiplicative models; NCI 2002).

Page 25 of 73


NIOSH-IREP technical documentation June 18, 2002

Reconstruction methods and NIOSH-IREP is to make an assumption about duration of exposure

that is most favorable to the claimant. This is consistent with the approach used elsewhere in
NIOSH-IREP, of providing the benefit of doubt to the claimant where two or more plausible
alternatives for input exist. This approach was, additionally, recommended by the NAS panel
reviewing NCI-IREP: “... the officials responsible for adjudicating claims might routinely assume that
the exposure aggregated over the smallest unit of time available (such as a quarter-year) was received
as a single acute dose to provide a liberal estimate of risk” (NAS/NRC 2000, p. 13). In the case of
gamma exposures, such a liberal assumption would be that the dose was acute. For neutron
exposures, an assumption of chronic dose rate would produce the most liberal estimate of risk.

For these reasons, in the dose reconstruction process, gamma and x ray doses will be considered
acute over the smallest period of time during which the exposure measurement occurred. As a practical
matter, this means that the exposure rate will be categorized as acute for each badge reading, and each
will be specified separately within a given year in NIOSH-IREP. For example, if a claimant’s
dosimetry badges were exchanged and read on a quarterly basis, each of the four badge results would
be entered as a separate acute dose (or dose distribution) in NIOSH-IREP. In contrast, photon
exposures resulting from the intake of an internal emitter will be assumed to be chronic, as the decay
path of the alpha particle (which is a known physical quantity) produces a chronic exposure. For
reasons outlined above, neutron doses will be assumed to be chronic over the badge reading period.
This assumption will have the effect of increasing the probability of causation for neutron exposures,

because of the use of a protraction enhancement factor (e.g., see Section II.D and Kocher et al. 2002).

Page 9 of 73


NIOSH-IREP technical documentation June 18, 2002

Cardis E, Gilbert ES, Carpenter L, et al. Effects of low doses and low dose rates of external ionizing
radiation: cancer mortality among nuclear industry workers in three countries. Radiat. Res. 142:117-
132, 1995.

Carpenter L, Higgins C, Douglas A, Fraser P, Beral V, Smith P. Combined analysis of mortality in
three United Kingdom nuclear industry workforces, 1946-1988. Radiat. Res. 138:224-238, 1994.

Casagrande JT, Hanisch R, Pike MC, Ross RK, Brown JB, Henderson BE. A case-control study of
male breast cancer. Cancer Res. 48:1326-1330, 1988.

Correa P. Morphology and natural history of cancer precursors. Chapter 4 in: Cancer Epidemiology
and Prevention, 2" Edition, D Schottenfeld and JF Fraumeni Jr, eds. New York: Oxford University
Press, 1996.

Curtis RE, Boice JD Jr, Stovall M, et al. Relationship of leukemia risk to radiation dose following
cancer of the uterine corpus. J Natl Canc Inst 86:1315-1324, 1994.

Darby SC Doll R, Gill SK, et al. Long-term mortality after a single treatment course with X-rays in
patients treated for ankylosing spondylitis, Br J Cancer 55:179-190, 1987.

Davis MM, Hanke CW, Zollinger TW, Montebello JF, Hornback NB, Norins AL. Skin cancer in
patients with chronic radiation dermatitis. J Amer Acad Dermatol 20:608-616, 1989.

Greene MH, Goedert JJ, Bech-Hansen NT, McGuire D, Paterson MC, Radiogenic male breast cancer
with in vitro sensitivity to ionizing radiation and bleomycin. Cancer Investigation 1:379-386, 1983.

Grippo, PJ, and EP Sandgren. Highly invasive transitional cell carcinoma of the bladder in a simian virus
40 T-antigen transgenic mouse model. Am. J. Pathol. 157:805-813, 2000.

Grogan HA, Sinclair WK, Voilleque PG, Till JE. Final Report. Assessing Risks of Exposures to
Plutonium, Revision 2. Radiological Assessments Corporation Report No. 5-CDPHE-RFP-1998-
FINAL(Rev.2), February 2000.

Grogan HA, Sinclair WK, and Voillequé PG. Risks of fatal cancer from inhalation of °”°Plutonium
by humans: a combined four-method approach with uncertainty evaluation. Health Physics 80:447-461,
2001.

Harley N, Kolber A, Shore R, Albert RE, Altman SM, Pasternack BS. The skin dose and response for
the head and neck in patients irradiated with x-ray for tinea capitis: implications for environmental

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Table 4. Cancer models to be used in calculation of probability of causation. Derivation of
NIOSH-IREP models is described in Section II-B. Abbreviations. MN (malignant
neoplasm), CIS (carcinoma in situ), NUB (neoplasm of uncertain behavior), NUN (neoplasm
of unspecified nature).

Primary neoplasm ICD-9 code NIOSH-IREP model for
calculating PC

Malignant neoplasm (MN) of lip, oral | 140-149 Oral cavity and pharynx

cavity and pharynx

MN of esophagus 150 Esophagus

MN of stomach 151 Stomach

MN of small intestine 152 All digestive

MN of colon 153 Colon

MN of rectum and anus 154 Rectum

MN of liver 155.0, 155.2 Liver

MN of gall bladder and bile ducts 155.1, 156 Gall bladder

MN of pancreas 157 Pancreas

MN of retroperitoneum and 158 All digestive

peritoneum

MN of other digestive 159 All digestive

MN of nasal cavities, middle ear, and | 160 Other respiratory

sinuses

MN of larynx 161 Other respiratory

MN of trachea, bronchus and lung 162 Lung

MN of pleura 163 Other respiratory

MN of thymus, heart and mediastinum | 164 Other respiratory

MN of other respiratory organs 165 Other respiratory

MN of bone 170 Bone

MN of connective tissue 171 Connective tissue

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NIOSH-IREP technical documentation

June 18, 2002

Table 4 (continued). Cancer models to be used in calculation of probability of causation.
Derivation of NIOSH-IREP models is described in Section II-B. Abbreviations: MN
(malignant neoplasm), CIS (carcinoma in situ), NUB (neoplasm of uncertain behavior),
NUM (neoplasm of unspecified nature).

digestive organs

Primary neoplasm ICD-9 code NIOSH-IREP model for
calculating PC

Subacute and other (not chronic) 204.2, 204.8 Leukemia, less CLL

lymphoid leukemia

Acute and unspecified myelogenous 205.0, 205.9 Leukemia, less CLL AND Acute

leukemia myeloid leukemia

Chronic myelogenous leukemia 205.1 Leukemia, less CLL AND Chronic
myeloid leukemia

Subacute myelogenous leukemia, 205.2, 205.3, Leukemia, less CLL

myeloid sarcoma, and other myeloid 205.8

leukemia

Monocytic leukemia, other specified 206, 207 Leukemia, less CLL

leukemia

Acute leukemia of unspecified cell type] 208.0 Leukemia, less CLL AND Acute
lymphoid leukemia, AND Acute
myeloid leukemia

Chronic leukemia of unspecified cell | 208.1 Leukemia, less CLL AND Chronic

type myeloid leukemia

Carcinoma in situ (CIS) of lip, oral 230.0 Oral cavity and pharynx

cavity and pharynx

CIS of esophagus 230.1 Esophagus

CIS of stomach 230.2 Stomach

CIS of colon 230.3 Colon

CIS of rectum, anal canal, and anus 230.4, 230.5, Rectum

230.6
CIS of liver and biliary system 230.8 Liver
CIS of other and unspecified intestine, | 230.7, 230.9 All digestive

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NIOSH-IREP technical documentation June 18, 2002

effectiveness factors for alpha particles as compared to low-energy photons and by the dose-
and-dose rate effectiveness factor); studies of humans exposed to other alpha-emitters; and
studies of animals exposed to plutonium. A subjectively weighted combination of these risk
estimates for plutonium exposure was then used to produce estimates of lifetime risk per unit
dose and per unit intake of plutonium.

The approach of Grogan and colleagues is quite difficult to incorporate into IREP,
however, because of the need of IREP to incorporate risks from many types of radiation
exposure, not just plutonium and other alpha-emitting radionuclides. The problem with using
human and animal studies of alpha-exposed groups as a source of risk coefficients in IREP is
that, in the former, the risk per unit dose is expressed as a function of the initial (rather than the
committed dose), while in the Jatter, the risk per unit dose is expressed on an incremental basis
as dose is received by the target organ. In other words, in the studies upon which the risk
models are based, the radionuclide is deposited in the target organ (e.g., the bone surfaces),
and the dose to bone surfaces is delivered throughout the life of the individual. The expression
of risk in these studies is based on the initial exposure to the bone surface, which is an
underestimate of the total dose received by the organ. While this is not an inconsistent
approach for evaluating the risks of plutonium or other transuranic radionuclides, it is
incompatible with the approach used throughout IREP, which is concerned with both these
radionuclides and external ionizing radiation exposures. The model implemented by Grogan

and colleagues that is most compatible with the approach of IREP is the bone cancer model

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