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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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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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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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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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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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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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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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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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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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 June 18, 2002

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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NIOSH-IREP technical documentation June 18, 2002

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

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

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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 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

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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

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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

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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

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).

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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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