[Federal Register Volume 87, Number 127 (Tuesday, July 5, 2022)]
[Notices]
[Pages 39892-39894]
[FR Doc No: 2022-14226]

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DEPARTMENT OF TRANSPORTATION

Federal Motor Carrier Safety Administration

[Docket No. FMCSA-2022-0083]

Qualification of Drivers; Exemption Applications; Implantable
Cardioverter Defibrillator (ICD)

AGENCY: Federal Motor Carrier Safety Administration (FMCSA), Department
of Transportation (DOT).

ACTION: Notice of denials.

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SUMMARY: FMCSA announces its decision to deny the applications from

three individuals treated with an ICD who requested an exemption from
the Federal Motor Carrier Safety Regulations (FMCSRs) prohibiting
operation of a commercial motor vehicle (CMV) in interstate commerce by
persons with a current clinical diagnosis of myocardial infarction,
angina pectoris, coronary insufficiency, thrombosis, or any other
cardiovascular disease of a variety known to be accompanied by syncope
(transient loss of consciousness), dyspnea (shortness of breath),
collapse, or congestive heart failure.

FOR FURTHER INFORMATION CONTACT: Ms. Christine A. Hydock, Chief,
Medical Programs Division,<PHONE_NUMBER>, [email protected], FMCSA,
DOT, 1200 New Jersey Avenue SE, Room W64-224, Washington, DC 20590-
0001. Office hours are from 8:30 a.m. to 5 p.m., ET, Monday through
Friday, except Federal holidays. If you have questions regarding
viewing materials in the docket, contact Dockets Operations, (202) 366-
9826.

SUPPLEMENTARY INFORMATION:

I. Public Participation

A. Viewing Comments

    To view comments go to www.regulations.gov. Insert the docket
number, FMCSA-2022-0083, in the keyword box, and click ``Search.''
Next, sort the results by ``Posted (Newer-Older),'' choose the first
notice listed, and click ``Browse Comments.'' If you do not have access
to the internet, you may view the docket online by visiting Dockets
Operations in Room W12-140 on the ground floor of the DOT West
Building, 1200 New Jersey Avenue SE, Washington, DC 20590-0001, between
9 a.m. and 5 p.m., ET, Monday through Friday, except Federal holidays.
To be sure someone is there to help you, please call<PHONE_NUMBER> or
(202) 366-9826 before visiting Dockets Operations.

B. Privacy Act

    In accordance with 49 U.S.C. 31315(b)(6), DOT solicits comments
from the public on the exemption request. DOT posts these comments,
without edit, including any personal information the commenter
provides, to www.regulations.gov, as described in the system of records
notice (DOT/ALL-14 FDMS), which can be reviewed at www.dot.gov/privacy.
Background
    On April 27, 2022, FMCSA published a Federal Register notice (87 FR
25079) announcing receipt of applications from three individuals
treated with ICDs and requested comments from the public. The
individuals requested an exemption from 49 CFR 391.41(b)(4) which
prohibits operation of a CMV in interstate commerce by persons with a
current clinical diagnosis of myocardial infarction, angina pectoris,
coronary insufficiency, thrombosis, or any other cardiovascular disease
of a variety known to be accompanied by syncope, dyspnea, collapse, or
congestive heart failure. The public comment period closed on May 27,
2022, and one comment was received.
    FMCSA has evaluated the eligibility of the applicants and concluded
that granting an exemption would not provide a level of safety that
would be equivalent to, or greater than, the level of safety that would
be obtained by complying with Sec.  391.41(b)(4). A summary of each
applicant's medical history related to their ICD exemption request was
discussed in the April 27, 2022, Federal Register notice and will not
be repeated here.
    The Agency's decision regarding this exemption application is based
on information from the Cardiovascular Medical Advisory Criteria, an
April 2007 evidence report titled ``Cardiovascular Disease and
Commercial Motor Vehicle Driver Safety,'' \1\ and a December 2014
focused research report titled ``Implantable Cardioverter
Defibrillators and the Impact of a Shock in a Patient When Deployed.''
Copies of these reports are included in the docket.
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    \1\ The report is available on the internet at https://rosap.ntl.bts.gov/view/dot/16462.
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    FMCSA has published advisory criteria to assist medical examiners
in determining whether drivers with certain medical conditions are
qualified to operate a CMV in interstate commerce.\2\ The advisory
criteria for Sec.  391.41(b)(4) indicates that coronary artery bypass
surgery and pacemaker implantation are remedial procedures and thus,
not medically disqualifying. ICDs are disqualifying due to risk of
syncope.
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    \2\ These criteria may be found in 49 CFR part 391, APPENDIX A
TO PART 391--MEDICAL ADVISORY CRITERIA, section D. Cardiovascular:
Sec.  391.41(b)(4), paragraph 4, which is available on the internet
at https://www.gpo.gov/fdsys/pkg/CFR-2015-title49-vol5/pdf/CFR-2015-title49-vol5-part391-appA.pdf.
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II. Discussion of Comments

    FMCSA received 109 comments in this proceeding. All of the comments
were from private citizens. The majority of the comments were in
support of Mr. Abiud Ortuno. The remaining comments were not attributed
to a specific applicant. All of the comments were supportive of
granting ICD exemptions to the applicants. No adverse comments were
received in this proceeding. Several commenters felt that FMCSA should
rely on the authority of a cardiologist's clearance to receive an ICD
exemption to drive a CMV. In one commenter's opinion, CMV operators and
other people in general without ICDs suffer cardiac arrest in greater
numbers than those with ICDs, and whether younger or older, one cannot
predict when this could happen. The commenter believes that texting and
other medical conditions were more of a risk to safety while driving a
CMV than the possibility of having a cardiac arrest and encouraged
FMCSA to grant the exemptions due to the shortage of CMV drivers.
Another commenter stated that FMCSA should revise its regulations in
accordance with current medical standards and with 49 U.S.C. 31136(e)
and 31315. One commenter referred to two research studies, one from the
American College of Cardiology that supported statistically low
fatality rates from road accidents among individuals with ICDs than
fatality rates of the general population, and a second study of a
subgroup analysis of the AVID trial, in which the annual incidence of
accidents in the ICD population was estimated to be 3.4 percent per
year, significantly lower than the 7.1 percent per year accident rate
in the general driving population in the USA.''
    Regarding the comment concerning medical clearance by a
cardiologist to grant ICD exemptions, while FMCSA does not rely solely
on a cardiologist's medical clearance or opinion to determine whether
to grant an ICD exemption, FMCSA does consider the cardiologist's
medical documentation and opinions received as a part of the
applicant's exemption request in evaluating whether to grant an
exemption. In response to the comments that other safety risks are
greater than the risk of ICD deployment due to a cardiac arrest, and
that FMCSA should update our standards and revise them in accordance
with 49 U.S.C. 31136(e) and 31315, FMCSA is concerned about all safety
risks concerning CMVs. FMCSA engages in research, and partners with the
Agency's Medical Review Board, medical experts, and our stakeholders to
provide evidence-based rulemaking and guidance with the ultimate goal
of keeping our roadways safe. FMCSA's exemption process is consistent
with the current requirements of 49 U.S.C. 31136(e) and 31315 as
further discussed in the Basis for Exemption Determination section that
follows in the next section. In response to the

comment regarding the two research studies, the studies do not appear
to have a clear relevance to ICDs and CMV-related crashes. The
commenter did not include specific citations for the study information
that was referenced. The Antiarrhythmics Versus Implantable
Defibrillators study appears to evaluate the efficacy of cardiac
medication treatment over treatment with an ICD rather than ICD crash
risk.

Basis for Exemption Determination

    Under 49 U.S.C. 31136(e) and 31315(b), FMCSA may grant an exemption
from the FMCSRs for no longer than a 5-year period if it finds such
exemption would likely achieve a level of safety that is equivalent to,
or greater than, the level that would be achieved absent such
exemption.
    The Agency's decision regarding these exemption applications is
based on an individualized assessment of the applicants' medical
information, available medical and scientific data concerning ICDs, and
any relevant public comments received.
    In the case of persons with ICDs, the underlying condition for
which the ICD was implanted places the individual at high risk for
syncope or other unpredictable events known to result in gradual or
sudden incapacitation. ICDs may discharge, which could result in loss
of ability to safely control a CMV. The December 2014 focused research
report referenced previously upholds the findings of the April 2007
report and indicates that the available scientific data on individuals
with ICDs and CMV driving does not support that individuals with ICDs
who operate CMVs are able to meet an equal or greater level of safety.

III. Conclusion

    The Agency has determined that the available medical and scientific
literature and research provides insufficient data to enable the Agency
to conclude that granting these exemptions would achieve a level of
safety equivalent to, or greater than, the level of safety maintained
without the exemption. Therefore, the following applicants have been
denied an exemption from the physical qualification standards in Sec.
391.41(b)(4):

Timothy Broome (SC); Bryce A. Norman (CA); Abiud J. Ortuno (FL)

    The applicants have, prior to this notice, received a letter of
final disposition regarding their exemption request.
    The decision letter fully outlined the basis for the denial and
constitute final action by the Agency. The names of these individuals
published today summarizes the Agency's recent denials as required
under 49 U.S.C. 31315(b)(4).

Larry W. Minor,
Associate Administrator for Policy.
[FR Doc. 2022-14226 Filed 7-1-22; 8:45 am]
BILLING CODE 4910-EX-P


[Federal Register Volume 82, Number 213 (Monday, November 6, 2017)]
[Notices]
[Pages 51470-51471]
[FR Doc No: 2017-24031]

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DEPARTMENT OF TRANSPORTATION

Federal Aviation Administration

Thirty Sixth RTCA SC-213 Enhanced Flight Vision Systems/Synthetic
Vision Systems (EFVS/SVS) Joint Plenary With EUROCAE Working Group 70

AGENCY: Federal Aviation Administration (FAA), U.S. Department of
Transportation (DOT).

ACTION: Thirty Sixth RTCA SC-213 Enhanced Flight Vision Systems/
Synthetic Vision Systems (EFVS/SVS) Joint Plenary with EUROCAE Working
Group 70.

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SUMMARY: The FAA is issuing this notice to advise the public of a
meeting of the Thirty Sixth RTCA SC-213 Enhanced Flight Vision Systems/
Synthetic Vision Systems (EFVS/SVS) Joint Plenary with EUROCAE Working
Group 70.

DATES: The meeting will be held December 04, 2017, 10:00 a.m.-12:00
p.m.

ADDRESSES: The meeting will be held at: RTCA Headquarters, 1150 18th
Street NW., Suite 910, Washington, DC 20036 and a webex will be hosted.

FOR FURTHER INFORMATION CONTACT: Rebecca Morrison at [email protected]

or<PHONE_NUMBER>, or The RTCA Secretariat, 1150 18th Street NW., Suite
910, Washington, DC 20036, or by telephone at<PHONE_NUMBER>, fax at
(202) 833-9434, or Web site at http://www.rtca.org.

SUPPLEMENTARY INFORMATION: Pursuant to section 10(a)(2) of the Federal
Advisory Committee Act (Pub. L. 92-463, 5 U.S.C., App.), notice is
hereby given for a meeting of the Thirty Sixth RTCA SC-213 Enhanced
Flight Vision Systems/Synthetic Vision Systems (EFVS/SVS) Joint Plenary
with EUROCAE Working Group 70. The agenda will include the following:

Monday, December 4, 2017 10:00 a.m.-12:00 p.m.

1. Welcome/Administrative Duties
2. IPR/Membership Call-Out and Introductions
3. Consider a Motion To Begin Open Consultation/Final Review and
Comment for the CVS MASPS
4. New Business
5. Review Action Items
6. Adjourn

    Attendance is open to the interested public but limited to space
availability. With the approval of the chairman, members of the public
may present oral statements at the meeting. Persons wishing to present
statements or obtain information should contact the person listed in
the FOR FURTHER INFORMATION CONTACT section. Members of the public may
present a written statement to the committee at any time.

    Issued in Washington, DC, on October 4, 2017.
Mohannad Dawoud,
Management & Program Analyst, Partnership Contracts Branch, ANG-A17,
NextGen, Procurement Services Division, Federal Aviation
Administration.
[FR Doc. 2017-24031 Filed 11-3-17; 8:45 am]
 BILLING CODE 4910-13-P


[Federal Register: July 31, 2007 (Volume 72, Number 146)]
[Notices]
[Page 41775-41777]
[DOCID:fr31jy07-116]

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DEPARTMENT OF LABOR

Occupational Safety and Health Administration

[Docket No. OSHA-2007-0060]

Cranes and Derricks in Construction; Extension of the Office of
Management and Budget's (OMB) Approval of Information Collection
(Paperwork) Requirements

AGENCY: Occupational Safety and Health Administration (OSHA), Labor.

ACTION: Request for public comment.

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SUMMARY: OSHA solicits public comment concerning its proposal to extend
OMB approval of the information collection requirements specified in
the Construction Standard on Cranes and Derricks (29 CFR

1926.550). The Standard is designed to protect employees who work with,
or in the vicinity of, cranes or derricks.

DATES: Comments must be submitted (postmarked, sent, or received) by
October 1, 2007.

ADDRESSES:
    Electronically: You may submit comments and attachments
electronically at http://www.regulations.gov, which is the Federal

eRulemaking Portal. Follow the instructions online for submitting
comments.
    Facsimile: If your comments, including attachments, are not longer
than 10 pages, you may fax them to the OSHA Docket Office at (202) 693-
1648.
    Mail, hand delivery, express mail, messenger, or courier service:
When using this method, you must submit three copies of your comments
and attachments to the OSHA Docket Office, Docket No. OSHA-2007-0060,
U.S. Department of Labor, Occupational Safety and Health
Administration, Room N-2625, 200 Constitution Avenue, NW., Washington,
DC 20210. Deliveries (hand, express mail, messenger, and courier
service) are accepted during the Department of Labor's and Docket
Office's normal business hours, 8:15 a.m. to 4:45 p.m., e.t.
    Instructions: All submissions must include the Agency name and OSHA
docket number for the ICR (OSHA-2007-0060). All comments, including any
personal information you provide, are placed in the public docket
without change, and may be made available online at http://www.regulations.gov.
 For further information on submitting comments see

the Public Participation heading in the section of this notice titled
Supplementary Information.
    Docket: To read or download comments or other material in the
docket, go to http://www.regulations.gov or the OSHA Docket Office at

the address above. All documents in the docket (including this Federal
Register notice) are listed in the http://www.regulations.gov index; however,

some information (e.g., copyrighted material) is not publicly available
to read or download through the Web site. All submissions, including
copyrighted material, are available for inspection and copying at the
OSHA Docket Office. You may also contact Stewart Burkhammer at the
address below to obtain a copy of the ICR.

FOR FURTHER INFORMATION CONTACT: Stewart Burkhammer, Directorate of
Construction, OSHA, U.S. Department of Labor, Room N-3468, 200
Constitution Avenue, NW., Washington, DC 20210; telephone (202) 693-
2020.

SUPPLEMENTARY INFORMATION:

I. Background

    The Department of Labor, as part of its continuing effort to reduce
paperwork and respondent (i.e., employer) burden, conducts a
preclearance consultation program to provide the public with an
opportunity to comment on proposed and continuing information
collection requirements in accordance with the Paperwork Reduction Act
of 1995 (44 U.S.C. 3506(c)(2)(A)). This program ensures that
information is in the desired format, reporting burden (time and costs)
is minimal, collection instruments are clearly understood, and OSHA's
estimate of the information collection burden is accurate. The
Occupational Safety and Health Act of 1970 (the OSH Act) (29 U.S.C. 651
et seq.) authorizes information collection by employers as necessary or
appropriate for enforcement of the Act or for developing information
regarding the causes and prevention of occupational injuries,
illnesses, and accidents (29 U.S.C. 657). The OSH Act also requires
that OSHA obtain such information with minimum burden upon employers,
especially those operating small businesses, and to reduce to the
maximum extent feasible unnecessary duplication of efforts in obtaining
information (29 U.S.C. 657).
    Several paragraphs of the Cranes and Derricks Standard for
Construction (Sec.  1926.550) contain notification requirements,
including paragraphs (a)(1), (a)(2), (a)(4), (a)(16), (d)(1), (f)(1),
(f)(2) and (g)(4). If an equipment manufacturer's specifications are
not available, paragraph (a)(1) requires employers to operate a crane
or derrick using specifications determined and recorded by a qualified
engineer who is competent to make such determinations. Under paragraph
(a)(2), employers must post on each crane and derrick its rated load
capacities, and recommended operating speeds, special hazard warnings,
or instructions. Paragraph (a)(4) requires employers to post at the
worksite an illustration of the hand signals prescribed by the
applicable ANSI standard for that type of crane or derrick. According
to paragraph (a)(16), employers must revise as appropriate the
capacity, operation, and maintenance instruction plates, tags, or
decals if they make alterations that involve the capacity or safe
operation of a crane or derrick.
    Paragraph (d)(1) requires employers to plainly mark the rated loads
of overhead and gantry cranes on each side of the cranes, and if the
crane has more than one hoisting unit, each hoisting unit shall have
its rated load marked on it or its load block. These markings must be
clearly legible from the ground or floor. Similarly, paragraph
(f)(1)(ii) requires employers to ensure that floating cranes and
derricks have a load rating chart, with clearly legible letters and
figures, and are securely fixed at a location easily visible to the
operator. When load ratings are reduced to stay within the limits for
the list of the barge with a crane mounted on it, paragraph (f)(1)(iii)
requires employers to provide a new load rating chart. For permanently
mounted floating cranes and derricks, paragraph (f)(2)(ii), requires
that a load rating chart with clearly legible letters and figures be
provided and securely fixed at a location easily visible to the
operator. Paragraph (g)(4)(ii)(I) requires employers to ensure that the
personnel platform be conspicuously posted with a plate or other
permanent marking which indicates the weight of the platform and its
rated load capacity or maximum intended load.
    In summary, these provisions require employers to provide
notification of specified operating characteristics through
documentation, posting, or revising maintenance instruction plates,
tags, or decals, and to notify employees of hand signals used to
communicate with equipment operators by posting an illustration of
applicable signals at the worksite. These paperwork requirements ensure
that employers operate a crane or derrick according to the limitations
and specifications developed for that equipment, and that hand signals
used to communicate with equipment operators are clear and correct.
Therefore, these requirements prevent employers from exceeding the
operating specifications and limitations of cranes and derricks, and
ensure that they use accurate hand signals regarding equipment
operation. By operating the equipment safely and within specified
parameters, and communicating effectively with equipment operators,
employers will prevent serious injury and death to the equipment
operators and other employees who use or work near the equipment.
    The Cranes and Derricks Standard also contains two paragraphs
requiring employers to inspect and document crane inspections.
Paragraph (a)(6) requires employers to perform annual inspections of
cranes and derricks and to establish and maintain a written record of
the dates and results of these inspections. Paragraph (b)(2) requires
the employer to prepare and maintain a certification record which
includes the date, listing of critical items inspected, signature of
person performing the

inspections, and a serial number or identifier of the crane inspected
as specified in ANSI B30.5-1968, Safety Code for Crawler, Locomotive
and Truck Cranes.
    These inspections identify problems such as deterioration caused by
exposure to adverse weather conditions, worn components and other flaws
and defects that develop during use, and accelerated wear resulting
from misalignments of connecting systems and components. Establishing
and maintaining a written record of the annual inspections alerts the
equipment mechanics to servicing or repair problems. Prior to returning
the equipment to service, employers can review the records to ensure
that the mechanics performed the necessary repairs and maintenance.
Accordingly, by using only equipment that is in safe working order,
employers will prevent severe injury and death to the equipment
operators and other employees who use or work near the equipment.
    Paragraph (a)(11) of OSHA's Cranes and Derricks Standard for
Construction (1926.550) addresses conditions in which a crane or
derrick powered by an internal combustion engine is exhausting in an
enclosed space that employees occupy or will occupy. Under these
conditions, employers must record tests made of the breathing air in
the space to ensure that adequate oxygen is available and that
concentrations of toxic gases are at safe levels.
    Establishing a test record allows employers to document oxygen
levels and specific atmospheric contaminants, ascertain the
effectiveness of controls, implement additional controls if necessary,
and readily provide this information to other crews and shifts who may
work in the enclosed space. Accordingly, employers will prevent serious
injury and death to equipment operators and other employees who use or
work near this equipment in an enclosed space. In addition, these
records provide the most efficient means for an OSHA compliance officer
to determine that an employer performed the required tests and
implemented appropriate controls.
    Paragraph (a)(15) requires that any overhead wire be considered to
be an energized line unless and until the person owning such line or
the electrical utility authorities indicate that it is not an energized
line and it has been visibly grounded. Failure to appropriately
identify overhead wires would require those working with or in the
vicinity of overhead lines to perform costly, time-consuming
activities, prior to performing their assigned duties.

II. Special Issues for Comment

    OSHA has a particular interest in comments on the following issues:
     Whether the proposed information collection requirements
are necessary for the proper performance of the Agency's functions,
including whether the information is useful;
     The accuracy of OSHA's estimate of the burden (time and
costs) of the information collection requirements, including the
validity of the methodology and assumptions used;
     The quality, utility, and clarity of the information
collected; and
     Ways to minimize the burden on employers who must comply;
for example, by using automated or other technological information
collection and transmission techniques.

III. Proposed Actions

    OSHA is requesting that OMB extend its approval of the information
collection requirements contained in the Construction Cranes and
Derricks Standard (29 CFR 1926.550). The Agency will summarize the
comments submitted in response to this notice and will include this
summary in the request to OMB.
    Type of Review: Extension of a currently approved collection.
    Title: The Construction Standard on Cranes and Derricks (29 CFR
1926.550).
    OMB Number: 1218-0113.
    Affected Public: Business or other for-profit.
    Number of Respondents: 91,997.
    Frequency: Annually; On occasion.
    Average Time Per Response: Varies from 5 hours to inspect a crane
with a capacity of more than 60 tons to 3 minutes (.05 hour) to
maintain and disclose exposure monitoring data of an enclosed space
where exhaust from cranes or derricks may expose employees to a
deficiency of oxygen and/or toxic gases.
    Estimated Total Burden Hours: 103,076.
    Estimated Cost (Operation and Maintenance): $570,074

IV. Public Participation--Submission of Comments on This Notice and
Internet Access to Comments and Submissions

    You may submit comments in response to this document as follows:
(1) Electronically at http://www.regulations.gov, which is the Federal

eRulemaking Portal; (2) by facsimile (FAX); or (3) by hard copy. All
comments, attachments, and other material must identify the Agency name
and the OSHA docket number for the ICR (Docket No. OSHA-2007-0060). You
may supplement electronic submissions by uploading document files
electronically. If you wish to mail additional materials in reference
to an electronic or facsimile submission, you must submit them to the
OSHA Docket Office (see the section of this notice titled Addresses).
The additional materials must clearly identify your electronic comments
by your name, date, and the docket number so the Agency can attach them
to your comments.
    Because of security procedures, the use of regular mail may cause a
significant delay in the receipt of comments. For information about
security procedures concerning the delivery of materials by hand,
express delivery, messenger, or courier service, please contact the
OSHA Docket Office at<PHONE_NUMBER> (TTY<PHONE_NUMBER>).
    Comments and submissions are posted without change at http://www.regulations.gov.
 Therefore, OSHA cautions commenters about

submitting personal information such as social security numbers and
date of birth. Although all submissions are listed in the
http://www.regulations.gov index, some information (e.g., copyrighted

material) is not publicly available to read or download through this
Web site. All submissions, including copyrighted material, are
available for inspection and copying at the OSHA Docket Office.
Information on using the http://www.regulations.gov Web site to submit

comments and access the docket is available at the Web site's User Tips
link. Contact the OSHA Docket Office for information about materials
not available through the Web site, and for assistance in using the
Internet to locate docket submissions.

V. Authority and Signature

    Edwin G. Foulke, Jr., Assistant Secretary of Labor for Occupational
Safety and Health, directed the preparation of this notice. The
authority for this notice is the Paperwork Reduction Act of 1995 (44
U.S.C. 3506 et seq.) and Secretary of Labor's Order No. 5-2002 (67 FR
65008).

    Signed at Washington, DC, on July 26, 2007.
Edwin G. Foulke, Jr.,
Assistant Secretary of Labor for Occupational Safety and Health.
 [FR Doc. E7-14714 Filed 7-30-07; 8:45 am]

BILLING CODE 4510-26-P


February 27, 2015

EPA-HSRB-15-01

Thomas A. Burke, Ph.D., MPH
EPA Science Advisor
Office of the Science Advisor
1200 Pennsylvania Avenue, NW
Washington, DC 20460

Subject: January 14, 2015 EPA Human Studies Review Board Meeting Report

Dear Dr. Burke,

      The United States Environmental Protection Agency (EPA or Agency) requested that the Human Studies Review Board (HSRB) provide scientific and ethics reviews of three items: a recent study of airway inflammation in asthmatics repeatedly exposed to nitrogen dioxide (Ezratty et al., 2014), a pre-Rule publication by Spak et al. (1989) of gastric mucosal effects after ingestion of fluoride, and a pre-Rule publication concerning the effects of fluoride and calcium on spinal bone mineral content (Hansson and Roos, 1987). The Board's key responses to the charge questions are summarized in this letter and are detailed in the enclosed final meeting report.

A published report: Ezratty, Veronique et al. (2014) Repeated Nitrogen Dioxide Exposures and Eosinophilic Airway Inflammation in Asthmatics: A Randomized Crossover Study
Science
      *       If the statistical analysis cited was the methodology used, the Board finds that parts of the results may not be scientifically sound. If the authors, in fact, used a model and analysis procedure that corresponds to the statistical description of the double-blind crossover with repeated measures design, the HSRB finds the study to be scientifically sound.

      *       The study is adequate for use in a weight-of-evidence analysis in support of an inhalation risk assessment for the use of nitrogen dioxide as a medical equipment sterilant, pending resolution of the statistical issues noted in the enclosed report.
Ethics
   * The Board concluded that the published report by Ezratty et al. (2014) submitted for review meets the applicable requirements of 40 CFR part 26 subpart Q.
A published report: Spak, C.J. et al. (1989) Tissue Response of Gastric Mucosa after Ingestion of Fluoride. Karolinska Institute, Huddinge University Hospital, Huddinge, Sweden
Science
   * The study by Spak et al. (1989) is scientifically sound, providing reliable data.

   * This study is adequate for point of departure use in support of an acute dietary risk assessment for fluoride.
Ethics
   * Considering the time the study was conducted and based on the information provided, the Board found that no children or obviously pregnant or nursing women were included and the HSRB did not find convincing evidence that the study was conducted in a way that placed participants at increased harm or impaired their informed consent. Therefore, this study meets the ethical standards of 40 CFR part 26 subpart Q.
A published report: Hansson, T. and Roos, B. (1987). The Effect of Fluoride and Calcium on Spinal Bone Mineral Content: A Controlled, Prospective (3 years) study. Sahlgren's Hospital, University of Gothenberg, Sweden
Science
   *   While the lack of numerous details in the article reporting this study leads to the uncertainties noted separately by the Agency and the Board, the study appears to be scientifically sound and provides reliable data.

   *   Because the authors report that "some mildly adverse side effects" may have occurred below 30 mg sodium fluoride (NaF)/day (Hansson and Roos, 1987, p. 317) and adverse effects may have occurred below that dose that were not reported by subjects, this study cannot be used in support a LOAEL or NOAEL, but it may be used as part of the overall weight-of-evidence for a lower limit in an acute dietary risk assessment for fluoride.
Ethics
   * Considering the time the study was conducted and based on the information provided, the HSRB found that no children or pregnant or nursing women were included and the Board did not find convincing evidence that the study was conducted in a way that placed participants at increased harm or impaired their informed consent. Therefore, this study meets the ethical standards of 40 CFR part 26 subpart Q.
Sincerely,

Rebecca T. Parkin, PhD, MPH
Chair
EPA Human Studies Review Board
                                    NOTICE

This report has been written as part of the activities of the EPA Human Studies Review Board, a Federal advisory committee providing advice, information and recommendations on issues related to scientific and ethical aspects of human subjects research. This report has not been reviewed for approval by the Agency and, hence, the contents of this report do not necessarily represent the view and policies of the Environmental Protection Agency, nor of other agencies in the Executive Branch of the Federal government, nor does the mention of trade names or commercial products constitute a recommendation for use. You may obtain further information about the EPA Human Studies Review Board from its website at http://www.epa.gov/osa/hsrb. You may also contact the HSRB Designated Federal Officer, via e-mail at<EMAIL_ADDRESS>
In preparing this document, the Board carefully considered all information provided and presented by the Agency presenters, as well as information presented by public commenters. This document addresses the information provided and presented within the structure of the charge by the Agency.

                      US ENVIRONMENTAL PROTECTION AGENCY
                          HUMAN STUDIES REVIEW BOARD

Chair

Rebecca Parkin, Ph.D., M.P.H., Professorial Lecturer, Environmental and Occupational Health and of Epidemiology & Biostatistics, Milken Institute School of Public Health, The George Washington University, Washington, DC

Vice Chair

Jewell H. Halanych, M.D., M.Sc., Assistant Professor, Internal Medicine Residency Program, Montgomery Regional Campus, University of Alabama at Birmingham, Montgomery, AL

Members

Gary L. Chadwick, Pharm.D., M.P.H., C.I.P., Senior Consultant, HRP Consulting Group, Inc. Fairport, NY

Liza Dawson, Ph.D., Research Ethics Team Leader, Division of AIDS National Institutes of Health (NIH), National Institute of Allergy and Infectious Disease (NIAID), Bethesda, MD

George Fernandez, Ph.D., Statistical Training Specialist, SAS Institute, Statistical Training and Technical Services, Sparks, NV

Kyle L. Galbraith, Ph.D., Manager, Human Subjects Protection, Carle Foundation Hospital,
Urbana, IL

Edward Gbur, Jr., Ph.D., Professor, Agricultural Statistics Laboratory, University of Arkansas,
Fayetteville, AR

Elizabeth Heitman, Ph.D., Associate Professor of Medical Ethics, Center for Biomedical Bioethics and Society, Vanderbilt University Medical Center, Nashville, TN

John C. Kissel, Ph.D., Professor, Department of Environmental and Occupational Health, School of Public Health, University of Washington, Seattle, WA

Randy Maddalena, Ph.D., Physical Research Scientist, Indoor Environment, Lawrence Berkeley National Laboratory, Berkeley, CA

William Popendorf, Ph.D., M.P.H., Professor Emeritus, Department of Biology, Utah State University, Logan, UT

Kenneth Ramos, M.D., Ph.D., PharmB, Associate Vice President, Precision Health Sciences, Professor of Medicine, Arizona Health Sciences Center, Tucson, AZ

Suzanne M. Rivera, Ph.D., M.S.W., Associate Vice President for Research, Case Western University, Cleveland, OH

Jun Zhu, Ph.D., Professor of Statistics and of Entomology, Department of Statistics, University of Wisconsin  -  Madison, Madison, WI

Human Studies Review Board Staff

Toby Schonfeld, Ph.D., Human Subjects Research Review Official, Office of the Science Advisor, United States Environmental Protection Agency, Washington, DC

INTRODUCTION
On January 14, 2015, the United States Environmental Protection Agency's (EPA or Agency) Human Studies Review Board (HSRB or Board) met to finish the final report of the Board's November 5, 2014, meeting, and to address the scientific and ethical charge questions related to three agenda items: a recent study of airway inflammation in asthmatics repeatedly exposed to nitrogen dioxide (Ezratty et al., 2014), a pre-Rule publication by Spak et al. (1989) of gastric mucosal effects after ingestion of fluoride, and a pre-Rule publication concerning the effects of fluoride and calcium on spinal bone mineral content (Hansson and Roos, 1987).

REVIEW PROCESS
The Board conducted a public meeting using Adobe Connect, on January 14, 2015. Advance notice of the meeting was published in the Federal Register as "Human Studies Review Board; Notification of a Public Meeting" (EPA, 2014, pp. 78861-78863).

Following welcoming remarks from Agency officials, the Board discussed the draft final report for their November 5, 2014, meeting.  One revision was made before the Board voted to accept the report as final. The report has been posted on the HSRB website at http://www.epa.gov/hsrb/.

Then the Board heard presentations from EPA for the other three agenda items in sequence; all three were publications. This Final Report of the meeting describes the HSRB's discussion, recommendations, rationale and consensus in response to each charge question for each of these publications.

For each agenda item, Agency staff first presented their review of the science and the Board asked the Agency presenters clarifying questions. The staff then described their review of the ethical aspects and the Board asked clarifying questions about those. The HSRB solicited public comments and next asked Agency staff to read the Charge Questions for the publication under consideration.  The Board discussed the science questions first and then the ethics question. The Chair then called for a vote to confirm concurrence on a summary statement in response to each charge question.

For their evaluation and discussion, the Board considered materials presented at the meeting, oral comments, the original published reports, related materials and published articles, the Agency's science and ethics reviews of the publications, and a public comment. A comprehensive list of background documents is available online at http://www.epa.gov/hsrb/.

CHARGE TO THE BOARD AND BOARD RESPONSE

A published report: Ezratty, Veronique et al. (2014) Repeated Nitrogen Dioxide Exposures and Eosinophilic Airway Inflammation in Asthmatics: A Randomized Crossover Study
Overview of the Study
This randomized, double-blind, crossover study of 19 non-smoker participants (14 men and 5 women, ages 20-69) was conducted in France to assess whether repeated short-term exposures to  nitrogen dioxide (NO2) would increase airway inflammation in asthmatics. All of the participants had intermittent asthma and house dust mite allergies (both of which were clinically confirmed), had either gas stoves or unvented combustion appliances in their homes, and had not had an airway infection for at least six weeks before baseline measurements were taken. Each participant served as his/her own control and was instructed to not use their gas appliances during the study period.
The research included three series of three exposures randomly administered while the participants were at rest in a temperature and relative humidity controlled exposure chamber; each of the exposures were to clean air, 200 ppb (380 ug/m[3]) NO2 or 600 ppb (1130 ug/m[3]) NO2.   For each of the three-day exposure series, the administration of a single exposure level was for 30 minutes on day 1, twice  -  one hour apart  -  for 30 minutes each on day 2, and no exposure on day 3. Participants had two weeks free of exposure between each of the series. Methacholine challenge tests were done at baseline. Spirometry (forced expiratory volume in 1 second [FEV1] and peak expiratory flow [PEF]) were conducted at baseline (10-30 days before exposure) and on each of the three study days in each series. Additionally, sputum induction, differential cell counts and an enzyme assay were used to assess inflammatory markers at baseline and on each of the 9 study days. Furthermore, participants were asked about respiratory symptoms and feelings of discomfort on each study day and, along with questions about medications, during the two-week period between each series of exposures.
Using generalized linear modeling (GLM) for the 18 participants who completed the study, the investigators determined that there were significant increases in eosinophil percentages and eosinophil cationic protein in sputum but only after the repeated exposures to 600 ppb NO2; there was no effect on lung function at any exposure level.
Science
Charge to the Board
   * Is this study scientifically sound, providing reliable data?
   * If so, is this study adequate for quantitative use in support of an inhalation risk assessment for the use of nitrogen dioxide as a medical equipment sterilant?
Board Response to the Charge

HSRB Recommendations

      *       If the statistical analysis (GLM) cited was the methodology used, the Board finds that parts of the results may not be scientifically sound. If the authors, in fact, used a model and analysis procedure that corresponds to the statistical description of the double-blind crossover with repeated measures design, the HSRB finds the study to be scientifically sound.
      *       The study is adequate for use in a weight-of-evidence analysis in support of an inhalation risk assessment for the use of nitrogen dioxide as a medical equipment sterilant, pending resolution of the statistical issues noted in this report.
HSRB Detailed Recommendations and Rationale
Overall, the Board agreed with the Agency's scientific assessment of this study (Leshin, 2014) and commented that the research was very well documented by Ezratty et al. (2014). The clarity of their methods made the HSRB's review during the meeting quite brief.

Is this study scientifically sound, providing reliable data?
Based on their examination of the study methods, the Board determined that the study design and laboratory procedures were sound. The HSRB did not identify any concerns to bring forward to the Agency, thereby concluding that the data gathered in this study are reliable.

If so, is this study adequate for quantitative use in support of an inhalation risk assessment for the use of nitrogen dioxide as a medical equipment sterilant?
The statistical methods relied on well-known methods but may not have been appropriate for the type of data gathered from a crossover mixed model design with repeated measures. In particular, the Board questioned whether a mixed model procedure was used within the GLM analysis.

The experimental design of this study is a mixed model with 19 random subjects, 3 randomly assigned fixed crossover treatments (0, 200, and 600 ppb No2) within each subject and three repeated measurements (Day 1, 2 and 3) recorded from each treatment within each subject. Therefore, valid statistical analysis should include a repeated measures analysis with fixed treatments and random subjects, and a mixed model procedure such as MIXED in SAS software must be used to provide valid conclusions.
The random effects and the correlation among the repeated measures are not accounted correctly when using GLM methods. Therefore, the estimated standard errors, confidence intervals for treatment means, and the p-values reported for treatment mean comparisons are incorrect.
As a result of these findings, the Board recommended that the Agency verify from the authors of this study whether a MIXED or GLIMIXED procedure was used within the generalized linear mixed model analysis; if so, the results would provide valid conclusions.

Ethics
Charge to the Board
   * Does the study meet the applicable requirements of 40 CFR part 26, subpart Q?

Board Response to the Charge

HSRB Recommendation

   * The Board concluded that the published report by Ezratty et al. (2014) submitted for review meets the applicable requirements of 40 CFR part 26 subpart Q.
HSRB's Detailed Recommendation and Rationale
The article by Ezratty et al. (2014) reports on a medical study that investigated whether exposure to repeated peaks of "realistic" levels of nitrogen dioxide (NO2) induced changes in airway inflammation in non-smoking male and female adult volunteers with asthma (Ezratty et al., 2014, p. 854).   The study was carried out beginning in 2007 at the Clinical Center of Investigation at Bichat Hospital, Paris, France, and was funded by the Center for Research and Innovation in Gas and New Energy Sources, CRIGEN, CDF Suez, the Medical Studies Department of EDF, and the Clinical Center of Investigation at Bichat Hospital, Paris, France.  EPA identified the work from the published literature as a potential source of data for evaluating NO2 as a sterilant of medical equipment.
In the Materials and Methods section of the article, the investigators report that the study was approved by the Ethics Committee of the Hôtel-Dieu Hospital in Paris, France, and was registered with the French Ministry of Health under study number DGS 2006/0016.  The article states that investigators enrolled 19 participants (5 women, 14 men) ages 20-69 (Ezratty et al., 2014, p. 850), and that "All participants signed informed consent forms before enrollment in the study" (Ezratty et al., 2014, p. 851).
In response to a request from the Office of Pesticide Programs' (OPP) Human Studies Ethics Review Officer, Ms. Kelly Sherman (Sherman, 2014a, p. 21), Dr. Veronique Ezratty provided copies of the Ethics Committee's approval documents, the approved protocol, and the study's consent form (Aubier et al., 2007, pp. 26-96).  Although the article reporting the study's results was written in English, the protocol, consent document, and approval letter are in French.  The protocol states that the study was to be carried out following the principles of the World Medical Association's (WMA) Declaration of Helsinki and in keeping with French national regulations on the conduct of clinical trials, known as the Huriet Law (Aubier et al., 2007, p. 46). It may be assumed that because the protocol was approved in 2007, the protocol follows the 2000 edition and clarifications of the Declaration in place at the time (WMA, 2004).  Although the Ethics Committee of the Hôtel-Dieu Hospital does not have a Federal-wide assurance, the laws and ethical standards under which it operates are parallel to those that guide Institutional Review Boards in the U.S. (Berlin & Gorelick, 2003).
Does the study meet the applicable requirements of 40 CFR part 26, subpart Q?
The Board concurred with the conclusions of OPP's Ethics Review (Sherman, 2014a) that the reported research does not rely on data from intentional exposure of any human subject who was a pregnant or nursing woman or a child.  There is no evidence that the conduct of the research was fundamentally unethical or deficient relative to prevailing ethical standards at the time. The participants provided written informed consent, and there is no evidence that the research was conducted in a way that placed participants at increased risk of harm based on the knowledge available at the time the study was conducted.
   1.    Assessment of risks and benefits

The article reports that NO2 is a "ubiquitous atmospheric pollutant" (Ezratty et al., 2014, p. 850) and that many people are exposed to NO2 as an indoor air pollutant resulting from combustion, including cooking with gas, and outdoor pollution related to traffic. The highest concentration and longest duration of exposure studied were stated in the article to be consistent with those present in French homes where gas stoves are used for cooking meals.  The primary benefit of the study was to society, by generating knowledge of the effects of repeated exposures to "realistic" levels of NO2's on adults with asthma (Ezratty et al., 2014, p. 854).

The consent form identifies clearly that the study offered no benefit to participants (Aubier, 2007, p. 58), although the participants were members of a class of persons who may benefit in the future from knowledge gained in the study.  There is no statement in the article regarding the balance between risk to participants and benefit to society.  However, the approval of this study by the Ethics Committee of the Hôtel-Dieu Hospital can be interpreted as its assessment, under international ethical guidance and French regulatory standards, that the risks to participants did not outweigh the study's anticipated benefits.

   2.    Voluntary and informed consent of all participants

Participants were recruited from among adult patients at the Pulmonary-Allergy Clinic at the Bichat Hospital in Paris, France.  Although vulnerable populations were not targeted for the study, it is not possible to tell whether participants from potentially vulnerable populations were recruited, or whether the investigators employed protections to minimize coercive recruitment of clinic patients.

To participate in the study, subjects were required to be non-pregnant adults with a diagnosis of intermittent asthma and no history of smoking within the previous 10 years.  No children were enrolled.  All participants signed an informed consent document in which they certified that they were adults, and that they were not pregnant or lactating.  The consent document was supplemented by a six-page document outlining the study's procedures, which also affirmed participants' right to withdraw from the study for any reason and stated that women who did not use contraceptives during the study were excluded from participation.

   3.    Equitable selection of study participants

Although vulnerable populations were not targeted, it is not possible to determine whether the selection of study participants was equitable or whether individual members of vulnerable populations were enrolled in the study.  The final protocol (Aubier, 2007, p. 47) states that participants were to be compensated a total of Euro1500 (approximately US$2000 in 2007). This amount does not appear to have been disproportionate or coercive for participation in 12 study visits over several weeks.

A published report: Spak, C.J. et al. (1989) Tissue Response of Gastric Mucosa after Ingestion of Fluoride. Karolinska Institute, Huddinge University Hospital, Huddinge, Sweden
Overview of the Study
This single-dose study of fluoride (F) effects on the gastric mucosa was conducted in Sweden; it involved twelve voluntary participants (4 men and 8 women, ages 22-45). Each participant underwent two endoscopies after overnight fasts: the first fast occurred before the day of no dose and the first endoscopy (for the baseline control measurement);and the second fast took place before the participant ingested 20 ml sodium fluoride solution, containing 20 mg F (53 mmolls per liter). Endoscopies were done two weeks or more apart; the study endoscopy was conducted two hours after the participant ingested the solution. During both the control and study endoscopy, the mucosal integrity of the antrum and body of the stomach was examined and graded on a 0-4 scale. Additionally, two biopsy specimens were collected from each of these areas and categorized on a histopathological scale (0-3). The gastric mucosal control and response conditions in the stomach and antrum were evaluated first by a gastroenterologist during the procedure and second by a different gastroenterologist using a videotape taken during the endoscopies.
After taking the study dose, 100% of the participants had six or more petechiae or erosions of the stomach and 50% had a range of changes in the antrum. There were no indications of macroscopic changes in the esophagus or the duodenum. Based on the histopathological results, the authors noted that fluoride affected the gastric mucosa; it caused moderate injury to the surface epithelium, gastric pits and superficial stroma. The authors noted that 25% of the participants experienced nausea. Commenting that their study confirmed prior research results, Spak et al. (1989) concluded that only one dose of fluoride at the level then used to treat osteoporosis affected the gastric mucosa.
Science
Charge to the Board
   * Is this study scientifically sound, providing reliable data?
   * If so, is this study adequate for quantitative use in support of an acute dietary risk assessment for fluoride?

Board Response to the Charge

HSRB Recommendations

   * The study by Spak et al. (1989) is scientifically sound, providing reliable data.
   * This study is adequate for point of departure use in support of an acute dietary risk assessment for fluoride.
HSRB Detailed Recommendations and Rationale
Overall, the Board agreed with the Agency's scientific assessment of Spak et al. (D'Agostino, 2014a).

Is this study scientifically sound, providing reliable data?

Several issues were discussed to develop the response to this question.
1.      Study design
No major concerns were identified in the study design.  However, the authors did not provide a rationale for completion of the follow-up endoscopy 2 hours after exposure to the fluoride solution. This issue is potentially significant given that the erosive/irritant effects of fluoride are likely influenced by the duration of exposure.  As such, the severity and extent of lesions observed at 2 hours may be increased or decreased as a function of the time chosen for endoscopic evaluation after chemical ingestion.
2.      Endoscopy issues
The report did not provide photomicrographs of the lesions, so the Board could not evaluate the types of lesions reported or the appropriateness of the grading system. That said, the scale appears to be consistent with conventional pathological grading systems used at the time of the study.
3.      Histopathological results
Spak et al. did not specify whether the histopathological measurements were graded blindly or whether "another gastroenterologist" was one or more reviewers (Spak et al., 1989, p. 1686).
4.      Control irritants
Citing one reference, the authors attempted to compare their findings to aspirin and other well-known gastric irritants. They noted that repeated dosing might result in mucosal adaptation as occurs with aspirin. However, no control for gastric toxicity was included in the study and no quantitative references to the toxicological effects of control irritants, such as aspirin, were provided.
In spite of these weaknesses, the experimental design, data collection and interpretation of findings were judged to be scientifically sound.
If so, is this study adequate for quantitative use in support of an acute dietary risk assessment for fluoride?

1. Wilcoxon signed rank test
Spak et al. (1989) used the Wilcoxon signed rank test for all of their statistical analyses. This test is the non-parametric rank equivalent of the paired t-test. Differences between the treatment and control are calculated and their absolute values are ranked with adjustments made for tied differences. The statistic is the sum of the ranks corresponding to the positive differences. The assumptions underlying the test are that the differences represent a continuous variable whose probability distribution is symmetric about the hypothesized value of the median, which in this application is zero (Hollander and Wolfe, 1973, pp 27-32; Siegel and Castellan, 1988, pp 87-94). Violation of the underlying assumptions calls into question the validity of the statistical conclusions based on the test.
 The footnotes to the table (Spak et al., 1989, p 1686) indicate that the scale for the microscopic evaluation data consists of ordered categories. The scale for the macroscopic data consists of categories of grouped counts. All four sets of differences clearly do not satisfy the underlying continuity assumption of the Wilcoxon test and hence, call into question the validity of the p-values on which their conclusions are based.
2. Raw data conclusions
However, an examination of the raw data in the table does suggest that there are clear treatment effects in all but the macroscopic examination of the antrum. For those data, there was no change for five individuals, a reduction in petechiae or erosions for one individual, and an increase in six individuals (50% of the participants), which does not support the implication of the table footnote that there was a highly significant fluoride effect.
 In summary, despite the questionable use of the Wilcoxon test, examination of the raw data does indicate that the results would be adequate to support the authors overall conclusions of the existence of fluoride effects.

Ethics
Charge to the Board
   * Does the study meet the applicable requirements of 40 CFR part 26 subpart Q?
Board Response to the Charge

HSRB Recommendation

   * Considering the time the study was conducted and based on the information provided, the Board found that no children or obviously pregnant or nursing women were included and the HSRB did not find convincing evidence that the study was conducted in a way that placed participants at increased harm or impaired their informed consent. Therefore, this study meets the ethical standards of 40 CFR part 26 subpart Q.
HSRB's Detailed Recommendation and Rationale
Spak et al. (1989) present very little information about the ethical conduct of the study. Overall, the Board concurred with the Agency's review (Sherman, 2014b).
Does the study meet the applicable requirements of 40 CFR part 26 subpart Q?
The HSRB made the following observations about the study.
   1. The publication does not indicate whether pregnant or nursing women were included in the study.
   2. The age range begins at 22 years, so no children were participants in this research.
   3. There is no information in Spak et al. (1989) about informed consent, compensation or recruitment, including whether the participants experienced coercion during recruitment.
   4. There is no risk-benefit comparison in Spak et al. (1989). There was no known risk based on the knowledge available at the time of the study. The results of the study provided great value to society; it showed the need to reduce fluoride exposures to children.
   5. The HSRB recognized that Sweden required IRB reviews beginning 1978, which was likely before this study was conducted.

A published report: Hansson, T. and Roos, B. (1987). The Effect of Fluoride and Calcium on Spinal Bone Mineral Content: A Controlled, Prospective (3 years) study. Sahlgren's Hospital, University of Gothenberg, Sweden
Overview of the Study
This controlled, three-year prospective study of 100 postmenopausal women with idiopathic osteoporosis was conducted in Sweden to evaluate the effects on bone mineral content (BMC) of daily doses lower than 30 milligrams of sodium fluoride (NaF). The women were randomly assigned to four groups: 30 mg NaF fluoride and calcium, 10 mg NaF and calcium, calcium only, and placebo. The first two groups were instructed to take the NaF in the morning and the calcium in the evening; however, there is no record of the participants' compliance with the daily dosing regimen over the three-year study period. BMC was measured using two methods: roentgenograms (one month after treatment began and after 3 years) and dual photon absorptiometry (at the start and at 1, 1.5, 2 and 3 years of treatment). Using the data from these instruments, bone profile curves were calculated for each participant. Eighty-eight women completed the study with dropouts occurring in each of the four groups.
The investigators concluded that only the daily doses in Group A (30 mg NaF and 1 g calcium) increased lumbar spine BMC significantly (p<0.01), occurring within 1.5 years; this increase was in the lower range for "age-matched normals" (Hansson and Roos, 1987, p. 316). The authors also noted that five of the 24 women in this higher dose group experienced side effects: four had nausea and gastritis, and one dropped out at 10 months due to peptic ulcers likely unrelated to the treatments. Side effects occurred to lesser extents in the other three study groups.
Science
Charge to the Board
   * Is this study scientifically sound, providing reliable data?
   * If so, is this study adequate for qualitative use in support of an acute dietary risk assessment for fluoride?

Board Response to the Charge

HSRB Recommendations

   *    While the lack of numerous details in the article reporting this study leads to the uncertainties noted separately by the Agency and the Board, the study appears to be scientifically sound and provides reliable data.
   *    Because the authors report that "some mildly adverse side effects" may have occurred below 30 mg sodium fluoride (NaF)/day (Hansson and Roos, 1987, p. 317) and adverse effects may have occurred below that dose that were not reported by subjects, this study cannot be used in support a LOAEL or NOAEL, but it may be used as part of the overall weight-of-evidence for a lower limit in an acute dietary risk assessment for fluoride.

HSRB Detailed Recommendations and Rationale
This article presents a seemingly simple, scientifically sound study in a clear and concise manner but with a lot of missing details leading to the uncertainties noted both within the Agency science review (D'Agostino, 2014b) and by the Board.  In addition, four further weaknesses suggest that the study (as presented) has limitations in its qualitative use in support of an acute dietary risk assessment for fluoride (F).
Is this study scientifically sound, providing reliable data?

   1.    Missing information
The Board identified the following six missing details that add uncertainty to either the quality or/and significance of the study:
         a.          No information was provided about recruitment or tracking of participants that could have an impact on compliance.  The degree of noncompliance was mentioned by the authors as one explanation for the number of non-responders, and compliance could have had an impact on the incidence of side effects.
         b.          No information was provided about the level of blindedness within the study.  For instance, differences in the nature and/or the number of capsules implied by the "treatment" column in Table 1 (Hansson and Roos, 1987, p. 316) may have been evident to the patients.  Whether either individual patients or the researchers who interacted with the patients knew (or could determine) which group a patient was in could also have affected compliance and the incidence of side effects.
         c.          Insufficient information was provided about the statistical approaches taken to analyze the data.  It is not clear where the p-values came from.
         d.          Given the somewhat large number of patients who did not complete the study (12% overall) and their unequal distribution among the study groups, more details about the missing data could be helpful for understanding their implications on both BMC and side effects.
         e.          No data points are presented in Figure 1 (a plot of individual bone mineral content [BMC] over time) (Hansson and Roos, 1987, p. 316).  Most of the lines look eye-ball straight, but some are slightly curved; however, the degree of line-smoothing is unknown.  Thus, the degree of variance from the apparent smooth trends of BMC over time is unknown.
         f.          Insufficient information is presented about the distribution of side effects.  Despite the reduction of side effects being a secondary goal of this study, actual data are only provided for group A (see below).  The existence and number of side effects that happened in other groups is particularly relevant to the intended use by the Agency.
Despite these uncertainties, the Board agreed with the Agency that "The deficiencies do not change the conclusion of the study that gastrointestinal symptoms were observed following treatment with sodium fluoride.  However, they do present some uncertainties which must be considered when interpreting the results" (D'Agostino, 2014b, p. 9).
If so, is this study adequate for qualitative use in support of an acute dietary risk assessment for fluoride?

2. Weaknesses

In addition to the above uncertainties, four weaknesses in the study were identified (a-d below).
                 a.       The first pertains to the statistical analytic methods employed by the authors.  This is a controlled, prospective study that was meant to address an interesting, practical question for women's health.  It appears from the way the results are presented that changes over time were analyzed separately for each of the four treatment groups (including the controls).  However, a repeated measures analysis seems to be in order.
	The following three weaknesses have both an individual and collective bearing on the proposed use of this study by the Agency to establish a lowest-observed-adverse-effect level (LOAEL) and a no-observed-adverse-effects level (NOAEL).
                 b.        None of the lines in Figure 1 (Hansson and Roos, 1987, p. 316) appear to approach a plateau indicative of a new steady state if NaF dosing were to be continued beyond three years.  While such long-term exposures are clearly a chronic risk (rather than the acute toxicity as stated within the charge question) and the reported increases in BMC are beneficial, the existence of a steady state is essential to assure a benign long-term end point.
                 c.       The next weakness results from the lack of information regarding the incidence of side effects at doses lower than 30 mg/day. Although the lack of data provides some grounds for the statement in the Agency review that "No effects were observed in the lower fluoride treatment group, calcium only group, and placebo group" (D'Agostino, 2014b, p. 9), Hansson and Roos (1987, p. 317) state: "As in these earlier studies, however, not all individuals respond to fluoride treatment and there are some mildly adverse side effects even at low doses." This sentence suggests that such side effects occurred in this study as well, specifically to patients who received less than 30 mg NaF/day.  Imbedded within this weakness is the uncertainty of whether any difference was really intended by the authors between the phrases "mild gastrointestinal symptoms" experienced by four of the patients in Group A (Hansson and Roos, 1987, p. 316) and "mildly adverse side effects" (Hansson and Roos, 1987, p. 317).
                 d.         The last of these weaknesses refers back to the Spak et al. (1989) paper reviewed above.  The fact that all twelve of their subjects tested at 20 mg F showed mucosal damage but only four (25%) developed nausea led those authors to conclude that "using nausea as the first sign of fluoride toxicity might not be valid" (Spak et al., 1989, p. 1686).  While the lowest dose of fluoride given by Hansson and Roos was 4.5 mg F (D'Agostino, 2014b, p. 10), those 1989 findings may have a bearing on the argument that an NOAEL can be based only on symptoms in this 1987 study.

Because a) Hansson and Roos (1987, p. 317) reported that "there are some mildly adverse side effects even at low doses," they imply that effects may have occurred at 10 mg NaF/day and b) Spak et al. (1989, p. 1686) implied that side effects may have occurred that were not reported by subjects, the Hansson and Roos (1987) study (as reported) cannot justify the two key statements in the Agency's science review; viz., "The LOAEL is 30 mg sodium fluoride/day (13.6 mg F/dose), based on gastrointestinal symptoms (nausea and gastritis)" and "The NOAEL is 10 mg sodium fluoride/day (4.5 mg F/dose)" (D'Agostino, 2014b, p. 6).

Ethics
Charge to the Board
   * Does the study meet the applicable requirements of 40 CFR part 26 subpart Q?
Board Response to the Charge

 HSRB Recommendation

   * Considering the time the study was conducted and based on the information provided, the HSRB found that no children or pregnant or nursing women were included and the Board did not find convincing evidence that the study was conducted in a way that placed participants at increased harm or impaired their informed consent. Therefore, this study meets the ethical standards of 40 CFR part 26 subpart Q.
HSRB's Detailed Recommendation and Rationale
The Board generally agreed with the Agency's ethics assessment (Sherman, 2014c).

Does the study meet the applicable requirements of 40 CFR part 26 subpart Q?
The published article provided no information about whether any ethical oversight was provided, how the participants were recruited or compensated, whether informed consent of participants was obtained, whether they were told they could withdraw from the study, to what degree (if any) subjects and/or scientists were blinded to the treatment groups, or how risks to participants were minimized.
Given that the study was conducted on post-menopausal women, there were no children, pregnant or nursing women among the participants.
With very limited information provided about the conduct of the study, the Board determined that it was not possible to affirm whether the research, which was conducted in a foreign country, was done under procedures at least as protective as those in subparts A through L of Subpart Q (required by 26.1705).
However, the HSRB did not find clear and convincing evidence that the conduct of the research was fundamentally unethical (26.1704).

References

Aubier, M., Neukirch, C. Bonay, M. et al. (2007 Mars). Effets bronchiques de l'exposition repetee a de faibles doses de dioxyde d'azote chez des subjets asthmatiques intermittents. pp. 26-96. IN: Background Materials for Hansson and Roos (1987), Appendix 1. Last accessed at http://www.epa.gov/hsrb/jan-14-2015-public-meeting.htm on February 2, 2015.
Berlin, I., & Gorelick, D.A. (2003).  The French law on "protection of persons undergoing biomedical research": implications for the U.S. Journal of Law, Medicine & Ethics, 31, 434-441.
D'Agostino, J. (2014a). Acute oral toxicity study in humans, non-guideline: sodium fluoride. PC Code: 075202. pp. 4-8. IN: Background Materials for Spak (1989). Last accessed at http://www.epa.gov/hsrb/jan-14-2015-public-meeting.htm on February 2, 2015.
D'Agostino, J. (2014b). Controlled prospective study in humans; non-guideline: sodium fluoride (purity not specified). PC Code: 075202. pp. 5-9. IN: Background Materials for Hansson and Roos (1987). Last accessed at http://www.epa.gov/hsrb/jan-14-2015-public-meeting.htm on February 2, 2015.
Ezratty, V., Guillossou, G. Neukirch, C., et al. (2014, August). Repeated nitrogen dioxide exposures and eosinophilic airway inflammation in asthmatics: A Randomized Crossover Study. Environmental Health Perspectives, 122(8), 850-855.
Hansson, T., & Roos, B. (1987). The effect of fluoride and calcium on spinal bone mineral content: a controlled, prospective (3 years) study. Calcified Tissue International. 40, 315-317.
Hollander, M. and Wolfe, D.A. (1973). Nonparametric Statistical Methods. New York: John Wiley & Sons.
Leshin, J. (2014). Nitrogen dioxide: evaluation of inhalation toxicity study, Ezratty et al 2014.  pp. 8-19. IN: Background Materials for Ezratty (2014). Last accessed at http://www.epa.gov/hsrb/jan-14-2015-public-meeting.htm on February 2, 2015.
Sherman, K. (2014a). Ethics review of human toxicity study with nitrogen dioxide. pp. 20-24. IN: Background Materials for Ezratty (2014). Last accessed at http://www.epa.gov/hsrb/jan-14-2015-public-meeting.htm on February 2, 2015.
Sherman, K. (2014b). Ethics review of human toxicity with fluoride. pp. 9-12. IN: Background Materials for Spak (1989). Last accessed at http://www.epa.gov/hsrb/jan-14-2015-public-meeting.htm on February 2, 2015.
Sherman, K. (2014c). Ethics review of human toxicity with fluoride. pp. 9-12. IN: Background Materials for Hansson and Roos (1987). pp. 10-13. Last accessed at http://www.epa.gov/hsrb/jan-14-2015-public-meeting.htm on February 2, 2015.
Siegel, S. and Castellan, N.J. Jr. (1988). Nonparametric Statistics for the Behavior Sciences (Second edition). New York: McGraw-Hill Book Company.
Spak, C.-J., Sjostedt, S., Eleborg, L. et al. (1989, June 24). Tissue response of gastric mucosa after ingestion of fluoride. British Medical Journal. 298, 1686-1687.
U.S. Environmental Protection Agency (EPA). (2014, December 31). Human Studies Review Board; Notification of a Public Meeting. 79 FR [Federal Register], pp. 78861-78863. Retrieved January 19, 2015, from https://www.federalregister.gov/articles/2014/12/31/2014-30408/human-studies-review-board-notification-of-a-public-meeting
World Medical Association (WMA). (2004). Declaration of Helsinki - Ethical Principles for Medical Research Involving Human Subjects, with clarification. http://www.wma.net/en/40news/20archives/2004/index.html See "Clarification on Declaration of Helsinki" dated 11.10.2004 (which is October 11, 2004).


[Federal Register: August 19, 2008 (Volume 73, Number 161)]
[Notices]
[Page 48428]
[DOCID:fr19au08-89]

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DEPARTMENT OF TRANSPORTATION

Federal Aviation Administration

Fifth Meeting, RTCA Special Committee 216: Aeronautical System
Security

AGENCY: Federal Aviation Administration (FAA), DOT.

ACTION: Notice of RTCA Special Committee 216 meeting Aeronautical
Systems Security.

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SUMMARY: The FAA is issuing this notice to advise the public of a
meeting of RTCA Special Committee 216: Aeronautical Systems Security.

DATES: The meeting will be held on September 9-12, 2007, from 9 a.m. to
5 p.m.

ADDRESSES: The meeting will be held at EG&G, 2450 Crystal Drive, Suite
500, Crystal City, Arlington, VA 22202, (P)<PHONE_NUMBER>.

FOR FURTHER INFORMATION CONTACT: RTCA Secretariat, 1828 L Street, NW.,
Suite 805, Washington, DC, 20036-5133; telephone<PHONE_NUMBER>; fax
(202) 833 9434; Web site http://www.rtca.org.

SUPPLEMENTARY INFORMATION: Pursuant to section 10(a)(2) of the Federal
Advisory Committee Act (Pub. L. 92-463, 5 U.S.C., Appendix 2), notice
is hereby given for a Special Committee 216 meeting. The agenda will
include:

 September 9-12:
     Opening Session (Welcome, Introductions and Administrative
Remarks, Agenda Overview).
     Subgroup Reports.
     EUROCAE WG-72 Report.
     Other Industry Activities Related to Security--Reports.
     Evaluation of status, progress, and direction based on
subgroup recommendation and Terms of Reference.
     Continued development of SC-216 work products.
     Establish Dates, Location and Agenda for Next Meeting.
     Closing Session (Any Other Business, AssignmentlReview of
Future Work, Establish Agenda, Date and Place of Next Meeting, Closing
Remarks, Adjourn).

    Attendance is open to the interested public but limited to space
availability. With the approval of the chairmen, members of the public
may present oral statements at the meeting. Persons wishing to present
statements or obtain information should contact the person listed in
the ``FOR FURTHER INFORMATION CONTACT'' section. Members of the public
may present a written statement to the committee at any time.

    Issued in Washington, DC, on August 11, 2008.
Francisco Estrada C.,
RTCA Advisory Committee.
[FR Doc. E8-19013 Filed 8-15-08; 8:45 am]

BILLING CODE 4910-13-M


Site Summaries
Pease Air Force Base
Newington/Portsmouth
Contact: Scott Hilton 559-1512
The former Pease Air Force Base site is located in the towns of Newington and Greenland and the City of Portsmouth. Construction of the Strategic Air Command base was completed in 1956 and, on March 31, 1991, Pease AFB officially closed.
In 1983, the Air Force initiated installation restoration program (IRP) activities, to assess and control the migration of contamination that may have resulted from past operations and disposal practices. Based largely upon information gathered by the Air Force during IRP studies, Pease AFB was listed on the NPL on February 21, 1990.
A restoration advisory board (RAB), which includes representatives from local communities, EPA, and the state, was formed to facilitate communication and coordination concerning the IRP activities conducted at Pease AFB. Additional community input was acquired through Seacoast Citizens Overseeing Pease Environment (SCOPE), which received a technical assistance grant from EPA to hire a technical consultant to assist them in their review of the cleanup activities at Pease AFB.
NHDES has concurred with all of the 11 Superfund records of decisions (RODs) signed by EPA and the Air Force. By the summer of 2000, the Air Force had implemented all remedial actions required by Superfund.
In 1993, the Air Force completed the excavation of contaminated soils at the Jet Engine Test Cell site (Site 34), which removed a source of groundwater contamination and has resulted in an improvement in groundwater quality.
In 1994 and 1995, the Air Force excavated waste in contact with groundwater at Landfill 5. Concurrently, solid waste from Landfills 2, 4 and 6 was excavated and consolidated into Landfill 5. In addition, quantities of petroleum-contaminated soil, excavated under the Underground Storage Tank program were placed in Landfill 5. The landfill was then covered with a multi-layered cap, which is regularly inspected and maintained. Groundwater monitoring is ongoing.
In 1995, the Air Force constructed a soil vapor extraction (SVE) and groundwater treatment system to extract and contain contamination at Fire Department Training Area 2. A re-evaluation of the remedy was conducted in 2007 leading to the addition of an air sparge system, improved free-product removal methods and enhanced bio-remediation. The additional remedial components were installed and began operating in 2009. System operations and groundwater monitoring are ongoing.
Also in 1995, the Air Force installed sheet-piling to the top of bedrock to form a physical barrier around the source of groundwater contamination at Building 113 (Site 32) and constructed a groundwater treatment plant to treat groundwater pumped from seven hydraulic containment extraction wells.
At Site 32 it is technically impracticable to extract the source of contamination (dense non-aqueous phase liquids) from the subsurface. Until remedial response technologies are developed that the can overcome the limitations of current technologies, the Air Force will be required to contain the source of contamination until the threat to groundwater quality is mitigated. Performance monitoring is ongoing.
In 1996, the excavation and disposal of sediments in Upper Newfields Ditch and Upper Grafton Ditch was completed. In 1997, the Site 34/39 groundwater extraction system was brought on-line. This system consisted of seven extraction wells positioned to allow containment of groundwater contamination from Sites 34 and 39 and prevent it from migrating towards the Haven well. In 2001, based upon review of performance monitoring data, it was determined this remedial system was not operating properly and successfully in accordance with Section 120(h) (3) of CERCLA. Revision of the remedy through an amendment to the ROD was completed in 2003. The revised remedy includes wellhead treatment capacity for the Haven well and optimization of source area pumping. Construction of the revised remedy started in 2004 and was completed in 2005. Remedial system and groundwater monitoring is ongoing.
In May 1997, an SVE/air sparging system became operational at Burn Area 1, which is located on the west side of the runway. The SVE/Air Sparge treatment system was taken off line in 2004. Comprehensive groundwater sampling in the source area was completed in 2005 and it was determined additional active soil treatment was not needed and natural attenuation was appropriate. Plume monitoring is ongoing.
In 1997, the excavation and disposal of sediments in McIntyre Brook and Pauls Brook was completed.
At the Old Jet Engine Test Stand (Site 45) the SVE system has cleaned up contaminated soils to below regulatory standards and the system was shut down in 1998. Low levels of groundwater contamination are being naturally attenuated and groundwater monitoring is ongoing.
In 1999 the Air Force completed installation of a permeable reactive barrier (PRB) in overburden at Building 234 (Site 73) to clean up groundwater contamination associated with solvent releases. Performance monitoring data indicates the PRB is effective and an operating properly and successfully (OPS) determination was made in 2004. Monitoring is ongoing.
As a result of an environmental site assessment conducted at a site where redevelopment activities were planned, chlorinated solvents were discovered in groundwater in the vicinity of Building 22. The site is now identified as Site 49. In 1997 a site investigation and soil removal action were completed. In the summer of 2000, the Air Force completed installation of a PRB in overburden and shallow bedrock to cleanup groundwater contamination. Performance monitoring is ongoing.
In 2000, groundwater monitoring at Site 10 (Leaded Fuel Tank Sludge Disposal Area) showed dramatic increases in contamination up gradient of the site. Site 10 is located on the west side of the runway and is an area where leaded fuel tank sludge was buried. Source investigation work that included geophysical investigations, geo-probe installations, test pitting and soil sampling was conducted between 2001 and 2003, however no contamination source was found. A comprehensive monitoring program was conducted to track contamination trends. In 2008 it was determined further investigation was needed. A plan for follow on work is currently being discussed with the Air Force.
In 2003, groundwater pumping was terminated at Site 35 because remedial goals were achieved.
In 2003, information was released by the Air Force that indicated waste materials containing residual radioactive contamination generated during cleaning of certain weapons systems in the 1950s and early 1960s may have been buried within the former Weapons Storage Area. The site is being managed under the CERCLA program and geophysical and radiological survey investigations were completed in 2003. Follow on test-pitting investigations were conducted in December of 2004 and did not locate any radiological waste materials. The Final Preliminary Assessment and Site Inspection Report (PA/SI) was completed in November 2006 and recommended no further action.
In addition to Superfund sites at Pease there are over 60 petroleum release sites and several landfill sites that are managed outside of the CERCLA program. The landfill sites have been capped and long-term groundwater monitoring is ongoing. Natural attenuation was the selected remedy for many of the petroleum release sites; however a number have undergone soil removal actions or have active remedial systems. Long-term groundwater monitoring at all petroleum release sites is ongoing to track remedial progress.
At Plume 13/14, one of the larger petroleum release sites, the initial remedial action was not effective. A revised remedial action plan (RAP) was developed to address high levels of soil contamination that remain below the water table. The final revised RAP for Plume 13/14 was approved in 2005 and consisted of a soil vapor extraction and air sparge system. The Plume 13/14 remedial system is one of the largest remedial systems at the former Base. Construction for the SVE/AS remedial system was completed in the spring of 2008 and start-up began in early summer. Excessive explosive vapor generation however caused the system to be shut-down. Additional investigations are being conducted to better understand the causes of the operational problems.
At Pump-House 2, another large petroleum release site the original enhanced bio-remediation remedy was not effective. An alternatives analysis was conducted in 2007 to determine cost and feasibility of a number of remedial alternatives. A SVE/AS remedial system was selected by the Air Force and construction was completed in 2009 with start-up of the system beginning in 2010. Performance monitoring is ongoing.
In addition to the clean-up activities at Pease, environmental survey and property transfer work was completed at the remaining Pease land parcels and the deeded property transfer to the Pease Development Authority (PDA) was completed in 2005. NHDES works closely with the PDA, Air Force and EPA to review planned development activities occurring in areas of environmental use restrictions to ensure institutional controls and other issues associated with contaminated sites are addressed. The Air Force, EPA and NHDES will continue to evaluate long-term monitoring data to ensure response actions are optimized and remedial objectives are achieved in a timely and cost effective manner.