Rule2023-00645
World Trade Center (WTC) Health Program; Addition of Uterine Cancer to the List of WTC-Related Health Conditions
Primary source
Metadata and text below are from the Federal Register, a public-domain U.S. government work. Always verify the official published version before relying on it for any legal matter.
Published
January 18, 2023
Effective
January 18, 2023
Issuing agencies
Health and Human Services Department
Abstract
In accordance with the World Trade Center (WTC) Health Program's regulations, which establish procedures for adding a new condition to the list of covered health conditions, this final rule adds malignant neoplasms of corpus uteri and uterus, part unspecified (uterine cancer) to the List of WTC-Related Health Conditions.
Full Text
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<title>Federal Register, Volume 88 Issue 11 (Wednesday, January 18, 2023)</title>
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[Federal Register Volume 88, Number 11 (Wednesday, January 18, 2023)]
[Rules and Regulations]
[Pages 2845-2858]
From the Federal Register Online via the Government Publishing Office [<a href="http://www.gpo.gov">www.gpo.gov</a>]
[FR Doc No: 2023-00645]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
42 CFR Part 88
[Docket No. CDC-2022-0052; NIOSH-347]
RIN 0920-AA82
World Trade Center (WTC) Health Program; Addition of Uterine
Cancer to the List of WTC-Related Health Conditions
AGENCY: Centers for Disease Control and Prevention (CDC), Department of
Health and Human Services (HHS).
ACTION: Final rule.
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SUMMARY: In accordance with the World Trade Center (WTC) Health
Program's regulations, which establish procedures for adding a new
condition to the list of covered health conditions, this final rule
adds malignant neoplasms of corpus uteri and uterus, part unspecified
(uterine cancer) to the List of WTC-Related Health Conditions.
DATES: This rule is effective on January 18, 2023.
FOR FURTHER INFORMATION CONTACT: Rachel Weiss, Public Health Analyst,
National Institute for Occupational Safety and Health, 1090 Tusculum
Avenue, MS: C-46, Cincinnati, OH 45226; telephone: (404) 498-2500 (this
is not a toll-free number); email: <a href="/cdn-cgi/l/email-protection#eca2a5a3bfa49e898b9fac8f888fc28b839a"><span class="__cf_email__" data-cfemail="96d8dfd9c5dee4f3f1e5d6f5f2f5b8f1f9e0">[email protected]</span></a>.
SUPPLEMENTARY INFORMATION:
Table of Contents
I. Executive Summary
A. Purpose of Regulatory Action
B. Summary of Major Provisions
C. Costs and Benefits
II. Background
A. WTC Health Program Statutory Authority
B. Rulemaking History
C. Public Participation
D. Issuance of Final Rule With Immediate Effective Date
III. Summary of Public Comments and Independent Peer Reviews
A. Summary of Public Comments
B. Summary of Independent Peer Reviews
C. WTC Health Program Response to Public Comments
D. WTC Health Program Response to Independent Peer Reviews
E. WTC Health Program Science Team Conclusion
IV. Administrator's Final Decision Regarding Uterine Cancer
V. Summary of Final Rule
VI. Required Regulatory Analyses
A. Executive Orders 12866 and 13563
B. Regulatory Flexibility Act
C. Paperwork Reduction Act
D. Small Business Regulatory Enforcement Fairness Act
E. Unfunded Mandates Reform Act of 1995
F. Executive Order 12988 (Civil Justice)
[[Page 2846]]
G. Executive Order 13132 (Federalism)
H. Executive Order 13045 (Protection of Children From
Environmental Health Risks and Safety Risks)
I. Executive Order 13211 (Actions Concerning Regulations That
Significantly Affect Energy Supply, Distribution, or Use)
J. Plain Writing Act of 2010
I. Executive Summary
A. Purpose of Regulatory Action
In a notice of proposed rulemaking (NPRM) published in May 2022,
the Administrator of the WTC Health Program (Administrator) and the
Secretary of HHS proposed the addition of uterine cancer \1\ to the
List of WTC-Related Health Conditions (List) in 42 CFR 88.15.\2\ In
this final rule, the WTC Health Program summarizes and responds to both
independent peer reviews and public comments on the NPRM and finalizes
the addition of uterine cancer to the List.
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\1\ For the purposes of this action, the WTC Health Program
defines the term ``uterine cancer'' as ICD-10 code C54, including
the following specific malignant neoplasms: isthmus uteri (C54.0),
endometrium (C54.1), myometrium (C54.2), fundus uteri (C54.3),
overlapping sites of corpus uteri (C54.8), and corpus uteri,
unspecified (C54.9); and ICD-10 code C55, including only a single
sub-category, malignant neoplasm of uterus, part unspecified.
\2\ 87 FR 27961 (May 10, 2022).
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B. Summary of Major Provisions
This final rule adds malignant neoplasms of corpus uteri and
uterus, part unspecified (uterine cancer) to the List.
C. Costs and Benefits
The addition of uterine cancer to the List through this rulemaking
is estimated to cost the WTC Health Program between $1,706,454 and
$3,805,173 annually from 2023 through 2026. All of the costs to the WTC
Health Program are transfers.\3\ Benefits to current and future WTC
Health Program members \4\ are expected to include improved access to
care and better treatment outcomes than members would have experienced
in the absence of Program coverage.
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\3\ Due to the implementation of the Patient Protection and
Affordable Care Act in 2014, and as required under the authorizing
statute for the WTC Health Program, all current and future Program
members are assumed to have or have access to medical insurance
coverage other than through the WTC Health Program; therefore, all
projected treatment costs to be paid by the Program are considered
transfers.
\4\ Although this rulemaking refers, at times, to uterine cancer
in females, the WTC Health Program recognizes that some individuals
who identify as male also may be at risk for uterine cancer.
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The case numbers used to develop the cost estimates are,
themselves, only estimates; the certification of individual cancer
diagnoses will be conducted on a case-by-case basis, as required by the
Zadroga Act. Interested parties should visit the WTC Health Program
website for information about how to apply for enrollment in the
Program \5\ and about health condition certification.\6\
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\5\ See WTC Health Program, How to Apply web page, <a href="https://www.cdc.gov/wtc/apply.html">https://www.cdc.gov/wtc/apply.html</a>.
\6\ See WTC Health Program, ``Certifications and Covered
Conditions,'' Member Handbook, <a href="https://www.cdc.gov/wtc/handbook.html#certifications">https://www.cdc.gov/wtc/handbook.html#certifications</a>.
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II. Background
Title I of the James Zadroga 9/11 Health and Compensation Act of
2010, as amended, revised the Public Health Service Act (PHS Act) to
establish the WTC Health Program, which is administered by the National
Institute for Occupational Safety and Health (NIOSH), within CDC,
provides medical monitoring and treatment to eligible responders to the
September 11, 2001, terrorist attacks in New York City, at the
Pentagon, and in Shanksville, Pennsylvania, and to eligible survivors
of the New York City attacks. In an NPRM published in May 2022,\7\ the
Administrator of the WTC Health Program and the Secretary of HHS
proposed the addition of uterine cancer \8\ to the List of WTC-Related
Health Conditions in 42 CFR 88.15. In this final rule, the WTC Health
Program summarizes and responds to both independent peer reviews and
public comments on the NPRM and finalizes the addition of uterine
cancer to the List in Sec. 88.15(d).
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\7\ See supra note 2.
\8\ See supra note 1.
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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 and Pub. L. 116-
59), added Title XXXIII to the PHS Act \9\ establishing the WTC Health
Program within HHS. The WTC Health Program provides medical monitoring
and treatment benefits 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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\9\ Title XXXIII of the PHS Act is codified at 42 U.S.C. 300mm
to 300mm-61. Those portions of the Zadroga Act 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 in this document mean the
Director of NIOSH, within CDC, or his or her designee. Section
3312(a)(6) of the PHS Act requires the Administrator to conduct
rulemaking to propose the addition of a health condition to the List
codified in 42 CFR 88.15.
B. Rulemaking History
In 2020, the Administrator received requests from WTC responders,
survivors, and five of the WTC Health Program Clinical Centers of
Excellence (CCEs) to add ``uterine cancer'' to the List. The letter
from the CCEs raised important questions about the potential
association between endocrine disrupting chemicals (EDCs) present at
the WTC sites and uterine cancer, and noted that a previous WTC Health
Program evaluation of the evidence regarding a causal association
between endometrial cancer and 9/11 exposure did not address the
potential role of EDCs. In response to the requests, the Administrator
directed the WTC Health Program's Science Team to assess the available
scientific evidence for adding uterine cancer to the List pursuant to
the Policy and Procedures for Adding Types of Cancer to the List of
WTC-Related Health Conditions (Policy and Procedures).\10\
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\10\ WTC Health Program [Nov 2021], Policy and Procedures for
Adding Types of Cancer Conditions to the List of WTC-Related Health
Conditions, <a href="https://www.cdc.gov/wtc/pdfs/policies/WTCHP_PP_Addn_Cancer_11182021-508.pdf">https://www.cdc.gov/wtc/pdfs/policies/WTCHP_PP_Addn_Cancer_11182021-508.pdf</a>.
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The Policy and Procedures describes four methods for determining
whether to add a type of cancer to the List, summarized below:
<bullet> Method 1. Epidemiologic Studies of September 11, 2001,
Exposed Populations: A type of cancer may be added to the List if peer-
reviewed, published, epidemiologic studies of cancers in the 9/11-
exposed populations demonstrate a causal association between 9/11
exposures and that cancer.
<bullet> 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 peer-reviewed epidemiologic studies for a
causal association between a health condition already on the List and
that type of cancer.
<bullet> Method 3. Review of Evaluations of Carcinogenicity in
Humans: A type of cancer may be added to the List if a 9/11 agent \11\
included in the Inventory of
[[Page 2847]]
9/11 Agents \12\ has been determined by the National Toxicology Program
(NTP) to be a known human carcinogen or reasonably anticipated to be a
human carcinogen and the World Health Organization's International
Agency for Research on Cancer (IARC) has determined there is sufficient
or limited evidence in humans that the 9/11 agent causes that type of
cancer.
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\11\ The WTC Health Program defines 9/11 agents to mean
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 the Inventory of 9/11
Agents, infra note 12.
\12\ 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, published July 17, 2018, <a href="https://wwwn.cdc.gov/ResearchGateway/Content/pdfs/Development_of_the_Inventory_of_9-11_Agents_20180717.pdf">https://wwwn.cdc.gov/ResearchGateway/Content/pdfs/Development_of_the_Inventory_of_9-11_Agents_20180717.pdf</a>.
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<bullet> Method 4. Review of Information by the WTC Health Program
Scientific/Technical Advisory Committee (STAC): A type of cancer may be
added to the List if the STAC recommends the addition and provides a
reasonable basis for the recommendation.
The Science Team evaluated the available evidence and presented its
findings to the Administrator in a white paper (2021 White Paper) \13\
that was shared with the STAC and the public before the STAC's public
meeting on September 28-29, 2021 (see discussion below). The 2021 White
Paper concluded that insufficient evidence exists under Method 1 and
Method 3 to support a decision to add uterine cancer to the List. The
Science Team found that evidence considered under Method 2 supports the
addition of uterine cancer to the List, but only for those WTC Health
Program members who have a certified WTC-related estrogen-secreting
tumor.\14\ Finally, the 2021 White Paper included additional
information for the STAC to consider in its deliberations, conducted
pursuant to Method 4 and discussed below, including: mechanisms of
endometrial cancer development; other evidence from studies of uterine
cancer from exposure to the 9/11 agents 2,3,7,8-Tetrachlorodibenzo-p-
dioxin (TCDD), polychlorinated biphenyls, cadmium, asbestos, and
chloroethane; sex disparities in occupational cohort studies; and other
cancers causally associated with EDCs.
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\13\ The WTC Health Program released a draft of the white paper,
entitled Scientific Considerations for Potential Addition of Uterine
Cancer to the List of Covered Conditions by the World Trade Center
Health Program: Preliminary Assessment for the World Trade Center
Health Program Scientific/Technical Advisory Committee, on August
20, 2021, followed by a revised draft on September 16, 2021. The
September revision updated the August draft to include additional
information concerning 9/11 exposures and reorganized one section
for clarity but did not alter the findings or conclusions of the
August draft. The September revision was shared with the STAC and
public prior to the STAC meeting. All versions of the WTC Health
Program Science Team's white paper referenced in this final rule are
available at <a href="https://www.cdc.gov/wtc/stac_meeting.html">https://www.cdc.gov/wtc/stac_meeting.html</a> and in the
docket for this rulemaking.
\14\ The most common type of estrogen-secreting tumor are
granulosa cell tumors of the ovary. Another type of estrogen-
secreting tumor is adrenocortical cancers. The findings in the 2021
White Paper related to estrogen-secreting tumors are described in
detail in the NPRM, see 87 FR 27961, 27964.
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Pursuant to Method 4 of the Policy and Procedures, the
Administrator exercised his discretion to request a recommendation from
the STAC regarding whether the available evidence provides a reasonable
basis for adding uterine cancer to the List. The STAC held a public
meeting on September 28 and 29, 2021, during which it heard public
comments and deliberated on the evidence, including the evidence
presented in the Science Team's 2021 White Paper, and created a
workgroup to write a report describing the STAC's findings on uterine
cancer. In a subsequent public STAC meeting on November 18, 2021, the
full Committee voted unanimously to approve the workgroup report and
recommend that the Administrator add uterine cancer to the List.
In a letter received by the Administrator on November 29, 2021,\15\
the STAC formally recommended the addition of ``all types of uterine
cancer'' to the List. In its rationale, the STAC noted that the
Inventory of 9/11 Agents includes certain 9/11 agents which are
recognized as EDCs, and that EDC exposure-related imbalances in sex
steroid hormones are a ``plausible mechanism'' for the development of
uterine cancer among WTC responders and survivors. Moreover, the STAC
argued that other hormone-related cancers thought to be caused by EDC
exposure are on the List, including thyroid cancer, breast cancer,
testicular and prostate cancers, and all other female reproductive
organ cancers. Finally, the STAC commented on the likelihood that
future epidemiologic studies in the extensively studied 9/11-exposed
responder population may be unable to accurately capture uterine cancer
incidence because of the small number of female responders.
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\15\ Letter from Dr. Elizabeth Ward, Chair of the STAC, to the
Administrator, regarding the STAC's resolution on the addition of
uterine cancer to the List of WTCHP Covered Conditions, received
November 29, 2021. The letter from Dr. Ward, including the STAC's
recommendation, is available in the docket for this rulemaking and
on the WTC Health Program website, at <a href="https://www.cdc.gov/wtc/pdfs/stac/STAC.Recommendation.Received.29.November.2021.pdf">https://www.cdc.gov/wtc/pdfs/stac/STAC.Recommendation.Received.29.November.2021.pdf</a>.
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The Administrator reviewed the available body of evidence,
including the evidence presented in the Science Team's 2021 White Paper
and the STAC's comprehensive rationale and recommendation, and
concluded that the totality of the available information provided a
sufficient evidentiary basis to propose adding uterine cancer to the
List. Subsequently, the Administrator and Secretary of HHS published an
NPRM in May 2022 proposing the addition of uterine cancer to the List
in 42 CFR 88.15.\16\ The NPRM described the methodology used by the
Science Team to evaluate the scientific evidence and included a full
discussion of the Science Team's 2021 White Paper, the STAC
recommendation and rationale, and the Administrator's decision to
propose the addition of uterine cancer to the List.
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\16\ See supra note 2.
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C. Public Participation
The NPRM was published on May 10, 2022. The Administrator provided
a 45-day public comment period and invited interested persons and
organizations to submit written views, opinions, recommendations, and
data.\17\ The Administrator received 27 comments in the rulemaking
docket from the public, including current WTC Health Program members
and non-members who experienced 9/11 exposures who have or have had
uterine cancer; unaffiliated individuals; and the WTC Health Program
Survivors Steering Committee. Concurrently, as required by statute, the
Administrator solicited an assessment of the WTC Health Program's
evaluation of evidence supporting the proposal to add uterine cancer to
the List by three independent peer reviewers.\18\
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\17\ Pursuant to the Policy and Procedures, supra note 10, the
public comment period remained open for 45 days to allow the public
an additional 15 days to comment after the independent peer reviews
were posted to the docket.
\18\ See PHS Act, sec. 3312(a)(6)(F).
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Comments received from the three peer reviewers were de-identified
and compiled into one document which was published in the docket on
June 9, 2022, 30 days after the NPRM publication. This permitted the
public an additional 15 days to comment on the peer reviewers'
assessment of the proposed rulemaking. The three peer reviewers were
asked to respond to the following questions:
1. Are you aware of any other studies which should be considered?
If so, please identify them.
[[Page 2848]]
2. Have the requirements of this Policy and Procedures \19\ been
fulfilled? If not, please explain which requirements are missing or
deficient.
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\19\ See supra note 10.
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3. Is the interpretation of the available information appropriate,
and does it support the conclusion to add the health condition, as
described in the regulatory text, to the List? If not, please explain
why.
The peer reviews and public comments are found in the docket for
this rulemaking. Summaries of all peer reviews and public comments, as
well as the Administrator's responses, are found below.
D. Issuance of Final Rule With Immediate Effective Date
The Administrative Procedure Act (APA) requires the publication of
a rule ``not less than 30 days before its effective date,'' unless the
agency finds and publishes with the rule good cause for such
exception.\20\ In the context of the requirement for notice and comment
on rulemakings, the APA specifies that such procedures may be avoided
if an agency ``for good cause finds'' that ``notice and public
procedure thereon are impracticable, unnecessary, or contrary to the
public interest.'' \21\ To the extent that the same standard for
establishing ``good cause'' applies to both excepting a rulemaking from
notice and comment requirements and excepting a rulemaking from the 30-
day post-publication effective date requirement, the ``impracticable''
and ``contrary to the public interest'' prongs of the good-cause
exemption are particularly relevant to situations such as this, where
the typical delayed effective date would defer the agency's ability to
provide life-saving treatment and result in less favorable treatment
outcomes and survival rates for covered individuals.
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\20\ 5 U.S.C. 553(d).
\21\ 5 U.S.C. 553(b)(B). Courts differ on whether the good cause
standard for waiving notice and comment announced in sec. 553(b)(B)
of the APA is the same standard that should be applied in waiving
the 30-day publication rule in sec. 553(d). See Cole JP [Jan 2016],
The Good Cause Exception to Notice and Comment Rulemaking: Judicial
Review of Agency Action, Congressional Research Service, No. R44356
at 3-4 (noting that some courts have indicated that these are two
distinct standards and that the test for good cause to waive notice
and comment is more stringent than that used to waive the 30-day
rule).
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The purpose of the post-publication waiting period is to give
affected parties time to adjust their behavior before the final rule
takes effect. In this instance, however, the affected parties are
current and prospective members of the WTC Health Program who need
treatment for uterine cancer. Currently enrolled WTC Health Program
members who have already been diagnosed with uterine cancer do not
require an additional 30 days to ready themselves for implementation of
this rule; indeed, any delay in effective date could result in
postponed medical care for such members or necessitate their paying out
of pocket for care in the interim.
As discussed in the economic analysis in Section VI.A. of this
rulemaking, the WTC Health Program estimates that over 200 enrolled
members currently have uterine cancer; the Program anticipates these
members will submit requests for certification of their uterine cancers
as WTC-related as soon as the rule is issued. It is in these members'
best interest that treatment for their cancer is made available as soon
as possible. Neither these members nor the WTC Health Program require
additional time to prepare for the implementation of this rule.\22\
Treatment of cancer at the earliest stages has been shown to result in
the best outcomes and higher survival rates.\23\ As such, there is no
public interest served in further delaying the effective date of this
rulemaking.
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\22\ In anticipation of the potential addition of uterine cancer
to the List of covered health conditions, the WTC Health Program has
prepared internal procedures and has worked closely with the CCEs
and Nationwide Provider Network, the contractors tasked with
requesting cancer certifications for members where appropriate, to
ensure all parties are ready to begin processing uterine cancer
certification requests from Program physicians.
\23\ The American Cancer Society reports a 96 percent 5-year
relative survival rate for people diagnosed with uterine cancer that
is still confined to the uterus (generally considered Stage I); the
5-year survival rate drops exponentially to 20 percent for people
diagnosed with uterine cancer that has spread to distant parts of
the body (e.g., lungs, liver, or bones) (generally considered Stage
IV). See <a href="https://www.cancer.org/cancer/endometrial-cancer/detection-diagnosis-staging/survival-rates.html">https://www.cancer.org/cancer/endometrial-cancer/detection-diagnosis-staging/survival-rates.html</a>.
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For the forgoing reasons, the Administrator and the Secretary of
HHS find that good cause exists to make this rulemaking effective
immediately on publication.
III. Summary of Public Comments and Independent Peer Reviews
The WTC Health Program has considered whether the public comments
and the peer reviews of the evidence comprising the basis for the
proposed rulemaking warrant any revision to the findings and
determinations described in the NPRM. The public comments and the
independent peer reviews are summarized below, followed by the WTC
Health Program's response.
A. Summary of Public Comments
Twenty-seven public commenters submitted comments to the docket for
this rulemaking. Twenty-six expressed unequivocal agreement with the
addition of uterine cancer to the List. One commenter expressed
displeasure with the WTC Health Program's process for adding health
conditions to the List; that comment is outside the scope of this
rulemaking and is not further addressed.
Of the 26 supportive public comments, one asked that the
Administrator also consider adding fibroid tumors, endometriosis, and
infertility to the List. Another of the supportive comments described
concerns with inequities in the WTC Health Program's research agenda,
faulting the Program for ``routinely pass[ing] over'' research
proposals to study survivor cohorts. These comments are also outside
the scope of this rulemaking but are discussed further below.
No public commenter suggested additional references to scientific
evidence regarding causes of uterine cancer, nor did any commenter
indicate that there were any flaws in the WTC Health Program's
evaluation of the available evidence or the Administrator's
determination.
B. Summary of Independent Peer Reviews
The de-identified peer reviewers were labelled as Reviewer A,
Reviewer B, and Reviewer C; their reviews of the content of the NPRM
are summarized below.
Question 1: Are you aware of any other studies which should be
considered? If so, please identify them.
Reviewer A suggested that a study by Curtis et al. [2019] \24\
should be included in the evaluation.
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\24\ Curtis S.W., Cobb D.O., Kilaru V., Terrell M.L., Kennedy
E.M., Marder M.E., Barr D.B., Marsit C.J., Marcus M., Conneely K.N.,
Smith A.K. [2019], Exposure to Polybrominated Biphenyl (PBB)
Associates with Genome-Wide DNA Methylation Differences in
Peripheral Blood, Epigenetics 14(1):52-66.
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Reviewer B was not aware of any ``additional epidemiology studies
that should have been considered using Method 1,'' nor any other
studies using Method 2. Reviewer B described two concerns with the WTC
Health Program's analysis of evidence pursuant to Method 3 of the
Policy and Procedures. First, Reviewer B stated that the Science Team
did not consider the Endocrine Society's definition of EDCs (``an
exogenous chemical, or mixture of chemicals, that interferes with any
aspect of hormone action'') and noted that the list of EDCs found in
the
[[Page 2849]]
Inventory of 9/11 Agents ``is almost certainly incomplete.'' According
to the reviewer, the WTC Health Program should have evaluated several
other EDCs in the Inventory, including but not limited to
benzo[a]pyrene, carbazole, chlordane, chromium, dibenzofuran, dieldrin,
endosulfan, heptachlor, mirex, and oxychlordane. Second, Reviewer B
found some of the references cited in the 2021 White Paper concerning
U.S. Environmental Protection Agency (EPA) determinations of
carcinogenicity to be too dated to be authoritative. Reviewer B
ultimately found that the STAC's conclusions, pursuant to its review
under Method 4, are supported by a ``large body of evidence.''
Finally, Reviewer C also indicated that the Method 3 review in the
2021 White Paper does not include EDCs that have ``estrogenic
activity,'' but are not carcinogens, including: polyvinyl chloride,
trichloroethylene, TCDD, and some pesticides. Reviewer C provided
references to support that assertion and also asked that the WTC Health
Program add a discussion of studies demonstrating the association
between EDCs and uterine hyperplasia and other alterations to the
uterine lining that may have a causal relationship with uterine cancer.
The reviewer found the assertion in the 2021 White Paper that ``[n]one
of the 9/11 Agents identified as EDCs have been found by NTP, IARC, or
EPA to be known to cause or be reasonably anticipated to cause uterine
cancer'' to be misleading because (1) the exposures studied by these
organizations may not be comparable to the extensive exposures
experienced by WTC responders and survivors; (2) the reviews conducted
by NTP, IARC, and EPA are often outdated; and (3) many studies have
been conducted in male mice, precluding examination of uterine cancer.
Finally, Reviewer C indicated that ``women's health and women's health
related cancers have been under examined and grossly understudied,''
and offered a reference \25\ to demonstrate that breast and ovarian
cancer are associated with EDCs and that the mechanisms of action
through which EDCs can impair endocrine system function and cause those
cancers are similar to the known causes of uterine cancer.
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\25\ Racho[nacute] D. [2015], Endocrine Disrupting Chemicals
(EDCs) and Female Cancer: Informing the Patients, Rev Endocr Metab
Disord 16:359-364.
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Question 2: Have the requirements of this Policy and Procedures
been fulfilled? If not, please explain which requirements are missing
or deficient.
All three peer reviewers found that the WTC Health Program's
scientific evaluation and proposed rulemaking fulfilled the
requirements in the Policy and Procedures.
Question 3: Is the interpretation of the available information
appropriate, and does it support the conclusion to add the health
condition, as described in the regulatory text, to the List? If not,
please explain why.
Reviewer A agreed that it was appropriate for the Administrator
``to use Method 4 of the Policy and Procedures to include uterine
cancer.'' Reviewer A argued, however, that the WTC Health Program
should consider the addition of uterine cancer to the List pursuant to
Method 2, based on the association of uterine cancer with estrogen-
secreting tumors, which may themselves be associated with EDCs.
Reviewer A also pointed to their own research on polybrominated
biphenyl, a type of flame retardant, which is similar to a chemical
found at the WTC site and shows ``considerable overlap with endogenous
estrogen.''
Reviewer B stated that they believed the rationale used by the
Administrator to support the addition of uterine cancer to the List was
sound.
Reviewer C agreed that the interpretation of the available
information was appropriate but thought that ``some important evidence
of risk factors for developing uterine cancer were under identified.''
Reviewer C suggested EDCs and other toxins contained in WTC dust may
lead to risk factors that, in turn, may lead to uterine cancer.
C. WTC Health Program Response to Public Comments
The WTC Health Program finds that the comment regarding the
addition of other female reproductive health conditions (i.e., fibroid
tumors, endometriosis, and infertility) to the List to be outside the
scope of this rulemaking, which only contemplates the sufficiency of
the scientific evidence for the addition of uterine cancer to the List.
Although the comment about purported inequities in the WTC Health
Program research agenda is also outside the scope of the rulemaking,
the Administrator notes that the Program continually evaluates its
research priorities and is committed to funding research that includes
all 9/11-exposed populations. The WTC Health Program manages and
solicits research on a broad range of health conditions related to the
9/11-exposed population of workers and community members, including
health conditions among women, members of minority groups, and persons
exposed as children. With input from researchers and community members,
the WTC Health Program monitors the progress of each award cycle and
adjusts solicitations as needed to promote an appropriate balance of
health conditions and exposure cohorts.\26\ All extramural research
funded by grant or cooperative agreement is awarded under a competitive
process following the widely accepted National Institutes of Health
framework.\27\ Each research proposal is rigorously reviewed by an
independent panel of experts and is subsequently scored according to
its merits, including aims that address health equity. The research
portfolio has been and continues to be the product of the quantity and
quality of the proposed research.\28\
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\26\ For example, a multi-year WTC survivor-only research
solicitation was initiated in the most recent cycle in response to
concerns raised by community members. See <a href="https://grants.nih.gov/grants/guide/rfa-files/RFA-OH-22-004.html">https://grants.nih.gov/grants/guide/rfa-files/RFA-OH-22-004.html</a>.
\27\ All WTC Health Program extramural research grant and
cooperative agreement applications accepted for funding
consideration: (1) are evaluated for scientific and technical merit
by appropriate Scientific Review Group(s) convened by CDC/NIOSH in
accordance with CDC peer review policy and procedures (<a href="http://www.cdc.gov/os/quality/support/peer-review.htm">www.cdc.gov/os/quality/support/peer-review.htm</a>), the HHS Grant Policy Statement
(<a href="http://www.hhs.gov/sites/default/files/grants/grants/policies-regulations/hhsgps107.pdf">www.hhs.gov/sites/default/files/grants/grants/policies-regulations/hhsgps107.pdf</a>), and specific guidance contained in published
research funding opportunity announcements (FOAs); (2) receive a
second level of review for programmatic relevance and balance by a
WTC Health Program Secondary Review Committee; and (3) compete for
available funds with all other recommended applications submitted in
response to an FOA. Additional information on the peer review
process used can be found at <a href="https://grants.nih.gov/grants/peer-review.htm">https://grants.nih.gov/grants/peer-review.htm</a>.
\28\ For more information about the WTC Health Program's
research priorities, see <a href="https://wwwn.cdc.gov/ResearchGateway">https://wwwn.cdc.gov/ResearchGateway</a>.
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The public comments were overwhelmingly supportive of the proposal
to add uterine cancer to the List. Moreover, public commenters did not
suggest any additional references or identify concerns with the
evaluation of evidence presented in the NPRM or the Administrator's
determination. Therefore, there are no changes to this rulemaking as a
result of the public comments.
D. WTC Health Program Response to Independent Peer Reviews
The WTC Health Program has considered the independent peer reviews
of the scientific and technical evidence presented in the NPRM. The
peer reviewers favored the addition of uterine cancer to the List and
offered supplemental evidence in support of the addition. Many of the
reviewers' suggestions for improving the Program's evaluation of the
evidence supporting the addition of uterine cancer to the List
[[Page 2850]]
were compelling. As a result, the Science Team has revised and
finalized the White Paper (final White Paper) to address the peer
reviewers' suggestions.\29\ The final White Paper is included in the
docket for this rulemaking. The WTC Health Program's evaluation of the
supplemental evidence provided by the peer reviewers is discussed
below.
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\29\ Following review of public comments and peer reviews on the
May 2022 NPRM, the WTC Health Program Science Team revised the 2021
White Paper twice. In an August 2022 revision of the white paper,
the Science Team added the definition of EDC by the Endocrine
Society and a reference to the Society's position statement on EDCs;
revised Table 3 to include an additional 84 agents, mixtures, and
categories of agents known and potential EDCs; and to exclude the
EPA classifications of carcinogenicity found in the earlier drafts.
In January 2023, the white paper was finalized and retitled
Scientific Considerations for Addition of Uterine Cancer to the List
of Covered Conditions by the World Trade Center Health Program:
Final Assessment and Follow-Up to November 18, 2021, Scientific/
Technical Advisory Committee (STAC) Meeting. In the final White
Paper, the Science Team revised Table 3 to sort the 9/11 agents,
mixtures, and categories in alphabetical order; revised the section
named ``WTC Health Program's Actions after Receipt of the STAC
Recommendation'' to clarify that the Administrator initiated this
rulemaking to add uterine cancer to the List in response to the STAC
recommendation; and added an appendix reflecting the discussion
about mechanisms of endocrine disruption in the preamble of this
rulemaking. Both the August 2022 revision and the January 2023 final
White Paper are available at <a href="https://www.cdc.gov/wtc/stac_meeting.html">https://www.cdc.gov/wtc/stac_meeting.html</a> and in the docket for this rulemaking.
---------------------------------------------------------------------------
Endocrine Disrupting 9/11 Agents
Upon careful evaluation of the information provided by all three
reviewers in response to Question 1, the WTC Health Program has found
that the scientific analysis described in the NPRM did not fully
capture all of the 9/11 agents identified in the Inventory of 9/11
Agents that are known or potential endocrine disruptors. Accordingly,
the Science Team has reevaluated whether the 9/11 agents that are
included as known or potential EDCs in Table 3 of the 2021 White Paper
\30\ was comprehensive or if additional 9/11 agents may also be
considered known and potential EDCs. Following the reevaluation, the
Science Team concluded that 9/11 agents beyond those listed in the 2021
White Paper, might also exhibit endocrine disrupting properties. The
Science Team's process and conclusion are described below.
---------------------------------------------------------------------------
\30\ Table 3 includes a list of substances in the Inventory of
9/11 Agents that are known and potential endocrine disruptors and
their reported carcinogenicity by authoritative bodies.
---------------------------------------------------------------------------
In the absence of an internationally harmonized list of known and
potential EDCs, the Science Team has evaluated 9/11 agents by comparing
each 9/11 agent listed in the Inventory to publicly available lists of
known and potential endocrine disruptors. Comparison lists included the
following:
<bullet> The Endocrine Disruptor Lists published by the national
authorities in six European Union (EU) member countries: List of
Substances Identified as Endocrine Disruptors at EU Level, the List of
Substances Under Evaluation for Endocrine Disruption Under an EU
Legislation, and the List of Substances Considered, by the Evaluating
National Authority, to Have Endocrine Disrupting Properties,\31\ which
altogether identify 194 chemicals recognized as known or potential
endocrine disruptors. The EU lists are updated at least bi-annually and
were most recently updated in June 2022.
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\31\ The Endocrine Disruptor Lists are compiled by the national
authorities of Belgium, Denmark, France, The Netherlands, Sweden,
and Spain. See <a href="https://edlists.org/">https://edlists.org/</a>.
---------------------------------------------------------------------------
<bullet> The United Nations Environment Programme's List of
Identified Endocrine Disrupting Chemicals,\32\ which identifies 45
chemical substances as endocrine disruptors and was last updated in
July 2017.
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\32\ United Nations Environment Programme, International Panel
on Chemical Pollution [2017], Worldwide Initiatives to Identify
Endocrine Disrupting Chemicals (EDCs) and Potential EDCs, <a href="https://wedocs.unep.org/bitstream/handle/20.500.11822/25633/EDC_report1.pdf?sequence=1&isAllowed=y">https://wedocs.unep.org/bitstream/handle/20.500.11822/25633/EDC_report1.pdf?sequence=1&isAllowed=y</a>.
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<bullet> The Endocrine Disruption Exchange's List of Potential
Endocrine Disruptors, a master list of 1,482 chemicals with at least
one study demonstrating endocrine disrupting properties, last updated
in September 2018.\33\
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\33\ The Endocrine Disruption Exchange (TEDX), <a href="https://endocrinedisruption.org/interactive-tools/tedx-list-of-potential-endocrine-disruptors/search-the-tedx-list">https://endocrinedisruption.org/interactive-tools/tedx-list-of-potential-endocrine-disruptors/search-the-tedx-list</a>.
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<bullet> The SIN (Substitute It Now) List developed by the non-
profit International Chemical Secretariat (ChemSec).\34\ ChemSec
recommends ceasing use of 32 EDCs on the SIN List, last updated in
2014, because of their threat to human health and the environment.
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\34\ The International Chemical Secretariat, Endocrine
Disrupting Chemicals, <a href="https://sinlist.chemsec.org/endocrine-disruptors/">https://sinlist.chemsec.org/endocrine-disruptors/</a>.
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As a result of this reevaluation, the Science Team has concluded
that additional 9/11 agents and categories of 9/11 agents should be
added to the 9/11 agents and categories previously listed in Table 3 of
the 2021 White Paper as known or potential EDCs. Accordingly, Table 3
of the final White Paper now includes 136 individual 9/11 agents, one
mixture (diesel exhaust), and 10 categories of 9/11 agents that may be
evaluated as a group.
Of the 9/11 agents and categories of 9/11 agents that are now
included in Table 3 and recognized by the WTC Health Program as known
or potential EDCs, 78 have been evaluated by IARC for carcinogenicity.
EDC 9/11 agents have been classified by IARC as follows:
<bullet> 12 EDC 9/11 agents and categories as carcinogenic to
humans (Group 1),
<bullet> 8 EDC 9/11 agents and categories as probably carcinogenic
to humans (Group 2A),
<bullet> 20 EDC 9/11 agents and categories as possibly carcinogenic
to humans (Group 2B), and
<bullet> 38 EDC 9/11 agents and categories as not classifiable as
to carcinogenicity to humans (Group 3).
The remainder--55 individual EDC 9/11 agents and three categories--
have not been evaluated by IARC.\35\ NTP classifies seven EDC 9/11
agents and categories as known to be human carcinogens and 23 EDC 9/11
agents and categories as reasonably anticipated to be human
carcinogens; \36\ the rest of the EDCs--101 individual 9/11 agents and
5 categories--have not been evaluated by NTP. For each cancer site,
IARC identifies chemical, physical, and biological entities or exposure
circumstances with sufficient or limited evidence of carcinogenicity in
humans. IARC does not identify any EDC 9/11 agents, categories, or any
other hazard included in the Inventory of 9/11 Agents as having
sufficient or limited evidence in humans of causing cancer in the
uterus.\37\
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\35\ World Health Organization, International Agency for
Research on Cancer (IARC), List of Classifications; Agents
Classified by the IARC Monographs, Volumes 1-132, <a href="https://monographs.iarc.who.int/list-of-classifications">https://monographs.iarc.who.int/list-of-classifications</a>. Last visited August
22, 2022.
\36\ National Toxicology Program (NTP), HHS, 15th Report on
Carcinogens, <a href="https://ntp.niehs.nih.gov/go/roc15">https://ntp.niehs.nih.gov/go/roc15</a>. Last visited August
22, 2022.
\37\ World Health Organization, International Agency for
Research on Cancer (IARC), List of Classifications by Cancer Sites
with Sufficient or Limited Evidence in Humans, IARC Monographs,
Volumes 1-132, <a href="https://monographs.iarc.who.int/wp-content/uploads/2019/07/Classifications_by_cancer_site.pdf">https://monographs.iarc.who.int/wp-content/uploads/2019/07/Classifications_by_cancer_site.pdf</a>. Last visited September
15, 2022.
---------------------------------------------------------------------------
The Science Team also has acknowledged Reviewer B's concerns that
the EPA classifications of carcinogenicity are not always up to date
and should not be relied upon for current scientific knowledge. Some
EPA evaluations of the carcinogenicity of 9/11 agents in the Inventory
were conducted decades ago (e.g., evaluations for phthalates such as
benzyl butyl phthalates and dibutyl phthalate were last updated between
1987 and 1990) and some assessments are currently in development (e.g.,
chloroform, chromium, cobalt, formaldehyde, mercury, naphthalene,
[[Page 2851]]
perfluorodecanoic acid, perfluorohexanesulfonic acid, polychlorinated
biphenyls, uranium, and vanadium).\38\ Additionally, the Science Team
has found that use of EPA references may be confusing since they are
not required for review under any of the methods in the Policy and
Procedures discussed above. To address these concerns, the Science Team
has decided to remove the EPA carcinogenicity classification column
from Table 3 of the final White Paper.
---------------------------------------------------------------------------
\38\ See U.S. Environmental Protection Agency (EPA), Integrated
Risk Information System (IRIS) Assessments, <a href="https://iris.epa.gov/AtoZ/?list_type=erd">https://iris.epa.gov/AtoZ/?list_type=erd</a>.
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Mechanisms of Endocrine Disruption
The Science Team also has evaluated the references provided by peer
reviewers to supplement the STAC's discussion of some potential
mechanisms of action \39\ through which EDCs might cause uterine cancer
in humans. Much of the available research on EDCs' mechanisms of action
has focused on EDCs which are not also identified 9/11 agents in the
Inventory of 9/11 Agents. Indeed, some of the specific chemicals and
toxins identified as EDCs by the peer reviewers based on supplemental
sources have not been identified by the WTC Health Program as 9/11
agents. The Science Team has recognized, however, that the list of 9/11
agents identified by the WTC Health Program in the Inventory may not be
complete and that WTC-related uterine cancer may be associated with
chemicals and toxins that exhibit estrogenic properties that may be
identified as 9/11 agents in the future. Regardless of whether there
are EDCs that may be associated with uterine cancer that may be added
to the Inventory in the future, the Science Team has found it
instructive to examine mechanisms of action for endocrine disruption
even for those EDCs that have not been recognized as 9/11 agents. The
supplemental references' descriptions of mechanisms of endocrine
disruption illustrate the various ways in which exposure to EDCs could
impact the female reproductive system and result in uterine cancer. The
similar mechanisms of action for other EDCs help provide a complete
picture of the possible causal relationship between the September 11,
2001, terrorist attacks, and uterine cancer among WTC responders and
survivors.\40\
---------------------------------------------------------------------------
\39\ Mechanisms of action are the biochemical processes
underlying the adverse response to exposure; these processes may
lead to risk factors for or development of disease, such as cancer.
\40\ The EDCs discussed in this section include:
<bullet> 9/11 agents: 2,4-dichlorodiphenyltrichloroethane (DDT);
polyvinyl chloride plastics (which contain phthalates);
trichloroethylene (and its major metabolites); TCDD; chlordane;
dieldrin; endosulfan; hexachlorobenzene (HCB); lindane; heptachlor;
metribuzin; mirex; cadmium; and WTC dust.
<bullet> Non-9/11 agents: alkylphenols (e.g., nonylphenol and
oxylphenol); bisphenol A (BPA); di(2-ethylhexyl)phthalate (DEHP);
and polybrominated biphenyl (PBB).
---------------------------------------------------------------------------
Most endometrial tumors are hormonally driven through estrogen
signaling via estrogen receptors [alpha] and [beta] acting as an
oncogenic signal. The main risk factors (i.e., estrogen therapy without
progestins, tamoxifen for the treatment of breast cancer, parity, oral
contraceptive use, age at menarche) and some treatment options (i.e.,
progestin therapies) for endometrial cancer patients underscore a key
role for estrogen signaling in the disease.\41\ Estrogen-like chemicals
have been shown to mimic the estrogen pathway and affect the normal
function of female sex hormones. This mechanism is suspected to lead to
carcinogenesis in women, including the development of endometrial
cancer, breast and ovarian cancers, and prostate cancer in men.\42\
EDCs can interfere with the function and metabolism of estrogen; breast
and ovarian cancers are associated with EDCs and their current known
mechanisms of action are similar to those of uterine cancer.\43\ For
example, experimental studies in animals exposed to endocrine-
disrupting alkylphenols such as nonylphenol and oxylphenol, as well as
a case-control study, suggest an association between exposure to EDCs
and endometrial cancer.\44\ Experimental animal and in vitro studies
have shown that exposure to the EDCs bisphenol A (BPA) and 2,4-
dichlorodiphenyltrichloroethane (DDT) result in changes that could lead
endometrial cells towards malignancy.\45\
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\41\ Rodriguez AC, Blanchard Z, Maurer KA, Gertz J [2019],
Estrogen Signaling in Endometrial Cancer: A Key Oncogenic Pathway
with Several Open Questions, Horm Cancer 10(2-3), 51-63.
\42\ Deroo BJ, Korach KS [2006], Estrogen Receptors and Human
Disease, J Clin Invest 116(3):561-570.
\43\ See supra note 26.
\44\ Zhang W, Yang J, Wang J, Xia P, Xu Y, Jia H, Chen Y [2007],
Comparative Studies on the Increase of Uterine Weight and Related
Mechanisms of Cadmium and p-Nonylphenol, Toxicology 241(1-2):84-91;
Kim J, Cha S, Lee MY, Hwang YJ, Yang E, Ryou C, Jung HI, Cheon YP
[2018], Chronic Low-Dose Nonylphenol or Di-(2-ethylhexyl) Phthalate
Has a Different Estrogen-Like Response in Mouse Uterus, Dev Reprod
22(4):379-391; Wen HJ, Chang TC, Ding WH, Tsai SF, Hsiung CA, Wang
SL [2020], Exposure to Endocrine Disruptor Alkylphenols and the
Occurrence of Endometrial Cancer, Environ Pollut 267:115475.
\45\ Scsukova S, Rollerovab E, Mlynarcikovaa AB [2016], Impact
of Endocrine Disrupting Chemicals on Onset and Development of Female
Reproductive Disorders and Hormone-Related Cancer, Reprod Biol
16:243-254.
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Studies in animal models show that exposure to some EDCs can cause
endometrial hyperplasia (a proliferation of endometrial glands) and
other alterations to the uterine lining.\46\ Endometrial hyperplasia
with atypia is of clinical significance because it may progress to, or
coexist with, endometrial carcinoma. However, no human studies that
showed an association between EDCs and endometrial hyperplasia were
identified. Nonetheless, experimental animal studies have identified
some evidence that suggests the likelihood of occurrence in humans.
---------------------------------------------------------------------------
\46\ Singh P, Bhartiya D [2022], Molecular Insights into
Endometrial Cancer in Mice, Stem Cell Rev Rep 18(5):1702-1717;
Guerrero Schimpf M, Milesi MM, Zanardi MV, Varayoud J [2022],
Disruption of Developmental Programming with Long-Term Consequences
after Exposure to a Glyphosate-Based Herbicide in a Rat Model, Food
Chem Toxicol 159:112695; Neff AM, Blanco SC, Flaws JA, Bagchi IC,
Bagchi MK [2019], Chronic Exposure of Mice to Bisphenol-A Alters
Uterine Fibroblast Growth Factor Signaling and Leads to Aberrant
Epithelial Proliferation, Endocrinology 160(5):1234-1246; Nasiadek
M, Danilewicz M, Sitarek K, [Sacute]wi[aogon]tkowska E,
Darag[oacute] A, Stragierowicz J, Kilanowicz A [2018], The Effect of
Repeated Cadmium Oral Exposure on the Level of Sex Hormones, Estrous
Cyclicity, and Endometrium Morphometry in Female Rats, Environ Sci
Pollut Res Int 25(28):28025-28038; Padmanabhan R, Hendry IR, Knapp
JR, Shuai Bin, Hendry WJ [2017], Altered MicroRNA Expression
Patterns During the Initiation and Promotion Stages of Neonatal
Diethylstilbestrol-Induced Dysplasia/Neoplasia in the Hamster
(Mesocricetus auratus) Uterus, Cell Biol Toxicol 33(5):483-500;
Wikoff DS, Rager JE, Haws LC, Borghoff SJ [2016], A High Dose Mode
of Action for Tetrabromobisphenol A-Induced Uterine Adenocarcinomas
in Wistar Han Rats: A Critical Evaluation of Key Events in an
Adverse Outcome Pathway Framework, Regul Toxicol Pharmacol 77:143-
159; Hendry WJ, Hariri HY, Alwis ID, Gunewardena SS, Hendry IR
[2014], Altered Gene Expression Patterns During the Initiation and
Promotion Stages of Neonatally Diethylstilbestrol-Induced
Hyperplasia/Dysplasia/Neoplasia in the Hamster Uterus, Reprod
Toxicol 50:68-86.
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EDCs such as di(2-ethylhexyl)phthalate (DEHP) and cadmium have also
been associated with uterine leiomyoma (a benign smooth muscle tumor,
also known as a fibroid, that causes symptoms such as uterine bleeding
and severe pelvic pain, which may result in infertility or major
surgery). A meta-analysis of five studies showed that urinary DEHP
metabolites were statistically significantly associated with an
increased risk of uterine leiomyoma, although the mechanism is still
not well understood.\47\ Moreover, an in vitro study showed that
fibroid cells subjected to cadmium exposure for two months show
enhanced migration potential, augmented anchorage-independent growth,
and increased
[[Page 2852]]
DNA synthesis, suggesting EDC-induced potential progression towards
uterine cancer.\48\
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\47\ Fu, Z, Zhao F, Chen K, Xu J, Li P, Xia D, Wu Y [2017],
Association Between Urinary Phthalate Metabolites and Risk of Breast
Cancer and Uterine Leiomyoma, Reprod Toxicol 74:134-142.
\48\ Yan Y, Liu J, Lawrence A, Dykstra MJ, Fannin R, Gerrish K,
Tucker CJ, Scappini E, Dixon D [2021], Prolonged Cadmium Exposure
Alters Benign Uterine Fibroid Cell Behavior, Extracellular Matrix
Components, and TGFB Signaling, FASEB J 35(8):e21738.
---------------------------------------------------------------------------
In addition to interacting with estrogen receptors [alpha] and
[beta], EDCs are known to bind to and activate the estrogen-related
receptor gamma (ERR[gamma]). BPA has weak estrogenic activity due to
its limited capacity to bind to nuclear estrogen receptors [alpha] and
[beta]. Nonetheless, ERR[gamma] is activated by BPA and interacts with
the ligand domain of estrogen receptors.\49\ Multiple studies show that
BPA may increase the risk of estrogen-related cancers.\50\
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\49\ Hwang KA, Choi KC [2015], Chapter One: Endocrine-Disrupting
Chemicals with Estrogenicity Posing the Risk of Cancer Progression
in Estrogen-Responsive Organs, in Advances in Molecular Toxicology,
Volume 9, (Fishbein JC and Heilman JM, eds., Elsevier).
\50\ Soto AM, Sonnenschein C [2010], Environmental Causes of
Cancer: Endocrine Disruptors as Carcinogens, Nat Rev Endocrinol
6(7):363-370.
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EDCs are also known to play a role in endocrine disruption leading
to epigenetic \51\ changes. An instructive example is a study among
Michigan residents accidentally exposed to the EDC polybrominated
biphenyl (PBB). The study's authors found differences in epigenetic
marks (chemicals which turn genes ``on'' and ``off'') that suggest that
PBB acts similarly to estrogen and is associated with dysregulated
immune system pathways. The authors also found evidence that PBB could
be acting like an estrogen, impacting gene expression.\52\ Furthermore,
EDCs may increase uterine sensitivity to estrogens due to epigenetic
alterations. Another example is a study in female mice in which BPA
administered in utero increased the expression of the developmental
homeobox gene Hoxa10 that controls uterine organogenesis. Alterations
in methylation of Hoxa10 have been associated with several human
cancers.\53\
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\51\ Changes in gene expression caused by environmental factors
that do not involve alteration of the DNA sequence.
\52\ Curtis SW, Cobb DO, Kilaru V, Terrell ML, Kennedy EM,
Marder ME, Barr DB, Marsit CJ, Marcus M, Conneely KN, Smith AK
[2019], Exposure to Polybrominated Biphenyl (PBB) Associates with
Genome-Wide DNA Methylation Differences in Peripheral Blood,
Epigenetics 14(1):52-66.
\53\ See Scsukova S, et al., supra note 46; Bromer JG, Zhou Y,
Taylor MB, Doherty L, Taylor HS [2010], Bisphenol-A Exposure in
Utero Leads to Epigenetic Alterations in the Developmental
Programming of Uterine Estrogen Response, FASEB J 24:2273-2280.
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In addition, endocrine disruption caused by some 9/11 agents alters
reproductive and sexual development, and may lead to other health
outcomes such as obesity and diabetes that affect the risk of uterine
cancer development.\54\ The following identified EDC 9/11 agents may
pose such risks for the development of uterine cancer: polyvinyl
chloride plastics, which contain phthalates; \55\ trichloroethylene and
its major metabolites; \56\ TCDD, which is an EDC that has
antiestrogenic properties; \57\ and pesticides such as chlordane, DDT,
dieldrin, endosulfan, hexachlorobenzene, lindane, heptachlor,
metribuzin, and mirex.\58\
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\54\ Eales J, Bethel A, Galloway T, Hopkinson P, Morrissey K,
Short RE, Garside R [2022], Human Health Impacts of Exposure to
Phthalate Plasticizers: An Overview of Reviews, Environ Int
158:106903.
\55\ Ohashi A, Kotera H, Hori H, Hibiya M, Watanabe K, Murakami
K, Hasegawa M, Tomita M, Hiki Y, Sugiyama S [2005], Evaluation of
Endocrine Disrupting Activity of Plasticizers in Polyvinyl Chloride
Tubes by Estrogen Receptor Alpha Binding Assay, J Artif Organs
8(4):252; Bang DY, Kyung M, Kim MJ, Jung BY, Cho MC, Choi SM, Kim
YW, Lim SK, Lim DS, Won AJ, Kwack SJ, Lee Y, Kim HS, Lee BM [2012],
Human Risk Assessment of Endocrine-Disrupting Chemicals Derived from
Plastic Food Containers, Compr Rev Food Sci Food Saf 11:453-70; Yan
Y, Zhu F, Zhu C, Chen Z, Liu S, Wang C, Gu C [2021], Dibutyl
Phthalate Release from Polyvinyl Chloride Microplastics: Influence
of Plastic Properties and Environmental Factors, Water Res
204:117597; Mariana M, Feiteiro J, Verde I, Cairrao E [2016], The
Effects of Phthalates in the Cardiovascular and Reproductive
Systems: A Review, Environ Int 94:758-776.
\56\ Tachachartvanich P, Sangsuwan R, Ruiz HS, Sanchez SS,
Durkin KA, Zhang L, Smith MT [2018], Assessment of the Endocrine-
Disrupting Effects of Trichloroethylene and its Metabolites Using In
Vitro and In Silico Approaches, Environ Sci Technol 52(3):1542-1550.
\57\ Boverhof DR, Kwekel JC, Humes DG, Burgoon LD, Zacharewski
TR [2006], Dioxin Induces an Estrogen-Like, Estrogen Receptor-
Dependent Gene Expression Response in the Murine Uterus, Mol
Pharmacol 69(5):1599-1606.
\58\ Mnif W, Hassine AI, Bouaziz A, Bartegi A, Thomas O, Roig B
[2011], Effect of Endocrine Disruptor Pesticides: A Review, Int J
Environ Res Public Health 8(6):2265-303.
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Finally, the development of most endocrine cancers is likely to be
the result of low-dose exposures to complex chemical mixtures in the
environment throughout a person's life.\59\ WTC dust is a complex
mixture of EDCs and other environmental chemicals. Exposure to WTC
dust, when added to the usual low-dose environmental chemical exposures
experienced in a person's lifetime, may directly or indirectly
influence the development of uterine cancer. Combined exposures have
simultaneous effects on the endocrine system that could affect the
development of uterine cancer and its risk factors.\60\
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\59\ Darbre PD [2022], Chapter 8: Exposure to Mixtures of EDCs
and Long-Term Effects, in Endocrine Disruption and Human Health
(Darbre PD, ed., Elsevier, 2nd ed.).
\60\ See supra note 26.
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E. WTC Health Program Science Team Conclusion
In response to the peer reviews, the Science Team has updated its
analysis and issued the final White Paper \61\ including the Endocrine
Society's definition of EDC and a reference to the Society's position
statement on EDCs; the final White Paper recognizes 84 additional 9/11
agents in the Inventory of 9/11 Agents as known or potential EDCs in
Table 3. The Science Team has also clarified in the final White Paper
that among all 9/11 agents that are known or potential EDCs and that
have been evaluated for their carcinogenicity by NTP and IARC, none are
currently known to cause or reasonably anticipated to cause uterine
cancer. Finally, the Science Team has modified the final White Paper to
incorporate an appendix reflecting the discussion about mechanisms of
endocrine disruption in this preamble.
---------------------------------------------------------------------------
\61\ See supra note 30.
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The evidence provided by independent peer reviewers is compelling.
However, the additional information does not alter the evaluations and
conclusions found in the Science Team's final White Paper because the
scope of the White Paper was limited to an assessment of the evidence
for adding uterine cancer to the List based on Methods 1-3 of the
Policy and Procedures described above. The peer reviewers did not
suggest any epidemiologic studies of uterine cancer in the 9/11-exposed
population; therefore, no further analysis was conducted under Method
1. No studies were suggested to demonstrate support for a causal
association between a health condition already on the List and uterine
cancer; therefore, no further analysis was conducted under Method 2.
Finally, Method 3 relies on: (1) an NTP finding that the 9/11 agent is
known or reasonably anticipated to be a human carcinogen, and (2) an
IARC finding that there is sufficient or limited evidence in humans
that the 9/11 agent causes that cancer. Although some of the 9/11
agents identified as known or potential EDCs that have been added to
Table 3 of the final White Paper are considered by NTP to be known
human carcinogens or reasonably anticipated to be human carcinogens,
IARC has not determined that there is sufficient or limited evidence in
humans that any 9/11 agent EDC or any other hazard in the Inventory
causes uterine cancer. Therefore, the Science Team has continued to
find that there is insufficient evidence available to
[[Page 2853]]
support the addition of uterine cancer to the List pursuant to Method
3.
For the reasons discussed above, the Science Team's analysis and
conclusion are unchanged: there continues to be no evidence to support
the addition of uterine cancer to the List pursuant to Methods 1 or 3,
but sufficient evidence supports the addition of uterine cancer to the
List for qualified WTC Health Program members, pursuant to Method 2
(i.e., only for those Program members who have a certified WTC-related
estrogen-secreting tumor). However, the Science Team has found that the
evaluations and supplemental information provided by the peer reviewers
in response to the NPRM provide additional support for the STAC
recommendation and rationale provided to the Administrator under Method
4.
IV. Administrator's Final Decision Regarding Uterine Cancer
The Administrator and Secretary of HHS proposed the addition of
uterine cancer \62\ to the List after reviewing the available body of
scientific evidence describing the causal relationship between 9/11
exposures and uterine cancer, including certain 9/11 agents which are
known or potential EDCs, as well as evaluating the STAC's comprehensive
rationale and recommendation. In accordance with the WTC Health
Program's Policy and Procedures, the Administrator evaluated the
available information under the four methods developed for determining
whether to add a type of cancer to the List. The Administrator's
evaluation was discussed in full in Section III.E. of the NPRM.\63\
During the NPRM public comment period, 26 public commenters and three
independent peer reviewers expressed unanimous support for the addition
of uterine cancer to the List based on the STAC's recommendation. Peer
reviewers found that the totality of evidence points to a causal
association between 9/11 agents that are known or potential EDCs and
uterine cancer in the 9/11-exposed population.
---------------------------------------------------------------------------
\62\ ICD-10 codes C54 and C55. See supra note 1.
\63\ Supra note 2 at 27966.
---------------------------------------------------------------------------
The Administrator considered the public comments and peer reviews
as well as the Science Team's description and evaluation of the
supplemental evidence regarding mechanisms by which EDCs could affect
the development of uterine cancer and its risk factors. First, the
Administrator assessed whether there was sufficient evidence in peer-
reviewed, published, epidemiologic studies of 9/11-exposed populations
to support adding uterine cancer to the List under Method 1. The
Administrator concurred with the Science Team's evaluation of the
literature pursuant to Method 1 and found that the available literature
did not provide sufficient support for the addition of uterine cancer
to the List under Method 1. Because no peer-reviewed, published,
epidemiologic studies of uterine cancer in 9/11-exposed populations
were identified by peer reviewers or public commenters, the
Administrator has determined that the evidence available under Method 1
is insufficient to support the addition of uterine cancer to the List.
Next, the Administrator reviewed whether multiple peer-reviewed
epidemiologic studies establish a causal association between a
condition already on the List and that type of cancer to permit an
addition to the List under Method 2. In the NPRM, the Administrator
agreed with the Science Team's finding that there is evidence of a
causal association between estrogen-secreting tumors, which are
considered rare cancers within the WTC Health Program, and uterine
cancer. Thus, the Administrator found that uterine cancer may be
proposed for addition to the List pursuant to Method 2, but such an
addition would be limited to only those WTC Health Program members who
have a certified WTC-related estrogen-secreting tumor. Neither peer
reviewers nor public commenters provided studies refuting a causal
association between estrogen-secreting tumors and uterine cancer.
Therefore, the Administrator has determined that uterine cancer may be
added to the List pursuant to Method 2, but only for those WTC Health
Program members with a qualifying certified WTC-related estrogen-
secreting tumor.
Pursuant to Method 3, the Administrator examined NTP and IARC
evaluations of carcinogenicity of 9/11 agents. Method 3 permits an
addition to the List if: (1) NTP has determined that a specific 9/11
agent is known to be a human carcinogen or reasonably anticipated to be
a human carcinogen, and (2) IARC has determined that there is
sufficient or limited evidence in humans that the 9/11 agent causes
uterine cancer. As described in the NPRM, the Administrator concurred
with the Science Team's conclusion that there was insufficient evidence
to add uterine cancer to the List because IARC has not determined there
is sufficient or even limited evidence in humans that any of the 9/11
agents in the Inventory of 9/11 Agents cause uterine cancer. Following
publication of the NPRM, the Administrator also reviewed the 9/11
agents added to the list of EDCs in Table 3 of the final White Paper in
response to the peer reviews. He agrees that 9/11 agents that are
considered by NTP to be known or reasonably anticipated human
carcinogens but that are not determined by IARC to have sufficient or
limited evidence of uterine carcinogenicity in humans do not meet the
requirements of Method 3. Because IARC has not identified any EDCs
among the 136 EDC 9/11 agents and categories of EDC 9/11 agents now
recognized in Table 3 of the final White Paper, nor any other hazard
included in the Inventory as having sufficient or limited evidence in
humans of uterine carcinogenicity, the Science Team's analysis and the
Administrator's determination remains unchanged. Accordingly, the
Administrator has determined that the evidence available under Method 3
is insufficient to support the addition of uterine cancer to the List
but acknowledges that some 9/11 agents in the Inventory have never been
evaluated for carcinogenicity by NTP or IARC.
The Administrator ultimately proposed adding uterine cancer to the
List pursuant to Method 4, which permits an addition where the STAC
recommends such an addition and provides a reasonable basis for the
recommendation. As explained in the NPRM, the Administrator found that
the STAC's recommendation provided a reasonable basis for the addition
of uterine cancer under Method 4 and the recommendation was further
supported by the supplemental information presented by the Science Team
in the 2021 White Paper.
Specifically, the Administrator agreed with the STAC that
mechanisms of initiation and progression of uterine cancer are similar
to those for several other cancers on the List.\64\ The Administrator
agreed with the STAC's finding that the shared etiology and
pathogenesis described in the scientific literature suggest it would be
unlikely that uterine cancer would be the only cancer type not related
to 9/11 exposures. The Administrator also agreed that an association
between exposure to EDCs in WTC dust and uterine cancer risk is
plausible.\65\
---------------------------------------------------------------------------
\64\ See supra note 2 at 27966 and supra note 15.
\65\ See supra note 2 at 27967 and supra note 15.
---------------------------------------------------------------------------
Following publication of the NPRM and upon review of the public
comments and peer reviews and the Science Team's response, including
the final White Paper, the Administrator has found that the
supplemental scientific evidence complements the evidence provided by
the STAC by comprehensively demonstrating the variety of mechanisms of
endocrine disruption and providing additional general support for the
addition of
[[Page 2854]]
uterine cancer to the List. Given the growing body of scientific
evidence suggesting that exposure to EDCs may be a risk factor for
female reproductive organ cancers, the Administrator has found that it
is reasonable to assume that exposure to EDCs in WTC dust may
contribute to uterine cancer risk, even in the absence of a robust body
of evidence conclusively demonstrating EDC carcinogenic risks in
occupational cohorts of women. The Administrator continues to recognize
that the disproportionally low representation of women in the most
studied cohorts of exposed responders makes it epidemiologically
unlikely that a definitive association between 9/11 exposures and the
occurrence of uterine cancer will be identified during the lifetime of
even the most highly exposed WTC Health Program members.\66\
---------------------------------------------------------------------------
\66\ Id.
---------------------------------------------------------------------------
After final review of the analyses by the STAC in its
recommendation, the WTC Health Program Science Team's 2021 White Paper,
public comments on the NPRM, the independent peer reviews of the
scientific and technical evidence comprising the basis for the proposed
rule, the Science Team's response to those comments, and the final
White Paper, the Administrator has concluded that evidence continues to
support the addition of uterine cancer to the List. For the reasons
discussed above, the Administrator has determined that there is
insufficient evidence to add uterine cancer to the List pursuant to
Methods 1 and 3 of the Policy and Procedures. Sufficient evidence
exists for the addition of uterine cancer pursuant to Method 2,
restricted to those members who have a qualifying estrogen-secreting
tumor. Finally, pursuant to Method 4, because the STAC provided a
reasonable basis for an association between 9/11 agents listed in the
Inventory of 9/11 Agents and uterine cancer, the Administrator has
determined that there is sufficient evidence to add uterine cancer to
the List for all eligible members.
With this rulemaking, the Administrator and the Secretary of HHS
finalize the addition of uterine cancer to the List of WTC-Related
Health Conditions. Adding uterine cancer to the List in a final rule
with an immediate effective date allows the WTC Health Program to begin
offering treatment services as soon as possible to members whose
uterine cancers are certified as WTC-related.
V. Summary of Final Rule
For the reasons discussed above, the Administrator amends 42 CFR
88.15 by adding a new paragraph (d)(15) to include ``malignant
neoplasms of corpus uteri and uterus, part unspecified'' \67\ on the
List of WTC-Related Health Conditions. The existing paragraph (d)(15)--
malignant neoplasm of the ovary--and the remainder of the cancer types
identified in existing paragraphs (d)(16) through (24)--rare cancers--
are renumbered paragraphs (d)(16) through (25), accordingly. Finally,
in renumbered paragraphs (d)(24) and (d)(25), the terms ``Childhood
cancers'' and ``Rare cancers'' are unitalicized but are otherwise
unchanged.
---------------------------------------------------------------------------
\67\ See supra note 1.
---------------------------------------------------------------------------
In addition to the changes described above, the Authority citation
for part 88 is revised to remove the Public Law citations, retaining
only the U.S. Code citations.
VI. Required Regulatory Analyses
A. Executive Order 12866 (Regulatory Planning and Review) and Executive
Order 13563 (Improving Regulation and Regulatory Review)
Executive Orders (E.O.) 12866 and 13563 direct agencies to assess
all costs and benefits of available regulatory alternatives and, if
regulation is necessary, to select regulatory approaches that maximize
net benefits (including potential economic, environmental, public
health and safety effects, distributive impacts, and equity). E.O.
13563 emphasizes the importance of quantifying both costs and benefits,
reducing costs, harmonizing rules, and promoting flexibility.
This final rule has been determined not to be a significant
regulatory action under section 3(f) of E.O. 12866, and therefore has
not been reviewed by the Office of Management and Budget (OMB). The
addition of uterine cancer finalized by this rulemaking is estimated to
cost the WTC Health Program between $1,706,454 and $3,805,173 per annum
for 2023 through 2026.\68\ All costs to the WTC Health Program will be
transfers due to the implementation of provisions of the Patient
Protection and Affordable Care Act (Pub. L. 111-148) in 2014 and as
required under the authorizing statute for the WTC Health Program.\69\
The rule will not interfere with state, local, or tribal governments in
the exercise of their governmental functions.
---------------------------------------------------------------------------
\68\ As discussed in this section, NIOSH estimated lower-and
upper-bound estimates to reflect the uncertainty in the Agency's
ability to predict the expected number of cancer cases in the three
years after this rulemaking. The lower-bound reflects the general
U.S. population cancer rate and uses undiscounted costs for 2023 and
costs for 2024-2026 discounted at the 7 percent discount rate. The
upper-bound reflects the estimated rate of uterine cancer among
existing WTC Health Program members and uses undiscounted rates for
2023 and costs for 2024-2026 discounted at the 3 percent discount
rate. Although, if added to the List, uterine cancer would be
considered a covered condition for the duration of the WTC Health
Program (currently authorized through FY 2090). The dates 2023-2026
were chosen to provide a snapshot of uterine cancer costs in the
coming years.
\69\ Because sec. 3331(c)(3) of the PHS Act requires WTC Health
Program members to maintain minimum essential insurance coverage,
all treatment costs to be paid by the WTC Health Program are
considered transfers.
---------------------------------------------------------------------------
Population Estimates
The WTC Health Program estimates that approximately 84,000 WTC
responders and approximately 34,000 survivors, or approximately 118,000
individuals in total, are current, living Program members. Of that
total population, approximately 60,000 individuals were participants in
previous WTC medical programs and were enrolled as ``legacy'' members
in the WTC Health Program established by Title XXXIII of the PHS Act.
For the purpose of calculating a baseline estimate of cancer prevalence
only, the Administrator assumed that a steady rate of enrollment would
continue, based on the trend in enrollees through September 2021.
According to WTC Health Program data, 12 percent of the current
responder members (approximately 10,000 individuals) and 50 percent of
survivor members (approximately 17,000 individuals) are female.\70\
Finally, because there are no existing data on cancer cases related to
9/11 exposures at either the Pentagon or in Shanksville, Pennsylvania,
the Administrator has used only data from studies of individuals who
were responders or survivors in the New York City disaster area.
---------------------------------------------------------------------------
\70\ See supra note 4.
---------------------------------------------------------------------------
Cost of Uterine Cancer Treatment
The Administrator estimated the treatment costs associated with
covering uterine cancer in this rulemaking in U.S. dollars. The costs
of treatment are divided into three treatment phases: the first year of
treatment following diagnosis; the intervening years or continuing
treatment after the first year; and treatment during the last year of
life. The first-year costs of cancer treatment are higher due to the
initial need for aggressive medical (e.g., radiation or chemotherapy)
and surgical care. The costs during the last year of life are often
dominated by increased hospitalization costs.\71\ Therefore, three
[[Page 2855]]
different treatment phase costs were used to provide a best estimate of
treatment costs in conjunction with expected incidence and long-term
survival rates for uterine cancer. Average 2022 treatment costs for
uterine cancer, the last year for which complete data were available,
are in Table A below.
---------------------------------------------------------------------------
\71\ Yabroff KR, Lamont EB, Mariotto A, Warren JL, Topor M,
Meekins A, Brown ML [2008], Cost of Care for Elderly Cancer Patients
in the United States, J Natl Cancer Inst 100(9):630-41.
Table A--Average Costs of Treatment for Uterine Cancer, 2022 Dollars
------------------------------------------------------------------------
Average
cost
Stage of treatment (U.S.
dollars)
------------------------------------------------------------------------
Initial (first 12 months after diagnosis).................... $41,283
Continuing (annual).......................................... 2,152
Last year of life (last 12 months of life)................... 122,954
------------------------------------------------------------------------
These cost figures were based on a study of cancer patients from
the Surveillance, Epidemiology, and End Results (SEER) Program
maintained by the National Cancer Institute and using Medicare
files.\72\ The average costs of treatment described above are given in
2022 prices, adjusted using the Medical Consumer Price Index for all
urban consumers.\73\
---------------------------------------------------------------------------
\72\ National Cancer Institute, Surveillance, Epidemiology, and
End Results (SEER) Program, SEER*Stat Database: Incidence--SEER
Research Data, 9 Registries, Nov 2020 Submission (1975-2018),
released Apr 2021, <a href="http://www.seer.cancer.gov">www.seer.cancer.gov</a>. Although patients who are
Medicare members are age 65 and older, cancer treatment costs are
not expected to vary with age.
\73\ Bureau of Labor Statistics, Consumer Price Index, <a href="https://www.bls.gov/cpi/data.htm">https://www.bls.gov/cpi/data.htm</a>. Accessed on November 10, 2022.
---------------------------------------------------------------------------
Incident Cases of Cancer
For the purpose of illustrating a lower-bound incidence estimate,
the Administrator used the same baseline analysis described in the
NPRM, calculating the number of cases of uterine cancer expected to be
observed in the cohort of approximately 27,000 female responders and
survivors in the WTC Health Program, based on U.S. population cancer
rates.\74\ Demographic characteristics of the cohort were assigned
since the actual data are not available for individuals in the
responder and survivor populations who have not yet enrolled in the WTC
Health Program. Sex and age (at the time of exposure) distributions for
responders and survivors were assumed to be the same as current members
in the WTC Health Program. Because uterine cancer occurs only in
females,\75\ all calculations only consider female WTC Health Program
members.
---------------------------------------------------------------------------
\74\ See supra note 2 at 27968.
\75\ See supra note 4.
---------------------------------------------------------------------------
The Administrator assumed race and ethnic origin distributions for
responders and survivors, respectively, according to distributions in
the WTC Health Registry cohort: \76\ 57 percent non-Hispanic white, 15
percent non-Hispanic black, 20 percent Hispanic, and 8 percent other
race/ethnicity for responders; 50 percent non-Hispanic white, 17
percent non-Hispanic black, 15 percent Hispanic, and 18 percent other
race/ethnicity for survivors. Registry follow-up for cancer morbidity
for each person began on January 1, 2002, or at age 15 years, whichever
occurred later. Age 15 was used because the cancer incidence rate file
did not include rates for persons of less than 15 years of age. Follow-
up ended on December 31, 2016, or the estimated last year of life,
whichever was earlier. The estimated last year of life was used since
not all persons would be expected to remain alive at the end of 2016.
The estimated last year of life was based on sex, race, age, and year-
specific death rates from CDC WONDER.\77\ A life-table analysis
program, LTAS.NET, was used to estimate the expected number of incident
cancers for uterine cancer.\78\ The Administrator calculated cancer
incidence rates using data through 2018 from the SEER Program and
estimated uterine cancer incidence in the WTC Health Program for 2002-
2026.\79\ The resulting sex, race, age, and year-specific cancer
incidence rates were applied to the estimated person-years at risk to
estimate the expected number of cancer cases for uterine cancer
starting from year 2002, the first full year following the September
11, 2001, terrorist attacks, to 2026.
---------------------------------------------------------------------------
\76\ Jordan H.T., Brackbill R.M., Cone J.E., Debchoudhury I.,
Farfel M.R., Greene C.M., Hadler J.L., 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 378:879-887. Note:
percentages may not sum to 100 percent due to rounding.
\77\ Centers for Disease Control and Prevention, National Center
for Health Statistics, Compressed Mortality File 1999-2016 on CDC
WONDER Online Database, released June 2017. Data are from the
Compressed Mortality File 1999-2016 Series 20 No. 2U, 2016, as
compiled from data provided by the 57 vital statistics jurisdictions
through the Vital Statistics Cooperative Program. <a href="http://wonder.cdc.gov/cmf-icd10.html">http://wonder.cdc.gov/cmf-icd10.html</a>. Accessed May 29, 2021.
\78\ Schubauer-Berigan M.K., Hein M.J., Raudabaugh W.M., Ruder
A.M., Silver S.R., Spaeth S., Steenland K., Petersen M.R., and
Waters K.M. [2011], Update of the NIOSH Life Table Analysis System:
A Person-Years Analysis program for the Windows Computing
Environment, Am J Ind Med 54:915-924.
\79\ See supra note 73.
---------------------------------------------------------------------------
For the purpose of illustrating an upper-bound incidence estimate,
the Administrator reviewed WTC Health Program records and Program Data
Center monitoring exam questionnaires to identify self-reported uterine
cancer diagnoses among current members. The Administrator found 254
self-reports of uterine cancer among members who filled out monitoring
exam questionnaires from January 2013 to November 2022; of those
members, 11 are now deceased. The limitations associated with the
review of WTC Health Program data are that some of the reported cases
of uterine cancer may have been diagnosed prior to 2001 and some
members may have mistakenly self-reported uterine cancer. The
Administrator calculated a WTC Health Program uterine cancer incidence
rate based on the January 2013-November 2022 WTC Health Program data
and used that rate to estimate incidence of uterine cancer among
Program members for 2023 through 2026.
These case numbers are offered as estimates only; the certification
of individual cancer diagnoses will be conducted on a case-by-case
basis, as required by the Zadroga Act.\80\ Please see the WTC Health
Program website for information about how to apply for enrollment in
the Program \81\ and about health condition certification.\82\
---------------------------------------------------------------------------
\80\ See supra note 9.
\81\ See WTC Health Program, How to Apply web page, <a href="https://www.cdc.gov/wtc/apply.html">https://www.cdc.gov/wtc/apply.html</a>.
\82\ See WTC Health Program, ``Certifications and Covered
Conditions,'' Member Handbook, <a href="https://www.cdc.gov/wtc/handbook.html#certifications">https://www.cdc.gov/wtc/handbook.html#certifications</a>.
---------------------------------------------------------------------------
Prevalence of Cancer
To determine the potential number of persons in the responder and
survivor populations with cancer, the Administrator conducted two
different analyses for the purposes of illustrating lower- and upper-
bound cost estimates.
As discussed above and in the NPRM, for the lower-bound, baseline
analysis, the Administrator used the number of incident uterine cancer
cases expected, based on U.S. population rates, for each year starting
with 2002 and estimated the prevalence of uterine cancer using SEER
survival rate statistics for corpus uteri through 2026.\83\ Using the
incident cases and survival rate statistics, the Administrator
estimated the lower-bound prevalence (number of persons living with
cancer) of cases during the 23-year period (2002-2026) since September
11, 2001. The resulting Table B summarizes those results for each year
from 2023 through 2026, the number of new cases estimated to have
occurred in that year (incidence), the number of persons surviving up
to 23 years beyond their first diagnosis (prevalence), and
[[Page 2856]]
the number of individuals who might be expected to have died from their
cancer in that year.\84\
---------------------------------------------------------------------------
\83\ See supra note 73.
\84\ The 23-year survival limit is imposed based on the analytic
time horizon.
---------------------------------------------------------------------------
For the upper-bound estimate, the Administrator used the incidence
rate calculated based on a review of data from the WTC Health Program
and the Program Data Centers of self-reported uterine cancer diagnoses
among current members, discussed above, and SEER survival rate
statistics for corpus uteri to estimate uterine cancer prevalence
during the 4-year period from 2023 through 2026.\85\ The resulting
Table C summarizes those results for each year from 2023 through 2026,
including the number of new cases estimated to have occurred in each
year, the number of persons surviving beyond their first diagnosis, and
the number of individuals who might be expected to have died from their
cancer in each year.
---------------------------------------------------------------------------
\85\ See supra note 73.
Table B--Estimated Incidence and Prevalence of Uterine Cancer; U.S. Population Cancer Rates Among ~27,000 WTC
Health Program Members
[2023-2026]
----------------------------------------------------------------------------------------------------------------
2023 2024 2025 2026
----------------------------------------------------------------------------------------------------------------
Vital status:
New cases............................................... 17.87 18.13 18.22 18.30
Live cases from previous years.......................... 85.50 87.58 89.50 91.08
Deaths.................................................. 15.27 15.79 16.41 16.44
---------------------------------------------------
Total new and live cases............................ 103.37 105.71 107.72 109.38
----------------------------------------------------------------------------------------------------------------
Table C--Estimated Incidence and Prevalence of Uterine Cancer; WTC Health Program Rates Among ~27,000 WTC Health
Program Members
[2023-2026{time}
----------------------------------------------------------------------------------------------------------------
2023 2024 2025 2026
----------------------------------------------------------------------------------------------------------------
Vital status:
New cases............................................... 243 25.84 30.90 31.90
Live cases from previous years.......................... n/a 266.54 296.09 326.52
Deaths.................................................. 1.07 1.23 1.35 1.47
---------------------------------------------------
Total new and live cases............................ 244.07 293.61 328.34 359.89
----------------------------------------------------------------------------------------------------------------
Cost Computation
To compute the lower-bound costs for uterine cancer, the
Administrator assumed that the rate of uterine cancer in the WTC Health
Program is equal to the rate of uterine cancer in the U.S. population.
The treatment costs for the first year of treatment (Table A, year
adjusted) were applied to the predicted newly incident (Year 1) cases
for each year (see Table B). Likewise, the costs of treatment for the
last year of life were applied in each year to the number of people
predicted to die from their cancer in that year. The costs of
continuing treatment from Table A were applied to the number of
individuals who had survived their cancers beyond their year of
diagnosis, for each year of survival (years two to four). Because some
of the members estimated to be living with uterine cancer may not meet
the WTC Health Program's exposure \86\ and latency \87\ requirements as
necessary for certification, the Administrator assumed that 11 percent
of uterine cancer certification requests will not be approved.\88\
Costs for future years are discounted at both seven percent and three
percent to reflect net present value.\89\
---------------------------------------------------------------------------
\86\ See WTC Health Program [Feb 2015], Policy and Procedures
for Certification of Physician Determinations for Aerodigestive and
Cancer Health Conditions, <a href="https://www.cdc.gov/wtc/pdfs/policies/WTCHPPPCertPhysDetFINAL20Feb2015-508.pdf">https://www.cdc.gov/wtc/pdfs/policies/WTCHPPPCertPhysDetFINAL20Feb2015-508.pdf</a>.
\87\ The minimum latency requirement for all solid cancers,
including uterine cancer, is 4 years after first 9/11 exposure. See
WTC Health Program [Jan 2015], Minimum Latency & Types or Categories
of Cancer, <a href="https://www.cdc.gov/wtc/pdfs/policies/WTCHP-Minimum-Cancer-Latency-PP-01062015-508.pdf">https://www.cdc.gov/wtc/pdfs/policies/WTCHP-Minimum-Cancer-Latency-PP-01062015-508.pdf</a>.
\88\ The 89 percent certification approval rate is based on
historic WTC Health Program data.
\89\ See OMB Circular A-94, Guidelines and Discount Rates for
Benefit-Cost Analysis of Federal Programs, <a href="https://obamawhitehouse.archives.gov/sites/default/files/omb/assets/a94/a094.pdf">https://obamawhitehouse.archives.gov/sites/default/files/omb/assets/a94/a094.pdf</a>.
---------------------------------------------------------------------------
To compute the upper-bound costs, the Administrator assumed that
cases of uterine cancer in the WTC Health Program will continue to
increase at the WTC Health Program incidence rate derived from self-
reported uterine cancer diagnoses. He further assumed that 243 cases of
uterine cancer in 2023 will be considered ``new'' and certified by the
WTC Health Program for treatment and monitoring and that every new case
in 2023 will incur first-year costs (see Table A) because no
information is available about the stage of treatment for each Program
member who has reported a uterine cancer diagnosis. For treatment costs
in future years, the Administrator applied the same formula as above
for the lower-bound estimate and assumed that 11 percent of uterine
cancer certification requests will not be granted.
The sum of the annual costs in the table for the years 2023 through
2026 represents the estimated treatment costs to the WTC Health Program
for coverage of uterine cancer for the 12 percent of approximately
84,000 WTC responders who are female and the 50 percent of
approximately 34,000 WTC survivors who are female.
Summary of Costs
Because HHS lacks data to account for recoupment from workers'
compensation insurance or primary payment by either private health
insurance or Medicare/Medicaid payments specific to uterine cancer, the
estimates offered here are reflective of estimated WTC Health Program
costs only and assume the Program is the primary payer. This analysis
offers assumptions about the number of
[[Page 2857]]
current and future WTC Health Program members who are and will likely
be diagnosed with uterine cancer and have their certification requests
granted, to provide a conservative estimate of treatment costs to the
WTC Health Program. The U.S. population average uterine cancer rate is
used to identify a baseline number of expected cases among WTC Health
Program members for the lower bound; an upper-bound estimate was based
on a review of the number of WTC Health Program members who self-
reported uterine cancer diagnoses in questionnaires completed from
January 2013 to November 2022. This analysis does not include
administrative costs associated with certifying additional WTC-related
uterine cancers that might result from this action.
Since the implementation of provisions of the Patient Protection
and Affordable Care Act on January 1, 2014, all members and future
members are assumed to have or have access to medical insurance
coverage other than through the WTC Health Program.\90\ Therefore, all
treatment costs to be paid by the WTC Health Program from 2023 through
2026 are considered transfers.
---------------------------------------------------------------------------
\90\ Sec. 3331(c)(3) of the PHS Act requires WTC Health Program
members to maintain minimum essential insurance coverage.
Table D--Medical Treatment Costs for Certified Uterine Cancer Cases During 2023-2026, 2022 Dollars
----------------------------------------------------------------------------------------------------------------
----------------------------------------------------------------------------------------------------------------
2023 Costs, undiscounted 2024-2026 Costs,* 2024-2026 Costs, 3%
7% discount rate discount rate
----------------------------------------------------------------------------------------------------------------
Cancer rate
Cancer rate
----------------------------------------------------------------------------------------------------------------
U.S. average WTCHP average U.S. average WTCHP average
----------------------------------------------------------------------------------------------------------------
Total................... $1,785,423 $9,508,626 $5,040,394 $5,712,066
----------------------------------------------------------------------------------------------------------------
* Since this table summarizes the lowest and highest cost estimates for treatment of uterine cancer, values
representing 2024-2026 costs at the 7% discount rate and at the increased cancer rate and 2024-2026 costs at
the 3% discount rate and at the U.S. population average rate were not included.
The Administrator found the total cost estimate range--$1,706,454
to $3,805,173 annually--by adding the low estimate for 2023, $1,785,423
(U.S. cancer rate average), and the low 2024-2026 estimate in Table D,
$5,040,394 (7 percent discount rate, U.S. cancer rate average, 89
percent certification rate), and dividing the sum by four to find the
annual low-cost estimate (i.e., $1,706,454). The same calculation was
done for the annual high-cost estimates, adding the high estimate for
2023, $9,508,626.20 (WTC Health Program average uterine cancer rate),
to the high 2024 through 2026 estimate, $5,712,066 (3 percent discount
rate, WTC Health Program average uterine cancer rate, 89 percent
certification rate), and dividing the sum by four (i.e., $3,805,173).
Examination of Benefits (Health Impact)
This section qualitatively describes the potential benefits of this
rulemaking to add uterine cancer to the List in terms of the expected
improvements in the health and health-related quality of life of
potential uterine cancer patients treated through the WTC Health
Program, compared to not conducting the rulemaking.
The Administrator does not have information on the health of the
population that may have experienced 9/11 exposures and is not
currently enrolled in the WTC Health Program. In addition, the
Administrator has only limited information about health insurance and
healthcare services available for cases of uterine cancer potentially
caused by 9/11 exposures and suffered by any population of responders
and survivors, among responders and survivors both currently enrolled
in the WTC Health Program and those who are not enrolled. For the
purposes of this analysis, the Administrator assumed that all
unenrolled responders and survivors are now covered by health insurance
due to access provided by the Patient Protection and Affordable Care
Act and may be receiving treatment outside the WTC Health Program.
Although the Administrator cannot quantify the benefits associated
with the WTC Health Program, members with certified WTC-related uterine
cancer are expected to experience better treatment outcomes with WTC
Health Program physicians as compared to receiving care outside of the
WTC Health Program. A recent study found that ``WTC-exposed responder
cancer patients enrolled in the Fire Department of the city of New York
Clinical Center of Excellence or in the General Responder Cohort had
higher survival rates compared with those not so enrolled.'' \91\
Moreover, under other insurance plans, patients would likely have
deductibles and copays, which impact access to care and, particularly,
its timeliness.\92\ WTC Health Program members have first-dollar
coverage and hence are likely to seek care sooner, when indicated,
resulting in improved treatment outcomes.
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\91\ Goldfarb D.G., Zeig-Owens R., Kristjansson D., Li J.,
Brackbill R.M., Farfel M.R., Cone J.E., Kahn A.R., Qiao B., Schymura
M.J., Webber M.P., Dasaro C.R., Lucchini R.G., Todd A.C., Prezant
D.J., Hall C.B., Boffetta P. [2021], Cancer Survival among World
Trade Center Rescue and Recovery Workers: A Collaborative Cohort
Study, Am J Ind Med 64(10):815-826.
\92\ Wharam J.F., Galbraith A.A., Kleinman K.P., Soumerai S.B.,
Ross-Degnan D., Landon B.E. [2008], Cancer Screening before and
after Switching to a High-Deductible Health Plan, Ann Intern Med
148(9):647-655.
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Finally, during public meetings, WTC Health Program members have
expressed that the lack of social and clinical support, and lack of
recognition that their diagnosed uterine cancer is a WTC-related health
condition, have had a significant negative impact on their morale and
quality of life.
Limitations
The analysis presented here was limited by the dearth of verifiable
data on the uterine cancer status of responders and survivors who have
yet to apply for enrollment in the WTC Health Program. Because of the
limited data, the Administrator is not able to estimate benefits in
terms of averted healthcare costs; nor is the Administrator able to
estimate administrative costs, or indirect costs, such as averted
absenteeism, short- and long-term disability, and productivity losses
averted due to premature mortality.
B. Regulatory Flexibility Act
The Regulatory Flexibility Act (RFA), 5 U.S.C. 601 et seq.,
requires each agency to consider the potential impact of its
regulations on small entities, including small businesses, small
governmental units, and small not-for-
[[Page 2858]]
profit organizations. The Administrator certifies that this final rule
has ``no significant economic impact upon a substantial number of small
entities'' within the meaning of the RFA.
C. Paperwork Reduction Act
The Paperwork Reduction Act (PRA), 44 U.S.C. 3501 et seq., requires
an agency to invite public comment on, and to obtain OMB approval of,
any regulation that requires 10 or more people to report information to
the agency or to keep certain records. The Administrator has determined
that this rulemaking does not contain any new information collection
requirements or recordkeeping requirements; thus, the PRA does not
apply to this rulemaking. Data collection and recordkeeping
requirements for the WTC Health Program are approved by OMB under
``World Trade Center Health Program Enrollment, Appeals &
Reimbursement'' (OMB Control No. 0920-0891, exp. September 30, 2025).
D. Small Business Regulatory Enforcement Fairness Act
As required by Congress under the Small Business Regulatory
Enforcement Fairness Act of 1996, 5 U.S.C. 801 et seq., HHS will report
the promulgation of this rule to Congress prior to its effective date.
E. Unfunded Mandates Reform Act of 1995
Title II of the Unfunded Mandates Reform Act of 1995, 2 U.S.C. 1531
et seq., directs agencies to assess the effects of Federal regulatory
actions on state, local, and tribal governments, and the private sector
``other than to the extent that such regulations incorporate
requirements specifically set forth in law.'' For purposes of the
Unfunded Mandates Reform Act, this final rule does not include any
Federal mandate that may result in increased annual expenditures in
excess of $100 million in 1995 dollars by state, local, or tribal
governments in the aggregate, or by the private sector.
F. Executive Order 12988 (Civil Justice)
This final rule has been drafted and reviewed in accordance with
Executive Order 12988, ``Civil Justice Reform,'' and will not unduly
burden the Federal court system. This rule has been reviewed carefully
to eliminate drafting errors and ambiguities.
G. Executive Order 13132 (Federalism)
The Administrator has reviewed this final rule in accordance with
Executive Order 13132 regarding federalism and has determined that it
does not have ``Federalism implications.'' The rule does not ``have
substantial direct effects on the states, on the relationship between
the national government and the states, or on the distribution of power
and responsibilities among the various levels of government.''
H. Executive Order 13045 (Protection of Children From Environmental
Health Risks and Safety Risks)
In accordance with Executive Order 13045, the Administrator has
evaluated the environmental health and safety effects of this final
rule on children. The Administrator has determined that the rule will
have no environmental health and safety effect on children.
I. Executive Order 13211 (Actions Concerning Regulations That
Significantly Affect Energy Supply, Distribution, or Use)
In accordance with Executive Order 13211, the Administrator has
evaluated the effects of this final rule on energy supply,
distribution, or use, and has determined that the rule will not have a
significant adverse effect.
J. Plain Writing Act of 2010
Under Public Law 111-274 (October 13, 2010), Executive Departments
and Agencies are required to use plain language in documents that
explain to the public how to comply with a requirement the Federal
Government administers or enforces. The Administrator has attempted to
use plain language in promulgating the final rule consistent with the
Federal Plain Writing Act guidelines.
List of Subjects in 42 CFR Part 88
Aerodigestive disorders, Appeal procedures, Cancer, Healthcare,
Mental health conditions, Musculoskeletal disorders, Respiratory and
pulmonary diseases.
For the reasons discussed in the preamble, the Administrator and
HHS Secretary amend 42 CFR part 88 as follows:
PART 88--WORLD TRADE CENTER HEALTH PROGRAM
0
1. The authority citation for part 88 is revised to read as follows:
Authority: 42 U.S.C. 300mm to 300mm-61.
0
2. Amend Sec. 88.15 as follows:
0
a. Redesignate paragraphs (d)(15) through (24) as paragraphs (d)(16)
through (25).
0
b. Add new paragraph (d)(15).
0
c. In newly redesignated paragraph (d)(24), remove ``Childhood
cancers:'' and add ``Childhood cancers:'' in its place.
0
d. In newly redesignated paragraph (d)(25), remove ``Rare cancers:''
and add ``Rare cancers:'' in its place.
The addition reads as follows:
Sec. 88.15 List of WTC-Related Health Conditions.
* * * * *
(d) * * *
(15) Malignant neoplasms of corpus uteri and uterus, part
unspecified.
* * * * *
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.
Xavier Becerra,
Secretary, Department of Health and Human Services.
[FR Doc. 2023-00645 Filed 1-17-23; 8:45 am]
BILLING CODE 4163-18-P
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</html>Indexed from Federal Register on January 18, 2023.
This is legal information, not legal advice. Laws vary by jurisdiction and change frequently. Always verify current law with official sources and consult a licensed attorney in your jurisdiction for advice on your specific situation.