[Federal Register Volume 84, Number 185 (Tuesday, September 24, 2019)]
[Rules and Regulations]
[Pages 49954-49959]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2019-20364]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
42 CFR Part 88
[NIOSH Docket 094]
World Trade Center Health Program; Petition 023--Uterine Cancer,
Including Endometrial Cancer; Finding of Insufficient Evidence
AGENCY: Centers for Disease Control and Prevention, HHS.
ACTION: Denial of petition for addition of a health condition.
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SUMMARY: On April 23, 2019, the Administrator of the World Trade Center
(WTC) Health Program received a petition (Petition 023) to add
``endometrial cancer'' to the List of WTC-Related Health Conditions
(List). Upon reviewing the scientific and medical literature, including
information provided by the petitioner, the Administrator has
determined that the available evidence does not have the potential to
provide a basis for a decision on whether to add the major site uterine
cancer, including its subtype, endometrial cancer, to the List. The
Administrator also finds that insufficient evidence exists to request a
recommendation of the WTC Health Program Scientific/Technical Advisory
Committee (STAC), to publish a proposed rule, or to publish a
determination not to publish a proposed rule.
DATES: The Administrator of the WTC Health Program is denying this
petition for the addition of a health condition as of September 24,
2019.
ADDRESSES: Visit the WTC Health Program website at https://www.cdc.gov/wtc/received.html to review Petition 023.
FOR FURTHER INFORMATION CONTACT: Rachel Weiss, Program Analyst, 1090
Tusculum Avenue, MS: C-48, Cincinnati, OH 45226; telephone (855) 818-
1629 (this is a toll-free number); email [email protected].
SUPPLEMENTARY INFORMATION:
Table of Contents
A. WTC Health Program Statutory Authority
B. Procedures for Evaluating a Petition for Cancer
C. Petition 023
D. Assessment of Scientific and Medical Information
E. Administrator's Final Decision on Whether To Propose the Addition
of Uterine Cancer, Including Endometrial Cancer, to the List
F. Approval To Submit Document to the Office of the Federal Register
A. WTC Health Program Statutory Authority
Title I of the James Zadroga 9/11 Health and Compensation Act of
2010 (Pub. L. 111-347, as amended by Pub. L. 114-113), added Title
XXXIII to the Public Health Service (PHS) Act,\1\ establishing the WTC
Health Program within the Department of Health and Human Services
(HHS). The WTC Health Program provides medical monitoring and treatment
benefits for health conditions on the List to eligible firefighters and
related personnel, law enforcement officers, and rescue, recovery, and
cleanup workers who responded to the September 11, 2001, terrorist
attacks in New York City, at the Pentagon, and in Shanksville,
Pennsylvania (responders), and to eligible persons who were present in
the dust or dust cloud on September 11, 2001, or who worked, resided,
or attended school, childcare, or adult daycare in the New York City
disaster area (survivors).
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\1\ Title XXXIII of the PHS Act is codified at 42 U.S.C. 300mm
to 300mm-61. Those portions of the James Zadroga 9/11 Health and
Compensation Act of 2010 found in Titles II and III of Public Law
111-347 do not pertain to the WTC Health Program and are codified
elsewhere.
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All references to the Administrator of the WTC Health Program
(Administrator) in this document mean the Director of the National
Institute for Occupational Safety and Health (NIOSH) or his designee.
Pursuant to section 3312(a)(6)(B) of the PHS Act, interested
parties may petition the Administrator to add a health condition to the
List in 42 CFR 88.15. Within 90 days after receipt of a valid petition
to add a condition to the List, the Administrator must take one of the
following four actions described in section 3312(a)(6)(B) of the PHS
Act and Sec. 88.16(a)(2) of the Program regulations: (1) Request a
recommendation of the STAC, (2) publish a proposed rule in the Federal
Register to add such health condition, (3) publish in the Federal
Register the Administrator's determination not to publish such a
proposed rule and the basis for such determination, or (4) publish in
the Federal Register a determination that insufficient evidence exists
to take action under (1) through (3) above.
B. Procedures for Evaluating a Petition for Cancer
In addition to the regulatory provisions, the WTC Health Program
has developed policies to guide the
[[Page 49955]]
review of submissions and petitions,\2\ as well as the analysis of
evidence supporting the potential addition of a type of cancer to the
List.\3\
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\2\ See WTC Health Program [2014], Policy and Procedures for
Handling Submissions and Petitions to Add a Health Condition to the
List of WTC-Related Health Conditions, May 14, 2014, http://www.cdc.gov/wtc/pdfs/WTCHPPPPetitionHandlingProcedures14May2014.pdf.
\3\ See WTC Health Program [2019], Policy and Procedures for
Adding Types of Cancer to the List of WTC-Related Health Conditions,
May 1, 2019, https://www.cdc.gov/wtc/pdfs/policies/WTCHP_PP_Addition_of_Cancer_Policy_UPDATED_050719-508.pdf.
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A valid petition must include sufficient medical basis for the
association between the September 11, 2001, terrorist attacks and the
health condition to be added; in accordance with WTC Health Program
policy, reference to a peer-reviewed, published, epidemiologic study
about the health condition among 9/11-exposed populations or to
clinical case reports of health conditions in WTC responders or
survivors may demonstrate the required medical basis.\4\ Studies
linking 9/11 agents \5\ or hazards to the petitioned health condition
may also provide sufficient medical basis for a valid petition.
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\4\ See supra note 2.
\5\ 9/11 agents are chemical, physical, biological, or other
hazards reported in a published, peer-reviewed exposure assessment
study of responders, recovery workers, or survivors who were present
in the New York City disaster area, or at the Pentagon site, or the
Shanksville, Pennsylvania site, as those locations are defined in 42
CFR 88.1, as well as those hazards not identified in a published,
peer-reviewed exposure assessment study, but which are reasonably
assumed to have been present at any of the three sites. See WTC
Health Program [2018], Development of the Inventory of 9/11 Agents,
July 17, 2018, https://wwwn.cdc.gov/ResearchGateway/Content/pdfs/Development_of_the_Inventory_of_9-11_Agents_20180717.pdf.
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After the Program has determined that a petition is valid, the
Administrator must direct the Program to conduct a systematic
literature search (a keyword search of relevant scientific databases)
to gather information about the following: (1) Studies about the type
of cancer requested to be added to the List among 9/11-exposed
populations, (2) studies showing a potential causal association between
the requested cancer and a health condition on the List, and (3)
classifications of the World Health Organization's International Agency
for Research on Cancer (IARC) and the National Toxicology Program (NTP)
Report on Carcinogens relevant to the requested cancer. Peer-reviewed,
published, epidemiologic studies of the cancer in 9/11-exposed
populations are considered relevant. The quantity and quality of
relevant studies are reviewed for their potential to provide a basis
for deciding whether to propose adding the type of cancer to the List.
If the Program determines that the relevant studies have the
potential to provide a basis for deciding whether to propose adding the
type of cancer to the List, the cancer type may be added to the List if
one of the four following methods is met:
Method 1. Epidemiologic Studies of September 11, 2001-Exposed
Populations.
The peer-reviewed, published, epidemiologic studies of 9/11-
exposed populations are assessed by applying the following criteria
extrapolated from the Bradford Hill criteria, as appropriate:
a. Strength of the association between a 9/11 exposure and a
type of cancer (including the precision of the risk estimate \6\),
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\6\ A precision of the risk estimate describes the uncertainty
inherent in estimating the strength of association (the effect size)
between exposure and health effect from observational data. It is
expressed as a confidence interval illustrating a range of values
that contains the true effect size. A narrow confidence interval
indicates a more precise measure of the effect size and a wider
interval indicates greater uncertainty.
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b. Consistency of the findings across multiple studies. If only
a single published epidemiologic study is available for assessment,
the consistency of findings cannot be evaluated and more emphasis
will be placed on evaluating the strength of the association and the
precision of the risk estimate,
c. Biological gradient, or dose-response relationships between
9/11 exposures and the type of cancer, and
d. Plausibility and coherence with known facts about the biology
of the type of cancer.
Method 2. Established Causal Associations.
A type of cancer may be added to the List if there is well-
established scientific support published in multiple epidemiologic
studies for a causal association between that cancer and a condition
already on the List of WTC-Related Health Conditions.
Method 3. Review of Evaluations of Carcinogenicity in Humans.
A type of cancer may be added to the List under Method 3 if both
of the following criteria are satisfied:
3A. Published Exposure Assessment Information. A 9/11 agent
included in the Inventory of 9/11 Agents \7\ is identified, and
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\7\ The Inventory of 9/11 Agents is composed of those agents
identified in Tables 1-4 of the document, Development of the
Inventory of 9/11 Agents. See supra note 5.
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3B. Evaluation of Carcinogenicity in Humans from Scientific
Studies. NTP has determined that the [identified] 9/11 agent is
known to be a human carcinogen or is reasonably anticipated to be a
human carcinogen, and IARC has determined there is sufficient or
limited evidence that the 9/11 agent causes [the requested] type of
cancer.
Method 4. Review of Information Provided by the WTC Health
Program Scientific/Technical Advisory Committee.\8\
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\8\ The WTC Health Program Scientific/Technical Advisory
Committee may be convened by the Administrator if he determines that
its advice would be helpful. See supra note 3 at Sec. V.
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A type of cancer may be added to the List if the STAC has
provided a reasonable basis for adding a type of cancer.
If the evaluation of evidence required for any of the four methods
demonstrates that the criteria in that method are satisfied, the
Administrator will propose the addition of the type of cancer to the
List.
C. Petition 023
On April 23, 2019, the Administrator received a petition (Petition
023) requesting the addition of ``endometrial cancer'' to the List.\9\
The petition included a 2002 study by Lioy et al.\10\ and a 2017 study
by McElroy et al.\11\ which together provided sufficient medical basis
for the petition to be considered valid because they demonstrate the
presence of 9/11 agents, including cadmium, at the WTC site and that
cadmium exposure is associated with a statistically significant
increase in endometrial cancer risk. However, because neither Lioy et
al. [2002] nor McElroy et al. [2017] is a peer-reviewed, published,
epidemiologic study of endometrial cancer (or the major site, uterine
cancer) in a 9/11-exposed population, neither study is considered
relevant nor are they further reviewed in this action.
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\9\ See Petition 023, WTC Health Program: Petitions Received,
http://www.cdc.gov/wtc/received.html.
\10\ Lioy PJ, Weisel CP, Millette JR, Eisenreich S, Vallero D,
Offenberg J, Turpin B, Zhong M, Cohen MD, Prophete C, Yang I, Stiles
R, Chee G, Johnson W, Porcja R, Alimokhtari S, Hale RC, Weschler C,
Chen LC [2002], Characterization of the Dust/Smoke Aerosol that
Settled East of the World Trade Center (WTC) in Lower Manhattan
after the Collapse of the WTC11 September 2001, Environ Health
Perspect 110(7), 703-714.
\11\ McElroy JA, Kruse RL, Guthrie J, Gangnon RE, Robertson JD
[2017], Cadmium Exposure and Endometrial Cancer Risk: A Large
Midwestern U.S. Population-Based Case-Control Study, PLoS ONE 12(7):
e0179360.
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In the Program's List of WTC-Related Health Conditions, types of
cancer are identified by the major cancer site/histology groups that
are commonly used in the reporting of cancer incidence data, using the
groupings standardized by the National Cancer Institute's Surveillance,
Epidemiology and End Results Program (SEER) for national cancer
surveillance.\12\ Cancer subtypes are not included in the List. Because
endometrial cancer is a subtype of uterine cancer,\13\ the Program has
[[Page 49956]]
determined that the scope of this petition and subsequent Program
review should include both endometrial cancer and the major site,
uterine cancer.
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\12\ National Cancer Institute [2008], Surveillance Epidemiology
and End Results: Site Recode ICD-O-3/WHO 2008 Definition, https://seer.cancer.gov/siterecode/icdo3_dwhoheme/index.html/.
\13\ Endometrial cancer develops in the lining of the uterus,
called the endometrium. Although endometrial uterine cancer is the
most common type of uterine cancer, accounting for more than 90
percent of cases, there are other types of uterine cancer. See
https://www.cancer.gov/types/uterine/patient/endometrial-treatment-pdq.
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D. Assessment of Scientific and Medical Information
In response to Petition 023, the Program conducted both a
systematic literature search to identify peer-reviewed, published
studies of uterine cancer, including endometrial cancer, in 9/11-
exposed women, as well as a review of NTP and IARC classifications of
9/11 agents, including those 9/11 agents identified by IARC as
carcinogenic agents with sufficient or limited evidence that the agent
causes uterine cancer, including endometrial cancer, in humans.\14\ The
National Cancer Institute has not identified any of the health
conditions on the List of WTC-Related Health Conditions as known risk
factors for uterine or endometrial cancer; therefore, a systematic
literature search for studies regarding a causal association between
uterine or endometrial cancer and a health condition on the List was
not conducted.\15\
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\14\ Databases searched include: CINAHL, Embase, NIOSHTIC-2,
ProQuest Health & Safety, PsycINFO, Ovid MEDLINE, Scopus, Toxicology
Abstracts/TOXLINE, and WTC Health Program Bibliographic Database.
Keywords used to conduct the search include: Endometrial neoplasm,
endometrial cancer, endometrial carcinoma, malignant neoplasm of
endometrium, adenocarcinoma of endometrium, cancer of the
endometrium, Uterine Neoplasm, malignant neoplasm of corpus uteri,
uterine cancer, uterine carcinoma. The literature search was
conducted in English-language journals on May 23, 2019.
\15\ No health conditions on the List of WTC-Related Health
Conditions are known risk factors for uterine cancer. See https://www.cancer.gov/types/uterine/hp/endometrial-prevention-pdq.
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Literature Search Results
Two publications were identified in the search for studies
specifically regarding uterine cancer, including endometrial cancer,
among 9/11-exposed populations, thus meeting the Program's criteria for
further evaluation: Li et al. [2012] \16\ and its update Li et al.
[2016].\17\ In addition to the two Li et al. publications found in the
literature search, the Program was aware of additional studies
examining all types of cancer in 9/11-exposed subpopulations (rescue
and recovery workers and survivors); these additional studies were also
reviewed to determine whether they may provide further insight into
cancer incidence and mortality applicable to the evaluation of uterine
cancer, including endometrial cancer: Jordan et al. [2011] \18\ and its
update Jordan et al. [2018],\19\ Zeig-Owens et al. [2011] \20\ and its
update Moir et al. [2016],\21\ Solan et al. [2013],\22\ Kleinman et al.
[2015],\23\ and Stein et al. [2016].\24\ Of the additional studies,
only Zeig-Owens et al. [2011] and its update Moir et al. [2016] were
found not to be relevant (they were not peer-reviewed, published,
studies of uterine or endometrial cancer in the 9/11-exposed
population) because neither addressed cancers in female WTC responders.
The other five additional studies, along with Li et al. [2012] and Li
et al. [2016], were found to be relevant and were reviewed for quantity
and quality, below.
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\16\ Li J, Cone JE, Kahn AR, Brackbill RM, Farfel MR, Greene CM,
Hadler JL, Stayner LT, Stellman SD [2012], Association between World
Trade Center Exposure and Excess Cancer Risk, JAMA 308(23):2479-88.
\17\ Li J, Brackbill RM, Liao TS, Qiao B, Cone JE, Farfel MR,
Hadler JL, Kahn AR, Konty KJ, Stayner LT, Stellman SD [2016], Ten-
Year Cancer Incidence in Rescue/Recovery Workers and Civilians
Exposed to the September 11, 2001 Terrorist Attacks on the World
Trade Center, Am J Ind Med 59(9):709-21.
\18\ Jordan HT, Brackbill RM, Cone JE, Debcoudhury I, Farfel MR,
Greene CM, Hadler JL, Kennedy J, Li J, Liff J, Stayner L, Stellman
SD [2011], Mortality among Survivors of the Sept 11, 2001, World
Trade Center Disaster: Results from the World Trade Center Health
Registry Cohort, Lancet 378(9794):879-87.
\19\ Jordan HT, Stein CR, Li J, Cone JE, Stayner L, Hadler JL,
Brackbill RM, Farfel MR [2018], Mortality among Rescue and Recovery
Workers and Community Members Exposed to the September 11, 2001
World Trade Center Terrorist Attacks, 2003-2014, Environ Res
163:270-9.
\20\ Zeig-Owens R, Webber MP, Hall CB, Schwartz T, Jaber N,
Weakley J, Rohan TE, Cohen HW, Derman O, Aldrich TK, Kelly K,
Prezant DJ [2011], Early Assessment of Cancer Outcomes in New York
City Firefighters after the 9/11 Attacks: an Observational Cohort
Study, Lancet 378(9794):898-905.
\21\ Moir W, Zeig-Owens R, Daniels RD, Hall CB, Webber MP, Jaber
N, Yiin JH, Schwartz T, Liu X, Vossbrinck M, Kelly K, Prezant D
[2016], Post-9/11 Cancer Incidence in World Trade Center-Exposed New
York City Firefighters as Compared to a Pooled Cohort of
Firefighters from San Francisco, Chicago and Philadelphia (9/11/
2001-2009), Am J Ind Med 59(9):722-30.
\22\ Solan S, Wallenstein S, Shapiro M, Teitelbaum SL, Stevenson
L, Kochman A, Kaplan J, Dellenbaugh C, Kahn A, Biro FN, Crane M,
Crowley L, Gabrilove J, Gonsalves L, Harrison D, Herbert R, Luft B,
Markowitz SB, Moline J, Niu X, Sacks H, Shukla G, Udasin I, Lucchini
RG, Boffetta P, Landrigan PJ [2013], Cancer Incidence in World Trade
Center Rescue and Recovery Workers, 2001-2008, Environ Health
Perspect 21(6):699-704.
\23\ Kleinman EJ, Christos PJ, Gerber LM, Reilly JP, Moran WF,
Einstein AJ, Neugut AI [2015], NYPD Cancer Incidence Rates 1995-2014
Encompassing the Entire World Trade Center Cohort, J Occup Environ
Med 57(10):e101-13.
\24\ Stein CR, Wallenstein S, Shapiro M, Hashim D, Moline JM,
Udasin I, Crane MA, Luft BJ, Lucchini RG, Holden WL [2016],
Mortality among World Trade Center Rescue and Recovery Workers,
2002-2011, Am J Ind Med 59(2):87-95.
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The Program reviewed the NTP Report on Carcinogens \25\ and found
that twelve 9/11 agents \26\ are known to be human carcinogens and
twenty-seven 9/11 agents are reasonably anticipated to be human
carcinogens. \27\ However, IARC has not determined that any of these
thirty-nine 9/11 agents demonstrate sufficient or limited evidence of a
causal association with uterine or endometrial cancer in humans.\28\
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\25\ National Toxicology Program, HHS [2016], Report on
Carcinogens, 14th Edition (Research Triangle Park, NC). https://ntp.niehs.nih.gov/go/roc14.
\26\ As identified in the Inventory of 9/11 Agents, see supra
notes 7 and 5.
\27\ The 39 total 9/11 agents identified by NTP are as follows:
Arsenic, Asbestos, Benzene, Beryllium, 1,3-Butadiene, Cadmium,
Nickel, Silica, Solar Radiation, Soot, Sulfuric Acid,
Trichloroethylene (Known To Be Human Carcinogens); as well as
Acetaldehyde, Acrylonitrile, Benz[a]anthracene,
Benzo[k]fluoranthene, Benzo[a]pyrene, Carbon Tetrachloride,
Chloroform, Cobalt, Dibenz[a,h]anthracene, 1,4-Dichlorobenzene,
Dichlorodiphenyltrichloroethane, 1,2-Dichloroethane,
Dichloromethane, 1,3-Dichloropropene, Diesel Exhaust Particulates,
1,4-Dioxane, Hexachlorobenzene, Lead, Hexachlorocyclohexane, Mirex,
Naphthalene, Nickel, Polybrominated Biphenyls, Polychlorinated
Biphenyls, Styrene, Tetrachloroethylene, and Toluene Diisocyanates
(Reasonably Anticipated To Be Human Carcinogens).
\28\ International Agency for Research on Cancer [1976], IARC
Monographs on the Evaluation of Carcinogenic Risk of Chemicals to
Man: Cadmium, Nickel, Some Epoxides, Miscellaneous Industrial
Chemicals and General Considerations on Volatile Anesthetics, Volume
11; Lyon, France.
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Review of Relevant Studies
The studies identified as relevant during the literature review
process were further assessed to determine whether they have sufficient
quality and quantity to demonstrate a potential to support the addition
of uterine cancer, including endometrial cancer. The relevant studies
introduced above are described below, including a description of their
respective strengths and limitations.
Jordan et al. [2011] conducted a mortality study among the cohort
of WTC Health Registry enrollees that included 13,337 rescue/recovery
workers (3,188 women) and 28,593 survivors (16,733 women) living in New
York City at the time of their enrollment. The authors identified
deaths occurring in 2003-2009 through linkage to New York City vital
records and the National Death Index (NDI). Standardized mortality
ratios (SMRs) were calculated with New York City rates from 2000 to
2009 as the reference. Within the cohort, proportional hazards were
used to examine the relation between WTC-related exposure levels (high,
intermediate, or low for each group, based on exposure to the dust
cloud, and time and duration working on the pile) and all-cause
mortality, but not mortality for specific cancers. All-
[[Page 49957]]
cause SMRs were significantly lower than that expected for rescue/
recovery workers (SMR = 0.45, 95% CI (confidence interval) 0.38-0.53)
and survivors (SMR = 0.61, 95% CI 0.56-0.66). There were no
significantly elevated SMRs for any category of cancer examined,
including cancer of female genital organs, among all studied Registry
enrollees (SMR = 0.82, 95% CI 0.49-1.28), rescue/recovery workers (SMR
= 0.67, 95% CI 0.08-2[middot]43), or survivors (SMR = 0.84, 95% CI
0.49-1.35). Separate SMRs for cancer of specific types of female
genital organs, including uterine cancer, were not provided. SMRs were
adjusted for age, sex, race, and calendar year. Adjusted hazard ratios
(AHRs) were adjusted for age, sex, race and ethnic origin, income,
smoking, and, for survivors, Registry recruitment source. This study's
limitations include possible selection bias, since enrollment in the
Registry is voluntary. Exposure reporting may also be subject to recall
error because 9/11 exposures were self-reported 2 to 3 years after the
September 11, 2001 terrorist attacks and subsequent clean-up of the
sites. The healthy worker effect puts the population of rescue/recovery
workers at a lower risk of cancer compared to the general
population,\29\ which includes persons who are chronically ill,
hospitalized, or otherwise unemployable. In addition, other potential
confounders, such as family cancer history and occupational exposures
prior to September 11, 2001, were not measured.
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\29\ The healthy worker effect is a form of selection bias
``typically seen in observational studies of occupational exposures
with improper choice of comparison group (usually general
population).'' See Chowdhury R, Shah D, Payal AR, [2017], Healthy
Worker Effect Phenomenon: Revisited with Emphasis on Statistical
Methods--A Review, Indian J Occup Environ Med 21(1), 2-8.
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Jordan et al. [2018] updated their 2011 study, discussed above, by
including the full cohort of WTC Health Registry enrollees, not only
those living in New York City at time of enrollment, and adding 5 years
of follow-up. The 2018 update included 29,280 rescue/recovery workers
(6,422 women) and 39,643 survivors (21,126 women). The authors used New
York City population mortality rates from 2003 to 2012 as the primary
reference, and also conducted a secondary analysis using U.S.
population comparison rates from 2003 to 2011. Proportional hazards
were used to examine the relation between WTC-related exposure levels
(high, intermediate, or low for each group, based on time and duration
in lower Manhattan) and total mortality, as well as overall cancer
mortality, but not mortality for specific cancer types. Overall cancer
SMRs were not elevated for rescue/recovery workers (SMR = 0.94, 95% CI
0.84-1.05), but were significantly elevated among survivors (SMR =
1.14, 95% CI 1.06-1.24) when compared to the New York City population;
no elevated SMRs were reported for all cancers using the general U.S.
population as reference. Cancers of the female genital organs were not
significantly elevated among rescue/recovery workers or survivors
(observed deaths = 7, SMR = 0.67, 95% CI 0.27-1.39 and observed deaths
= 43, SMR = 1.17, 95% CI 0.85-1.58, respectively). The authors also
examined 119 sub-categories of the major causes of death, but only
reported statistically significant results; uterine cancers were not
among the reported causes of death, suggesting that the risk of uterine
cancer was not significantly elevated. No statistically significant
elevations and no significant trends were observed in the analyses of
the association between WTC-related exposures and overall cancer
mortality. Like the previously reviewed study, Jordan et al. [2018] is
prone to selection bias, because enrollment in the Registry was
voluntary. Further, 9/11 exposures were self-reported 2 to 3 years
after the September 11, 2001 terrorist attacks, and thus are subject to
recall error. The healthy worker effect may put the population of
rescue/recovery workers at a lower risk of cancer compared with the
general population. An analogous effect has been seen in people who
volunteer for health studies and might have contributed to the low
relative mortality in both the rescue/recovery and survivor
participants. As in the previously described study, other potential
confounders, such as family cancer history and occupational exposures
prior to September 11, 2001, were not measured.
Li et al. [2012] conducted a cancer incidence study among enrollees
in the WTC Health Registry who were residents of New York State on
September 11, 2001, and had no history of cancer at the time of
enrollment. A total of 55,778 individuals were eligible for the study,
including 21,850 involved in rescue/recovery (4,185 women) and 33,928
survivors not involved in rescue/recovery (18,922 women). The authors
identified cancers by linkage to 11 state cancer registries based on
the state of residence of the cohort member, and based expected numbers
of cancers on New York State cancer rates. They used qualitative
descriptions of 9/11 exposures to classify Registry enrollee exposure
as high, intermediate, or low based on time and duration in lower
Manhattan. The authors conducted separate analyses for rescue/recovery
workers and for survivors, and presented separate results for the
period of enrollment through 2006 (early period) and 2007 through 2008
(later period). Among rescue/recovery workers, the standardized
incidence ratio (SIR) \30\ for all cancer sites combined was not
statistically significantly elevated in either period (early period,
SIR = 0.94; 95% CI, 0.82-1.08; later period SIR = 1.14; 95% CI, 0.99-
1.30). Uterine cancer incidence was not elevated for rescue/recovery
workers during the early period (five cases or less [the precise number
of cases was not reported, likely because of restrictions on reporting
small numbers], SIR = 0.97, 95% CI 0.2-2.83), and no cases were
reported during the later period. Among survivors, no significantly
increased incidence for all cancer sites combined was observed in
either period. Uterine cancer incidence was not elevated for survivors
during the early or late periods (early: observed uterine cancers = 16,
SIR = 1.01, 95% CI 0.58-1.65 and late: observed uterine cancers = 14,
SIR = 1.01, 95% CI 0.55-1.69, respectively). Results of analyses to
assess the risk of uterine cancer as a function of 9/11 exposure levels
were not reported. SIRs were stratified by age (5-year age groups),
race/ethnicity, sex, and calendar period (2003-2006 and 2007-2008).
Exposure covariates included age at enrollment, sex, race/ethnicity,
2002 household income level, education level, smoking status,
enrollment source (identified by employers, government agencies, and
other entities or by an outreach campaign), and history of asthma,
cardiovascular disease, stroke, emphysema, or diabetes reported at
enrollment. But other potential confounders, such as family cancer
history and occupational exposures prior to September 11, 2001, were
not measured. The study by Li et al. [2012] is prone to selection bias
because enrollment in the Registry was voluntary. The authors attempted
to mitigate this bias by restricting the analyses to individuals
without prior invasive cancer history documented in any of the 11 state
cancer registries and focusing on cancer incidence from 2007 to 2008.
Self-reported 9/11 exposures may be subject to recall error. Cancer
cases identified through linkages with
[[Page 49958]]
state cancer registries might be underestimated, especially among those
without a known Social Security number because a percentage of Registry
enrollees did not provide one. The findings on rescue/recovery workers
may also be prone to the healthy worker effect.
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\30\ SIR is a mathematical expression that compares the
incidence experience between the population under study and the
experience of that population had they had the same incidence
experience of a comparison population.
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Li et al. [2016] updated their 2012 study, discussed above, which
evaluated excess cancer among WTC Health Registry enrollees. In the
2016 update, the authors added 3 years of follow-up to allow for 10
years of cancer latency since the WTC-related exposures. The 2016 study
recalibrated the definition of ``WTC disaster physical exposures'' to
emphasize potential contaminants containing carcinogens. The analysis
focused on cancers occurring from 2007 through 2011. The study included
a total of 60,339 eligible individuals, including 24,863 rescue/
recovery workers (5,015 women) and 35,476 survivors not involved in
rescue/recovery (18,845 women). The authors identified cancers by
linkage to 11 state cancer registries based on the state of residence
of the cohort member, and based expected numbers of cancers on overall
New York State rates and person-years of follow-up during 2007-2011,
adjusted for age (5-year groups), race/ethnicity, sex, and calendar
period (2007-2011). The study found that overall cancer incidence was
significantly greater than the reference (non-9/11-exposed) population
among both rescue/recovery workers (SIR = 1.11, 95% CI 1.03-1.20) and
survivors (SIR = 1.08, 95% CI 1.02-1.15). Uterine cancer incidence was
not significantly elevated among rescue/recovery workers nor among
survivors (observed uterine cancers = 8, SIR = 0.82, 95% CI 0.35-1.62
and observed uterine cancers = 37, SIR = 1.03, 95% CI 0.72-1.41,
respectively). Comparisons among exposure groups were not reported for
uterine cancer. In internal analyses, hazard ratios and 95% CI were
adjusted for age at enrollment, sex, race/ethnicity, smoking,
education, income, and history of a serious non-malignant medical
condition; however, findings for uterine cancer were not reported.
Other potential confounders were not measured. This study was prone to
selection bias, because enrollment in the Registry was voluntary; the
authors attempted to mitigate this bias by restricting the analyses to
individuals without prior invasive cancer history documented in any of
the 11 state cancer registries and focusing on cancer incidence from
2007 through 2011. In addition, findings on rescue/recovery workers may
also be subject to the healthy worker effect.
Solan et al. [2013] conducted a cancer incidence study among 20,984
non-FDNY WTC Health Program members (3,203 women) involved in rescue,
recovery, and cleanup efforts at Ground Zero after 9/11. The authors
identified cancer cases through linkage with the tumor registries in
the four states in which 98 percent of WTC responders resided at time
of enrollment in the Program. Self-reported exposures were categorized
based on four variables: Pre-September 11, 2001 occupation, extent of
exposure to the dust cloud on September 11, 2001, duration of time
spent working at the site, and work on the debris pile during four
periods (September 2001, October 2001, November-December 2001, and
January-June 2002). An integrated exposure variable was created using a
4-point scale (very high, high, intermediate, and low) based on total
time spent working at Ground Zero, exposure to the dust cloud, and work
on the debris pile. The authors obtained vital status through linkage
with the NDI and next-of-kin reports. Expected numbers of cancer cases
were calculated based on state rates (for New York, New Jersey, and
Connecticut residents) and national rates (for Pennsylvania residents)
according to age (in 5-year groups), sex, and race/ethnicity for each
year at risk. The observed and expected numbers of cancers were used to
calculate SIRs. The SIR among study participants was elevated and
statistically significant for all cancer sites combined (SIR = 1.15;
95% confidence interval (CI), 1.06-1.25). Fewer than six cases of
uterine cancer were observed, and no additional information was
reported for this type of cancer. Furthermore, no SIRs were reported
for uterine cancer nor were risk ratios reported for the association
between 9/11 exposure variables and uterine cancer. Certain potential
confounders, such as family cancer history, were not measured. The
study is also prone to selection bias, because enrollment in the WTC
Health Program is voluntary. Although the authors used all available
exposure metrics, relative risk was not reported for the association
between 9/11 exposure variables and uterine cancer. This study may also
be subject to the healthy worker effect, which puts this population at
a lower risk of cancer compared to the general population.
Kleinman et al. [2015] investigated cancer incidence in 39,946
police officers employed by the New York City Police Department (NYPD)
on September 11, 2001 (6,366 women), followed during the time periods
1995 to 2000 and 2002 to 2014. The authors reported a 44 percent
increase in the overall median age-adjusted incidence rate for all
cancers, but no increase in the overall median age-adjusted incidence
rates for either malignant neoplasms of the uterus, unspecified part
(based on two cases diagnosed pre-9/11 and zero cases diagnosed post-9/
11) or uterine adenosarcomas (based on zero cases diagnosed pre-9/11
and three cases post-9/11). This study is limited by the inherent
problems with its design (i.e., the effects of age, time period, and
cohort parameters are intertwined in a manner which complicates study
interpretation); the study is further limited by the small number of
cancer cases observed as well as the absence of information regarding
participants' presence in the dust cloud and the dates and duration of
their 9/11 exposures.
Stein et al. [2016] conducted a mortality study of 28,918 rescue/
recovery workers (4,286 women) enrolled in the WTC Health Program
between July 16, 2002, and December 31, 2011. The authors were aware
that 16,177 WTC responders were alive due to follow-up visits after the
end of 2011, and therefore linked the remainder (n = 12,741) to the
National Death Index (NDI). Mortality information from the NDI was
supplemented by next-of-kin report. Similar to the study by Solan et
al. [2013], discussed above, the authors of this study created an
integrated exposure variable using a 4-point scale (very high, high,
intermediate, and low) based on total time spent working at Ground
Zero, exposure to the dust cloud, and work on the debris pile. SMRs
were standardized for age (5-year groups), sex, race, and calendar year
to compare all-cause and cause-specific mortality among responders with
mortality in the U.S. general population. Hazard ratios were adjusted
for age on September 11, 2001, pre-September 11, 2001 occupation, sex,
race/ethnicity, year of WTC Health Program enrollment, smoking, and
measured body mass index. Overall mortality in this cohort was
statistically significantly decreased (SMR = 0.43; 95% CI, 0.39-0.48),
although an overall cancer SMR was not reported. Most cancer site-
specific SMRs were significantly decreased; however, the SMR for cancer
of the female genital organs was decreased but was not statistically
significant (SMR = 0.65, 95% CI 0.08-2.37) and was based on only two
deaths. An SMR for uterine cancer was not provided, neither were hazard
ratios for the association between WTC-related exposure variables and
mortality from
[[Page 49959]]
uterine cancer. Some potential confounders, such as family cancer
history, were not measured. The study is prone to selection bias
because enrollment in the WTC Health Program was voluntary. Social
Security numbers were available for only 37 percent of the records sent
to NDI for linkage, limiting the quality of the matches. The healthy
worker effect may put this population at a lower risk of cancer
compared to the general population.
Quantity and Quality Review of Relevant Studies
The quantity and quality of these seven studies were reviewed
together to examine whether the available evidence has the potential to
provide a basis for a decision on whether to add uterine cancer,
including endometrial cancer, to the List. Prospective cohort studies,
like those described above, have the advantage that study participants
are considered to be disease-free at the beginning of the observation
period when their exposure occurred; therefore, in such studies it is
often possible to establish the temporal sequence between exposure and
outcome. Cancer studies, however, present unique concerns since some
cancers become apparent only after long periods of time following
exposure.\31\ This latency effect means it is possible that a cancer
may have been present but undetected prior to September 11, 2001. In
addition, all of the studies described above have had a relatively
short period of follow-up since September 11, 2001.
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\31\ This delay between environmental exposure and onset of
cancer symptoms is referred to as the ``cancer latency period.'' For
more information about latency for cancers and how the WTC Health
Program has addressed this issue, please see Minimum Latency & Types
or Categories of Cancer, Jan. 6, 2015, https://www.cdc.gov/wtc/pdfs/policies/WTCHP-Minimum-Cancer-Latency-PP-01062015-508.pdf.
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The size and makeup of the cohorts studied may also limit the
usefulness of the studies. The studies discussed above may not have the
necessary statistical power to detect excesses in uterine cancer, due
to the small number of females in the cohort. This is especially a
concern with studies of 9/11-exposed rescue/recovery workers since
those cohorts are not sizeable and only approximately 15 percent
female. Moreover, the overlap in participation in the studies may limit
the interpretation of consistency of findings among the studies.
Approximately 20 percent of 9/11-exposed rescue/recovery workers
enrolled in the WTC Health Program are also enrolled in the WTC Health
Registry. These two cohorts also may be prone to selection bias,
because enrollment in the respective programs was voluntary. For the
WTC Health Registry cohort, it is possible that differential
participation due to race/ethnicity, socioeconomic status, age, or
their perception of being affected by the 9/11 attacks, may have
occurred. For the rescue/recovery worker cohort enrolled in the WTC
Health Program, their health status, including their cancer diagnosis,
may have prompted them to enroll. A strength of these studies is that
findings are available for both 9/11-exposed rescue/recovery workers as
well as survivors.
The relevant studies published to date, and reviewed above, do not
provide consistent evidence that uterine cancer, including endometrial
cancer, incidence or mortality is elevated among WTC responders and/or
survivors. In addition, the studies did not report a dose-response
relationship between WTC-related exposures and uterine cancer,
including endometrial cancer. Taken together, these studies do not have
sufficient quality and quantity to demonstrate a potential to provide a
basis for a decision on whether to add uterine cancer, including
endometrial cancer, to the List. Accordingly, these studies are not
further reviewed.
Administrator Determination
Upon review of the evidence available in peer-reviewed, published,
epidemiological studies and updates regarding uterine cancer, including
endometrial cancer, among 9/11-exposed populations, the Administrator
has determined that the available evidence does not have the potential
to provide a basis for deciding whether to propose adding uterine
cancer, including endometrial cancer, to the List. Accordingly, the
Administrator has not directed the Program to assess the available
evidence using Methods 1, 2, or 3, nor has he directed the Program to
request advice from the STAC pursuant to Method 4, discussed above.
The WTC Health Program may consider uterine cancer, including
endometrial cancer, to be a condition medically associated with a
certified WTC-related health condition in individual cases. Program
members who think their uterine or endometrial cancer is a side effect
of treatment of a certified WTC-related health condition should ask
their WTC Health Program medical provider whether their endometrial
cancer might be considered a medically associated health condition.
E. Administrator's Final Decision on Whether To Propose the Addition of
Uterine Cancer, Including Endometrial Cancer, to the List
Pursuant to PHS Act, sec. 3312(a)(6)(B)(iv) and 42 CFR
88.16(a)(2)(iv), the Administrator has determined that insufficient
evidence is available to take further action at this time, including
proposing the addition of uterine cancer, including endometrial cancer,
to the List (pursuant to PHS Act, sec. 3312(a)(6)(B)(ii) and 42 CFR
88.16(a)(2)(ii)) or publishing a determination not to publish a
proposed rule in the Federal Register (pursuant to PHS Act, sec.
3312(a)(6)(B)(iii) and 42 CFR 88.16(a)(2)(iii)). The Administrator has
also determined that requesting a recommendation from the STAC
(pursuant to PHS Act, sec. 3312(a)(6)(B)(i) and 42 CFR 88.16(a)(2)(i))
is unwarranted.
For the reasons discussed above, the Petition 023 request to add
endometrial cancer to the List of WTC-Related Health Conditions is
denied.
F. Approval To Submit Document to the Office of the Federal Register
The Secretary, HHS, or his designee, the Director, Centers for
Disease Control and Prevention (CDC) and Administrator, Agency for
Toxic Substances and Disease Registry (ATSDR), authorized the
undersigned, the Administrator of the WTC Health Program, to sign and
submit the document to the Office of the Federal Register for
publication as an official document of the WTC Health Program. Robert
Redfield M.D., Director, CDC, and Administrator, ATSDR, approved this
document for publication on September 12, 2019.
John J. Howard,
Administrator, World Trade Center Health Program and Director, National
Institute for Occupational Safety and Health, Centers for Disease
Control and Prevention, Department of Health and Human Services.
[FR Doc. 2019-20364 Filed 9-23-19; 8:45 am]
BILLING CODE 4163-18-P