Clinical trial NCT03802721
Conditions: Environmental Exposure
Keywords: Benzo[a]pyrene Accelerator Mass Spectrometry Polycyclic Aromatic Hydrocarbons cruciferous vegetable Brussels sprouts 3,3'-diindolylmethane DIM indole-3-carbinol I3C PAH
Sponsor: Oregon State University
Start date: 2019-01-24; Completion date: 2024-02-01
Enrollment: 7 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Evaluation of the pharmacokinetics for \[14C\]-benzo\[a\]pyrene (\[14C\]-BaP) and metabolites in plasma and urine over 48 hours following a 50 ng dose (5.4 nCi) alone, following 7 days' consumption of Brussels sprouts, and following 7 days' consumption of a supplement containing 3,3'-diindolylmethane (DIM).

Detailed description:
The pharmacokinetics for \[14C\]-BaP and metabolites will be assessed by UHLPC-Accelerator Mass Spectrometry (AMS, Lawrence Livermore National Laboratory) in plasma and urine collected over 48 hours following oral doses of 50 ng dose (5.4 nCi) alone, following 7 days' consumption of Brussels sprouts, and following 7 days' consumption of a supplement containing 3,3'-diindolylmethane (DIM).

The investigators hypothesize that pre-administration of Brussels sprouts or DIM will alter \[14C\]-BaP metabolism and increase the rate of elimination consistent with predictions based on a previously developed Physiologically-Based Pharmacokinetic (PBPK) model for BaP. Briefly, this hypothesis will be tested by dosing individuals with 50 ng \[14C\]-BaP alone and, following a 3-week washout period, ingestion of about 50 g Brussels sprouts or 300 mg of 3,3'-diindolylmethane (DIM) supplement for 7 days prior to the \[14C\]-BaP micro-dose. The impact of the supplement and the whole food will be assessed with respect to alterations in uptake from the GI tract, metabolism and rate of elimination. The consumption of cruciferous vegetables will be assessed at the beginning of the study by completion of a dietary questionnaire to examine typical eating patterns in the previous 3 months and by collection and extraction of blood and urine to assay for DIM by LC/ESI-MS/MS-SRM). In addition, for each phase, urine will be assayed for DIM as an estimate of crucifer or DIM supplement intake.

In preclinical and clinical studies, administration of Brussels sprouts or DIM impacts the activity of the same enzymes responsible for the phase 1 (CYP1A1 and CYP1B1) and phase 2 enzymes (GSTM1, UGT, SULT). Monitoring changes in β-estradiol metabolites will confirm the mechanism of alteration in the metabolic profile of \[14C\]-BaP.

Metabolite profiles and kinetics of elimination are predicted to be consistent with a BaP physiologically based pharmacokinetic (PBPK) model developed by Pacific Northwest National Laboratory (PNNL). A non-smoker, not exposed occupationally, receives 270-700 ng of BaP daily; about 95% dietary. The WHO has set an estimated safe daily lifetime (70 year/70 Kg individual, cancer endpoint) exposure to BaP of 42-350 ng. This protocol represents de minimus risk.

Arms: arm 1: Cycle 1: Capsule containing 50 ng (5.4 nCi) \[14C\]-benzo\[a\]pyrene (BaP).

Cycle 2: Subjects will consume 50 g (about 1/2 cup) of lightly steamed Brussels sprouts each evening for 7 days prior to taking capsule containing 50 ng (5.4 nCi) \[14C\]-benzo\[a\]pyrene (BaP).

Cycle 3: Subjects will consume 300 mg DIM supplement ( 2 capsules of BioResponse DIM® 150) each evening for 7 days prior to taking capsule containing 50 ng (5.4 nCi) \[14C\]-benzo\[a\]pyrene (BaP). A 300 mg DIM dose will be co-administrated with the 50 ng BaP dose.

At least 3 weeks will pass between cycles as a washout period.
Interventions: intervention 1: [14C]-benzo[a]pyrene intervention 2: Brussels sprouts before 50 ng dose intervention 3: DIM supplement before 50 ng dose
Intervention descriptions: intervention 1: Oral micro-dose (50 ng) (5.4 nCi) intervention 2: Brussels sprouts for 7 days before 50 ng (5.4 nCi) dose of BaP intervention 3: DIM supplement for 7 days before 50 ng (5.4 nCi) dose of BaP and coadministration with DIM supplement

Protocol documents:
Prot_SAP_ICF_000.pdf: 
 
 
 
 
 
 
 
 
 
RESEARCH PROTOCOL and STATISTICAL ANALYSIS PLAN 
December 7, 2021 
and 
INFORMED CONSENT FORM 
December 3, 2019 
 
Pharmacokinetics of Benzo[a]Pyrene: Impact of Diet 
Principal Investigator: David E. Williams, PhD 
 
NCT03802721 
 
 
 
 
 
 


APPLICATION & PROTOCOL 
 
This new form reflects changes in federal and local policies and procedures and will serve as a bridge between the previous forms and the 
eventual web-based system. Your feedback on the content of this form is vital during this transition. Please email your questions, suggestions, 
and training requests to irb@oregonstate.edu  
 
Thank you for collaborating with the Human Research Protection Program to continuously improve the submission process. 
 
Contents – to link directly to a specific section, hold ‘ctrl’ and click the section in the table of contents 
Section 1 - Submission Type .......................................................................................................................................................................................... 1 
Section 2 - Study Title And Team ................................................................................................................................................................................... 1 
Section 3 - Study Summary ............................................................................................................................................................................................ 2 
Section 4 - Determination Of Whether The Project Requires IRB Review..................................................................................................................... 2 
Section 4.1 - Research ................................................................................................................................................................................................ 2 
Section 4.2 – Human Subjects .................................................................................................................................................................................... 3 
Section 4.3 – OSU Engagement .................................................................................................................................................................................. 4 
Section 5 - Extent Of The Review Required By OSU ...................................................................................................................................................... 5 
Section 6 - OSU Will Be The Responsible Institution ..................................................................................................................................................... 6 
Section 7 - OSU Will Be The Responsible Institution But Review External Documents ................................................................................................. 6 
Section 8 - OSU Will Be The Relying Institution ............................................................................................................................................................. 7 
Section 9 - Regulatory Flexibility .................................................................................................................................................................................... 7 
Section 10 - Review Category ........................................................................................................................................................................................ 9 
Section 10.1 - Exempt Categories............................................................................................................................................................................... 9 
Section 10.2 - Expedited Categories ......................................................................................................................................................................... 11 
Section 11 - Conflicts Of Interest And Competing Relationships ................................................................................................................................. 13 
Section 12 - Sources Of Funding And Support For This Project ................................................................................................................................... 14 
Section 13 - Study Overview ........................................................................................................................................................................................ 15 
Section 14 - Target Enrollment .................................................................................................................................................................................... 19 
Section 15 - Participant Demographics ........................................................................................................................................................................ 19 
Section 16 - Identification And Recruitment Of Participants ....................................................................................................................................... 23 
Section 17 - Informed Consent .................................................................................................................................................................................... 24 
Section 17.1 - Obtaining Consent ............................................................................................................................................................................. 24 
Section 17.2 - Written Consent ................................................................................................................................................................................ 25 
Section 17.3 - Consent Process ................................................................................................................................................................................. 25 
Section 17.4 - Parental Permission ........................................................................................................................................................................... 26 


APPLICATION & PROTOCOL 
 
Section 17.5 - Non-English Speakers ........................................................................................................................................................................ 27 
Section 17.6 - Education Records ............................................................................................................................................................................. 27 
Section 17.7 - Capacity To Consent .......................................................................................................................................................................... 28 
Section 18 - Assent ....................................................................................................................................................................................................... 28 
Section 19 - Eligibility Screening .................................................................................................................................................................................. 29 
Section 20 - Methods And Procedures ........................................................................................................................................................................ 31 
Section 21 - Compensation .......................................................................................................................................................................................... 37 
Section 22 - Costs ......................................................................................................................................................................................................... 38 
Section 23 - Education Records ................................................................................................................................................................................... 38 
Section 24 - Drugs Or Biologics .................................................................................................................................................................................... 39 
Section 25 - Dietary Supplements ................................................................................................................................................................................ 45 
Section 26 - Medical Devices ....................................................................................................................................................................................... 48 
Section 27 - Food Or Beverages ................................................................................................................................................................................... 51 
Section 27.1 - Food As Courtesy Or Compensation .................................................................................................................................................. 51 
Section 27.2 - Food As Intervention ......................................................................................................................................................................... 51 
Section 28 - Radiation .................................................................................................................................................................................................. 53 
Section 29 - Biological Samples .................................................................................................................................................................................... 55 
Section 30 - Privacy And Confidentiality ...................................................................................................................................................................... 58 
Section 31 - Record Retention ..................................................................................................................................................................................... 59 
Section 32 – Sharing Data And Biological Samples ...................................................................................................................................................... 61 
Section 33 – Publication ............................................................................................................................................................................................... 62 
Section 34 - Data Security ............................................................................................................................................................................................ 63 
Section 34.1 - Level 1 ................................................................................................................................................................................................ 63 
Section 34.2 - Level 2 ................................................................................................................................................................................................ 63 
Section 34.3 - Level 3 ................................................................................................................................................................................................ 64 
Section 35 - Mandatory Reporting ............................................................................................................................................................................... 65 
Section 36 - Certificate Of Confidentiality ................................................................................................................................................................... 66 
Section 37 - Risks.......................................................................................................................................................................................................... 66 
Section 38 - Benefits .................................................................................................................................................................................................... 69 
Section 39 - Training And Oversight ............................................................................................................................................................................ 69 
Section 40 - Principal Investigator’s Assurance Statements ........................................................................................................................................ 70 
Section 41 - Attachments ............................................................................................................................................................................................. 70 


APPLICATION & PROTOCOL 
1 
 
 
 
 
HRPP Form | v. 4 February 2018 
 
Additional information or instructions 
 
 
Link to information or additional forms 
  Only type into shaded rows that include this pencil icon 
 
External document may need to be submitted 
 
 
 
SECTION 1 - Submission Type  
Check ONE 
 
Track all changes after the initial submission 
 
1 
New submission, not previously reviewed or approved by OSU 
☒ 
2 
Re-submission of an expired protocol 
☐ 
3 
Previously approved protocol with proposed changes (project revision or minor change)  
☐ 
SECTION 2 - Study Title and Team 
 
1 
Study Title 
 
Pharmacokinetics of benzo[a]pyrene: impact of diet 
 
2 
Name of Principal Investigator  
 
David E. Williams, PhD  
 
Submissions will only be reviewed when received directly from the PI. 
 
FAQ Who can be a Principal Investigator (PI)? 
 
 
FAQ Who must be listed as study team members? This FAQ will also assist you in determining whether 
external collaborators must be listed here or whether some collaborators may be certified by the PI after 
approval. 
 
 
Do not list individuals who will receive IRB approval at their own external institution or whose institution 
has determined that they are not engaged 
 
3 
Name of additional study team member(s) to be copied on correspondence. If external to OSU, provide 
email address. 
 
Sandra Uesugi 
 


APPLICATION & PROTOCOL 
 
 
2 
 
 
 
 
HRPP Form | v. 4 March 2018 
 
4 
Name of additional study team member(s) who will not be copied on correspondence. If external to OSU, 
provide email address. 
 
Lisbeth Siddens,  
 
 
If this is a project revision and you are adding or removing study team members, confirm that the track 
change feature of MS Word is on before you make these changes. 
 
SECTION 3 - Study Summary 
 
1 
Using lay language, briefly describe the study purpose or primary research question: 
 
 
We will study how our bodies absorb and eliminate a common pollutant called benzo[a]pyrene (BaP). We 
will study how the body handles low levels of BaP and how this might be affected by cruciferous vegetables 
like Brussels sprouts.  BaP is in the family of PAH compounds, which come from burning material like 
cigarettes or coal. 
 
You will be asked for aims, background justification, and specific methods and procedures in later sections. 
 
SECTION 4 - Determination of Whether the Project Requires IRB Review 
Yes 
No 
N/A 
What types of projects require IRB review? 
 
 
 
SECTION 4.1 - Research 
Yes 
No 
N/A 
 1 
“Research” is defined as a systematic investigation, including research development, testing and 
evaluation, designed to develop or contribute to generalizable knowledge. Does the project involve 
research? 
☒ 
☐ 
 
 
Systematic Investigation 
Typically predetermined method for studying a specific topic, answering a specific question(s), testing a 
specific hypothesis, or developing theory.  A scientific or scholarly activity involving qualitative or 
quantitative data collection and/or data analysis that sets forth an objective(s) and a set of procedures 
intended to reach the objective(s), i.e., to acquire knowledge, develop a theory, or to answer a question. 
 
Includes: Observational studies, interview or survey studies, group comparison studies, pilot studies, test 
development and interventional research. 
 
Generalizable Knowledge 
The intent or purpose of the systematic investigation is dissemination of findings (publication or 
presentation) outside of OSU. Intended to have an impact (theoretical or practical) on others within one’s 
 
 
 


APPLICATION & PROTOCOL 
 
 
3 
 
 
 
 
HRPP Form | v. 4 March 2018 
 
discipline. Dissemination with the intent to influence behavior, practice, theory, future research designs, 
and the like, are contributing to generalizable knowledge. 
 
Research does NOT include: Class projects, some program evaluation, or an examination of just one 
person. Scholarly and journalistic activities (e.g., oral history, journalism, biography, literary criticism, legal 
research, and historical scholarship), including the collection and use of information, that focus directly on 
the specific individuals about whom the information is collected. 
 
2 
If you think the project does NOT involve research, please explain why and provide the relevant project 
details: 
 
 
☒ 
 
 
 
 
SECTION 4.2 – Human Subjects 
Yes 
No 
N/A 
1 
“Human subject” is defined by obtaining data about, or specimens from, one or more living individuals 
through: 
• 
intervention, OR 
• 
interaction, OR 
• 
the collection of identifiable private information  
 
Does the project involve human subjects? 
☒ 
☐ 
 
 
Human Subject 
A living individual about whom an investigator conducting research obtains: 
• 
data through intervention or interaction with the individual; or 
• 
identifiable private information or identifiable biospecimens 
 
Intervention: Includes physical procedures by which data are gathered and manipulation of the subjects or 
the subjects’ environment that are performed for research purposes. 
 
Interaction: Includes communication or interpersonal contact between investigator and subjects. The 
interaction may be as remote as an anonymous, online survey. 
 
Private information: Private information includes information about behavior that occurs in a context in 
which an individual can reasonably expect that no observation or recording is taking place, and 
information which has been provided for specific purposes by an individual and which the individual can 
 
 
 


APPLICATION & PROTOCOL 
 
 
4 
 
 
 
 
HRPP Form | v. 4 March 2018 
 
reasonably expect will not be made public (for example, a medical record). Private information must be 
individually identifiable (i.e., the identity of the subject is or may readily be ascertained by the investigator 
or associated with the information) in order for obtaining the information to constitute research involving 
human subjects. 
 
Identifiable private information: Identifiable private information is private information for which the 
identity of the subject is or may readily be ascertained by the investigator or associated with the 
information. 
 
Identifiable biospecimen: An identifiable biospecimen is a biospecimen for which the identity of the 
subject is or may readily be ascertained by the investigator or associated with the biospecimen. 
 
NOT considered to include human subjects: Projects limited to pre-existing data or samples that were (1) 
not collected for the current project, and (2) not collected by the team members on this project, and (3) 
de-identified by someone who is not associated with the current project. 
 
2 
If you think the project does NOT involve human subjects, please explain why and provide the relevant 
project details: 
 
 
☒ 
 
 
 
 
SECTION 4.3 – OSU Engagement 
Yes 
No 
N/A 
1 
Are any of the following true? 
• 
OSU is the only institution participating in this study 
• 
OSU is the primary awardee on the funding 
• 
OSU employees or students are obtaining consent from participants 
• 
OSU employees or students will have access to individually identifiable data or samples  
☒ 
☐ 
 
If “no” to all four, OSU is not engaged in this research. 
 
 
 
2 
If you think the project does NOT engage OSU in research, please provide the details of OSU’s role in this 
project: 
 
 
☒ 
 
 
 
 
 
If “no” to research, human subjects, OR engagement (4.1-4.3 above), proceed by completing ONLY THE FUNDING SECTION, then 
submit this form to the HRPP office for a formal determination regarding the requirement for IRB oversight. Please also attach any test 


APPLICATION & PROTOCOL 
 
 
5 
 
 
 
 
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instruments, including survey or interview questions, if applicable. 
SECTION 5 - Extent of the review required by OSU 
Yes 
No 
N/A 
FAQ If I am collaborating with researchers at external institutions, which IRB reviews my study? 
 
 
 
1 
Are OSU-affiliated individuals the only people conducting study activities; including recruitment, obtaining 
consent, data collection, data analysis, data or sample sharing or storage? 
☐ 
Skip to 
section 7 
☒ 
 
 
If any of the study team members have an appointment at OSU as well as an external institution, check 
“no” here and identify the additional institution as the “external site”. 
 
 
 
2 
Name of the external site(s) 
 
 
☐ 
Lawrence Livermore National Laboratory (LLNL) and Pacific Northwest National Laboratory (PNNL) 
 
 
 
3 
Name of non-OSU researcher(s) 
 
 
 
 
Dr. Kenneth Turteltaub at LLNL will only receive coded, de-identified samples for analysis.  Dr. Jordan 
Smith at PNNL will only receive coded, de-identified data for analysis. 
 
 
 
 
If this is a project revision and you are adding or removing sites, confirm that the track change feature of 
MS Word is on before you make these changes. 
 
 
 
 
While it need not be described for the IRB, researchers should have a plan for maintaining communication 
between research sites that includes a method for assuring all participating sites: 
• 
have the most current version of the protocol 
• 
are made aware of any adverse events and unanticipated problems involving risks to participants or 
others 
 
 
 
4 
What are the procedures for transferring and storing data or samples between research sites? 
 
 
☐ 
 
A portion of the de-identified coded study samples will be forwarded to LLNL for analysis with no personal 
identifying information contained within the shipment, so there is no risk of loss of confidentiality with the 
mailing of samples to LLNL.   
 
Samples sent to LLNL will be processed at OSU before shipment and are no longer considered 
biohazardous materials after processing.  The radioactivity level in collected blood and urine are well 
below what is considered a background level when we conduct routine laboratory swipe surveys (below 
the limit of detection by liquid scintillation counting) and thus, these samples are not considered 
radioactive material. OSU personnel processing the samples are not exposed to above background levels 
 
 
 


APPLICATION & PROTOCOL 
 
 
6 
 
 
 
 
HRPP Form | v. 4 March 2018 
 
of radioisotopes and/or carcinogen. This material does not pose a biohazard, carcinogen hazard, or 
radioactivity health risk to postal carriers or LLNL employees. 
 
Examples: All data will be stored in, and accessed via, [insert name of approved cloud server]. All mobile 
computer systems will be encrypted with at least the 256-bit. All samples are coded and the linked list of 
identifiers will be stored on a separate local server at the external institution only. 
 
 
 
Information on data security guidance 
 
 
 
SECTION 6 - OSU will be the RESPONSIBLE institution 
Yes 
No 
N/A 
1 
Will OSU be asked to provide IRB review for non-OSU researchers? 
☐ 
☒ 
Skip to 
section 
7 
 
2 
Will one or more of these researchers be affiliated with an institution that has an IRB? 
☐ 
☐ 
 
2a 
If yes, provide any details you have about the status of IRB review at the external institution(s):  
 
 
☐ 
 
 
 
 
3 
Will one or more of these researchers not be affiliated with an institution that has an IRB? 
☐ 
☐ 
 
 
Complete and attach an Individual Investigator Agreement form for each collaborator who is not affiliated 
with an institution that has an IRB. 
 
 
 
4 
Will anyone from the other research sites perform the following activities: 
 
 
 
4a 
Recruit participants  
☐ 
☐ 
 
4b 
Obtain informed consent from participants  
☐ 
☐ 
 
4c 
Collect data or samples 
☐ 
☐ 
 
4d 
Receive individually identifiable data or samples for analysis 
☐ 
☐ 
 
SECTION 7 - OSU will be the RESPONSIBLE institution but Review External Documents 
Yes 
No 
N/A 
1 
Will OSU be asked to approve this study based on review of documents that have already been approved 
by another IRB? 
☐ 
☒ 
Skip to 
section 
8 
 
 
Example: The Washington State University (WSU) IRB has reviewed and approved this study but OSU will 
also review this study and issue a separate approval notice. In this case, the PI can submit copies of the 
 
 
 


APPLICATION & PROTOCOL 
 
 
7 
 
 
 
 
HRPP Form | v. 4 March 2018 
 
documents that have been approved by WSU and skip many sections of this form.  
2 
If yes, are the OSU research activities described accurately and completely in that protocol? If no, please 
explain: 
☐ 
☐ 
 
 
 
 
 
 
If OSU will be asked to base this review on documents already approved by another IRB, proceed by completing ONLY THE CONFLICT 
OF INTEREST, FUNDING, AND ASSURANCE sections of this form, then submit this document, and all relevant external documents, to 
the HRPP office for review. 
SECTION 8 - OSU will be the RELYING institution 
Yes 
No 
N/A 
1 
Will OSU be asked to rely on an IRB at another institution for review of this study? 
☐ 
☒ 
Skip to 
section 
9 
 
 
Example: The Washington State University (WSU) IRB has reviewed and approved this study and the OSU 
will cede oversight to them, but retain a mirror copy of the study file, including all documents approved by 
WSU. 
 
 
 
2 
The external document(s) should describe the overall study. Please briefly describe just OSU’s involvement 
in this study: 
 
 
 
 
 
 
 
 
3 
Will anyone from OSU perform the following activities: 
 
 
 
3a 
Recruit participants  
☐ 
☐ 
 
3b 
Obtain informed consent from participants  
☐ 
☐ 
 
3c 
Collect data or samples 
☐ 
☐ 
 
3d 
Receive individually identifiable data or samples for analysis 
☐ 
☐ 
 
 
If OSU will be asked to rely on IRB review at another institution, proceed by completing ONLY THE CONFLICT OF INTEREST, FUNDING, 
AND ASSURANCE SECTIONS of this form, then submit this document, the external IRB approval letter, and documents approved by that 
IRB to the HRPP office for review. OSU will contact the external institution(s) for review of this request.  
SECTION 9 - Regulatory Flexibility 
Yes 
No 
N/A 
The requirement to comply with some regulations and policies can be waived for eligible studies. To assist 
 
 
 


APPLICATION & PROTOCOL 
 
 
8 
 
 
 
 
HRPP Form | v. 4 March 2018 
 
the HRPP in determining whether this study is eligible for a flexible application of the regulations, answer 
the questions in this section. If “yes” to any item in this section, you may stop and skip to the next section. 
1 
Does the study involve more than minimal risk to participants? 
☒ 
☐ 
 
 
Risk is minimal when the probability and magnitude of harm or discomfort anticipated in the proposed 
research are not greater, in and of themselves, than those ordinarily encountered in daily life or during the 
performance of routine physical or psychological examinations or tests. 
 
 
 
2 
Is there federal funding or a plan for future federal sponsorship for this study? 
☒ 
☐ 
 
 
Research funded or otherwise regulated by a federal agency that has signed on to the Common Rule, 
including all agencies within the Department of Health and Human Services. Included are proof of concept 
studies for federal RFPs, pilot studies intended to support a federal grant application, training and program 
project grants, no-cost extensions. 
 
 
 
3 
Are there contractual obligations or restrictions triggered by a non-federal award that require the 
application of the federal regulations or which require that annual review be conducted by an IRB? 
☒ 
☐ 
 
4 
Does the study involve federally classified research procedures and/or results that are legally knowable 
only by individuals with US government security clearance? 
☐ 
☒ 
 
5 
Is there an NIH-issued or pending Certificate of Confidentiality? 
☒ 
☐ 
 
 
Certificates of Confidentiality protect the privacy of research subjects by prohibiting disclosure of 
identifiable research information to anyone not connected to the research except when the subject 
consents or in a few other specific situations. NIH-funded researchers are automatically issued a Certificate 
through their award if the information collected could be individually identifiable.  
 
 
 
6 
Does the study involve any FDA-regulated components? 
☒ 
☐ 
 
7 
Does the study include any clinical interventions? 
☒ 
☐ 
 
 
For the purposes of this policy, clinical intervention is defined as one that is intended to change or assess a 
health-related processes and/or endpoint. Examples include the use of drugs, dietary supplements, 
devices, blood draws, imaging (e.g., DXA, x-ray), delivery systems (e.g., telemedicine, face-to-face), diet, 
cognitive therapy, exercise, and any intervention that includes treatment, prevention, or diagnostic 
strategies. 
 
 
 
8 
Does this study need to be registered with ClinicalTrials.gov? 
☒ 
☐ 
 
9 
Will any of the participants be prisoners or parolees? This refers to the target population, not incidental 
enrollment. 
☐ 
☒ 
 


APPLICATION & PROTOCOL 
 
 
9 
 
 
 
 
HRPP Form | v. 4 March 2018 
 
 
If “no” to all of the above, the study may be eligible for flexibility in the application of the regulations. 
When applicable, subsequent sections will contain special instructions related to these studies. 
 
 
 
Information on Regulatory flexibility 
 
 
 
SECTION 10 - Review Category 
Yes 
No 
N/A 
 
If the study involves more than minimal risk to participants, it cannot be reviewed as exempt or expedited, 
and is not eligible for regulatory flexibility. Skip to section 11. 
 
If “no” to all of the questions in Section 9, the study may be eligible for regulatory flexibility. For these 
studies, the exempt and expedited categories that follow will serve as examples of research that may be 
deemed minimal risk. However, an actual category will not be assigned and you may opt to skip to section 
11. 
 
The Human Research Protection Program staff will make the final determination of review level based on 
information that you provide throughout the form. However, the selection that you make here will assist 
both you and the HRPP in making an initial determination of the minimum level of review that the 
proposed project requires.  
 
 
 
SECTION 10.1 - Exempt Categories 
Yes 
No 
N/A 
 
Limitations on exemptions: 
 All of the exemptions can be applied to research involving pregnant women, human fetuses, and 
neonates 
 None of the exempt categories can be applied to research involving prisoners as subjects unless the 
research is aimed at a broader subject population and only incidentally includes prisoners 
 Exempt categories 1, 4, 5, 6, can be applied to research involving children 
 Exempt category 1 may not be applied to research involving deception  
 Exempt category 2 may not be applied to research involving children, with one exception:  Exempt 
category 2 can only be applied to research involving educational tests or the observation of public 
behavior when the investigator(s) do not participate in the activities being observed 
 Exempt category 6 may not be applied to research involving the ingestion of alcohol. 
 
 
 
 
Children are defined as persons who have not attained the legal age for consent under the applicable law 
of the jurisdiction in which the research will be conducted. In Oregon, legal age for consent is 18, but that 
is not the case for all states or countries. 
 
 
 
1 
Do ALL of the study activities fall within one or more of the federally defined exempt categories?  
☐ 
Skip to 
☒ 
Skip to 
 


APPLICATION & PROTOCOL 
 
 
10 
 
 
 
 
HRPP Form | v. 4 March 2018 
 
Check all that apply. 
section 
11 
section 
10.2 
1a 
Category 1: Research on educational practices, instructional techniques, and curricula. 
☐ 
 
 
 
Regulation: Research conducted in established or commonly accepted educational settings, involving 
normal educational practices, such as (i) research on regular and special education instructional 
strategies, or (ii) research on the effectiveness of or the comparison among instructional techniques, 
curricula, or classroom management methods. 
 
 
 
1b 
Category 2: Anonymous or non-sensitive research using educational tests, surveys, questionnaires, 
interviews, focus groups, or observation of public behavior. 
☐ 
 
 
 
Regulation: Research involving the use of educational tests (cognitive, diagnostic, aptitude, 
achievement), survey procedures, interview procedures or observation of public behavior, unless: 
(i) information obtained is recorded in such a manner that human subjects can be identified, directly or 
through identifiers linked to the subjects; and  
(ii) any disclosure of the human subjects' responses outside the research could reasonably place the 
subjects at risk of criminal or civil liability or be damaging to the subjects' financial standing, 
employability, or reputation. 
 
 
 
1c 
Category 3: Research using educational tests, surveys, questionnaires, interviews, focus groups, or 
observation of public behavior, not exempt under category 2 above. 
☐ 
 
 
 
Regulation: Research involving the use of educational tests (cognitive, diagnostic, aptitude, 
achievement), survey procedures, interview procedures, or observation of public behavior that is not 
exempt under [category 2 above], if: 
(i) the human subjects are elected or appointed public officials or candidates for public office; or  
(ii) federal statute(s) require(s) without exception that the confidentiality of the personally identifiable 
information will be maintained throughout the research and thereafter. 
 
 
 
1d 
Category 4: Secondary analysis of publicly available or de-identified information.  
☐ 
 
 
 
Regulation:  Research involving the collection or study of existing data, documents, records, 
pathological specimens, or diagnostic specimens, if these sources are publicly available or if the 
information is recorded by the investigator in such a manner that subjects cannot be identified, 
directly or through identifiers linked to the subjects. 
 
 
 
1e 
Category 5: Federally supported research designed to examine public benefit or service programs. 
☐ 
 
 
 
Regulation: Research and demonstration projects which are conducted by or subject to the approval of 
department or agency heads, and which are designed to study, evaluate, or otherwise examine: 
(i) public benefit or service programs;  
 
 
 


APPLICATION & PROTOCOL 
 
 
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HRPP Form | v. 4 March 2018 
 
(ii) procedures for obtaining benefits or services under those programs;  
(iii) possible changes in or alternatives to those programs or procedures; or  
(iv) possible changes in methods or levels of payment for benefits or services under those programs. 
1f 
Category 6: Taste and food quality evaluation and consumer acceptance studies. 
☐ 
 
 
 
Regulation: Taste and food quality evaluation and consumer acceptance studies: (i) If wholesome 
foods without additives are consumed, or (ii) If a food is consumed that contains a food ingredient at 
or below the level and for a use found to be safe, or agricultural chemical or environmental 
contaminant at or below the level found to be safe, by the Food and Drug Administration or approved 
by the Environmental Protection Agency or the Food Safety and Inspection Service of the U.S. 
Department of Agriculture. 
 
 
 
SECTION 10.2 - Expedited Categories 
Yes 
No 
N/A 
1 
If any of the activities do not fit into the exempt categories, do ALL of the study activities fall within the 
federally defined categories for expedited review? Check all that apply. 
 
☐ 
☒ 
Skip to 
section 
11 
☐ 
1a 
Category 1: Research involving drugs or devices that do not require an FDA-issued IND or IDE.  
☐ 
 
 
 
Regulation: Clinical studies of drugs and medical devices only when condition (a) or (b) is met. 
 
(a) Research on drugs for which an investigational new drug application (21 CFR Part 312) is not 
required. 
 
(b) Research on medical devices for which (i) an investigational device exemption application (21 
CFR Part 812) is not required; or (ii) the medical device is cleared/approved for marketing and the 
medical device is being used in accordance with its cleared/approved labeling. 
 
Research on marketed drugs that significantly increases the risks or decreases the acceptability of 
the risks associated with the use of the product is not eligible for expedited review. 
 
 
 
1b 
Category 2: Low volume blood draws. 
☐ 
 
 
 
Regulation: Collection of blood samples by finger stick, heel stick, ear stick, or venipuncture as 
follows: 
 
(a) from healthy, nonpregnant adults who weigh at least 110 pounds. For these subjects, the 
 
 
 


APPLICATION & PROTOCOL 
 
 
12 
 
 
 
 
HRPP Form | v. 4 March 2018 
 
amounts drawn may not exceed 550 ml in an 8 week period and collection may not occur more 
frequently than 2 times per week; or 
 
(b) from other adults and children, considering the age, weight, and health of the subjects, the 
collection procedure, the amount of blood to be collected, and the frequency with which it will be 
collected. For these subjects, the amount drawn may not exceed the lesser of 50 ml or 3 ml per kg 
in an 8 week period and collection may not occur more frequently than 2 times per week. 
 
1c 
Category 3: Non-invasive biospecimen collection (e.g., buccal swabs). 
☐ 
 
 
 
Regulation: Prospective collection of biological specimens for research purposes by noninvasive 
means. 
 
 
 
1d 
Category 4: Non-invasive data collection using routine clinical procedures (e.g., physical sensors applied to 
skin, moderate exercise). 
☐ 
 
 
 
Regulation: Collection of data through noninvasive procedures (not involving general anesthesia or 
sedation) routinely employed in clinical practice, excluding procedures involving x-rays or 
microwaves.  
 
Where medical devices are employed, they must be cleared/approved for marketing. (Studies 
intended to evaluate the safety and effectiveness of the medical device are not generally eligible 
for expedited review, including studies of cleared medical devices for new indications.) 
 
 
 
1e 
Category 5: Research on data or specimens that that have or will be collected for non-research purposes. 
☐ 
 
 
 
Regulation: Research involving materials (data, documents, records, or specimens) that have been 
collected, or will be collected, solely for nonresearch purposes (such as medical treatment or 
diagnosis, student or employment records). 
 
 
 
1f 
Category 6: Collection of data from voice, video, digital, or image recordings made for research purposes. 
☐ 
 
 
1g 
Category 7: Collection of data using surveys, interviews, or focus groups. 
☐ 
 
 
 
Regulation: Research on individual or group characteristics or behavior (including, but not limited 
to, research on perception, cognition, motivation, identity, language, communication, cultural 
beliefs or practices, and social behavior) or research employing survey, interview, oral history, 
focus group, program evaluation, human factors evaluation, or quality assurance methodologies. 
 
 
 
1h 
Category 8: Renewal of research previously approved by the full board that has not yet enrolled subjects; 
is now limited to data analysis; or is closed to enrollment, subjects have completed the interventions, and 
☐ 
 
 


APPLICATION & PROTOCOL 
 
 
13 
 
 
 
 
HRPP Form | v. 4 March 2018 
 
activities are limited to long-term follow up of subjects. 
 
Regulation: Continuing review of research previously approved by the convened IRB as follows: 
(a) the research is permanently closed to the enrollment of new subjects; all subjects have 
completed all research-related interventions; AND the research remains active only for long-term 
follow-up of subjects; OR 
(b) where no subjects have been enrolled and no additional risks have been identified; OR 
(c) where the remaining research activities are limited to data analysis 
 
 
 
1i 
Category 9: Renewal of research not involving an FDA-issued IND or IDE that is re-classified at a full board 
meeting because it involves no more than minimal risk and no new risks were identified at the meeting.  
☐ 
 
 
 
Regulation: Continuing review of research, not conducted under an investigational new drug 
application or investigational device exemption where categories two (2) through eight (8) do not 
apply but the IRB has determined and documented at a convened meeting that the research 
involves no greater than minimal risk and no additional risks have been identified. 
 
 
 
SECTION 11 - Conflicts of Interest and Competing Relationships 
Yes 
No 
N/A 
1 
Does a researcher or family member have a financial or other business interest in an entity that is 
supplying funding, materials, products, equipment, research participants, or the site of data collection for 
the current research project? 
☐ 
☒ 
 
 
Family member is defined as anyone having a relationship to a person as a spouse or domestic partner; 
the parent, child, or sibling of the individual or domestic partner; or any person for whom the individual 
has a legal support obligation 
Examples of conflicting or competing relationships: 
• 
A researcher or family member participates in research on a technology, process or product owned by 
a business in which the faculty member holds a financial interest. 
• 
A researcher participates in research on a technology, process, or product developed by that 
researcher. 
• 
A researcher or family member has a financial or other business interest in an entity that is supplying 
funding, materials, products, equipment, research participants, or the site of data collection for the 
current research project. 
• 
A researcher or family member is employed by or otherwise affiliated with the organization under 
study. 
• 
A researcher has an existing relationship with potential research participants recruited for this project. 
• 
A researcher or family member serves on the Board of Directors of a business that is supplying funding, 
materials, products, equipment, research participants, or the site of data collection for the current 
 
 
 


APPLICATION & PROTOCOL 
 
 
14 
 
 
 
 
HRPP Form | v. 4 March 2018 
 
research project. 
• 
A researcher receives consulting income from an entity that is funding the current research project. 
2 
If yes, please provide details: 
 
 
☐ 
 
 
 
 
 
Conflicts of interest and competing relationships must be disclosed to research participants as part of the 
consent process. 
 
 
 
SECTION 12 - Sources of Funding and Support for this project 
Yes 
No 
N/A 
 
Source(s) of support (check all that apply) 
 
 
 
1 
Is funding for the project pending/awarded? 
☒ 
☐ 
Skip to 
section 
13 
 
2 
Is there internal funding? If yes, indicate sources of funding: 
☐ 
☒ 
 
 
 
 
 
3 
Is there external funding? Check all that apply 
☐ 
☐ 
 
 
3a 
NSF 
☐ 
 
 
3b 
NIH 
☒ 
 
 
3c 
USDA 
☐ 
 
 
3d 
DoD 
☐ 
 
 
3e 
Other federal agency: 
☐ 
 
 
 
 
 
 
3f 
OSU Foundation 
☐ 
 
 
3g 
OSU Agricultural Research Foundation 
☐ 
 
 
3h 
Other non-federal source: 
☐ 
 
 


APPLICATION & PROTOCOL 
 
 
15 
 
 
 
 
HRPP Form | v. 4 March 2018 
 
 
 
 
 
4 
Details of external funding. This information enables OSRAA to match the HRPP/IRB notices to the 
information in Cayuse. 
 
 
☐ 
4a 
Cayuse number: 
 
 
 
17-1040;  17-1713 
 
 
 
 
If externally funded and no Cayuse number is provided, the grant or contract must be attached for 
congruency review. 
 
 
 
4b 
Grant or contract number: 
 
 
 
R01 ES028600 
 
 
 
4c 
Name of PI on grant or contract: 
 
 
 
David E. Williams, PhD 
 
 
 
4d 
Grant or contract title: 
 
 
 
 
Benzo[a]pyrene Micro-dosing of Humans: A New Tool for Exposure, Risk Assessment and Prevention (see 
IRB Protocol 8233 for this document) 
 
 
 
5 
Describe any substantive discrepancies or conflicting information between grant or contract and this 
protocol: 
 
 
☐ 
This protocol only pertains to Aim 3 of the grant. 
 
 
 
6 
Is an external (non-OSU) organization or company providing material, equipment, drugs, supplements, or 
devices for this study? If yes, describe: 
☐ 
☒ 
 
 
 
 
 
SECTION 13 - Study Overview 
Yes 
No 
N/A 
1 
List the study aims or research questions: 
 
 
 
 
Benzo[a]pyrene (BaP) is the most intensely studied of the polycyclic aromatic hydrocarbons (PAHs), 
environmental pollutants formed naturally from forest fires, volcanoes, etc. Anthropogenic sources include 
coal, tobacco smoke, creosotes, coal tar-based pavement sealants, petroleum products including diesel 
and gasoline, wood and mixtures from production of coke, aluminum and graphite, among others1. BaP is a 
class 1, known human carcinogen (Internal Agency for Research on Cancer)2 currently 8th on the ATSDR3 
 
 
 


APPLICATION & PROTOCOL 
 
 
16 
 
 
 
 
HRPP Form | v. 4 March 2018 
 
(Agency for Toxic Substances and Disease Registry, a division of the Centers for Disease Control and 
Prevention) list of agents of concern at high-priority pollutant sites. BaP is strongly associated with lung 
cancer (number one cause of cancer mortality). Previously, EPA IRIS estimated the oral exposure slope 
factor for lifetime cancer risk at 7.3 mg/(kg-day) (Linear Extrapolation Model, no threshold) but a recent 
review of BaP resulted in a lower of that value to 1 mg/(kg-day)4. This risk assessment is based on high 
dose rodent studies. Few studies have been done examining PAHs in human plasma and none following 
administration of defined doses.  
 
Our hypothesis is that pre-administration of Brussels sprouts or 3,3’-diindolylmethane (DIM) will alter 
[14C]-BaP metabolism and increase the rate of elimination consistent with predictions based on a 
previously developed Physiologically-Based Pharmacokinetic (PBPK) model for BaP5. Briefly, this hypothesis 
will be tested by dosing individuals with 50 ng [14C]-BaP alone and, following a 3-week washout period, 
ingestion of ½ cup (about 44 g) Brussels sprouts or 300 mg of 3,3’-diindolylmethane (DIM) supplement for 
1 week prior to the [14C]-BaP micro-dose. The impact of the supplement and the whole food will be 
assessed with respect to alterations in uptake from the GI tract, metabolism and rate of elimination. To 
date, our accelerator mass spectrometry (AMS) studies with PAHs have not investigated the impact of diet 
on [14C]-BaP pharmacokinetics6,7. The consumption of cruciferous vegetables will be assessed at the 
beginning of the study by completion of a dietary questionnaire8 to examine typical eating patterns in the 
previous 3 months and by collection and extraction of blood and urine to assay for DIM by LC/ESI-MS/MS-
SRM)9. In addition, for each phase, urine will be assayed for DIM as an estimate of crucifer or DIM 
supplement intake9. [14C]-BaP and metabolites will be extracted from plasma and urine (with and without 
β-glucuronidase/sulfatase) and shipped to Lawrence Livermore National Laboratory (LLNL) for UPLC-AMS 
analysis. The PK parameters will be assessed at PNNL and the impact of Brussels sprout or DIM 
consumption on uptake, metabolism and elimination of [14C]-BaP determined. In preclinical and clinical 
studies administration of Brussels sprouts or DIM impacts the activity of the same enzymes responsible for 
the phase 1 (CYP1A1 and CYP1B1) and phase 2 enzymes (GSTM1, UGT, SULT)10. Monitoring changes in β-
estradiol metabolites11 will confirm the mechanism of alteration in the metabolic profile of [14C]-BaP. 
 
The results from this study will be disseminated in peer-reviewed toxicology/environmental health 
journals, at scientific meetings and provided to the U.S. EPA for incorporation into their risk assessment 
models. The experimental procedure employs accelerator mass spectrometry (AMS) for analysis. AMS 
(103-109 more sensitive for 14C than scintillation counting) is increasingly used to determine 
pharmacokinetics of drugs under development. A dose given to human volunteers of no more than 1/100 
the expected therapeutic dose or less than 100 µg of [14C]-labeled drug (usually 100-200 nCi) is referred to 


APPLICATION & PROTOCOL 
 
 
17 
 
 
 
 
HRPP Form | v. 4 March 2018 
 
as “microdosing” (Phase 0 studies or eIND studies). This approach has been validated for exploratory 
clinical development by the Consortium for Resourcing and Evaluating AMS Microdosing (CREAM Trial) and 
the EU Microdosing AMS Partnership Programme (EUMAPP). This early use of human subjects in drug 
development is consistent with the goals of the FDA Critical Path Initiative and AMS in exploratory IND 
applications has been addressed by FDA12. AMS has been used in toxicology and carcinogenesis studies. 
AMS sensitivity allows the study of pharmacokinetics and DNA binding of environmental contaminants 
known to be animal carcinogens and suspected of being human carcinogens including the cooked meat 
mutagens PhIP and MeIQx, the mycotoxin and human hepatocarcinogen aflatoxin B1 (AFB1), in addition to 
BaP13. It is noteworthy that our group has successfully completed AMS studies with AFB1 and the PAH, 
dibenzo[def,p]chrysene (DBC)6,7,14. IARC estimates that a non-smoker, not exposed occupationally, will 
receive a daily dose of 270-700 ng of BaP; about 95% through the diet2. The European Union maximum 
limit for BaP in fish is 2,000 ng/Kg f.w. and the FDA Limit of Concern (LOC) is 35,000 ng/Kg. The dose of 50 
ng would be the equivalent of eating 25 or 1.4 g of fish at the EU, and FDA limits, respectively. The World 
Health Organization has set an estimated safe daily lifetime (70 years for a 70 Kg individual, cancer 
endpoint) exposure to BaP of 42-350 ng15. With respect to the internal dose of [14C] of 5.4 nCi, this 
represents 0.6% the dose given in a common diagnostic procedure (14C-urea test for Helicobacter)16 and 4 
to 5 orders of magnitude lower than a recently published paper dosing people with 300 µCi of 
epicatechin17. Therefore, from the standpoint of both chemical and radioisotope dose to the volunteers, 
this protocol represents de minimus risk and that was the finding of the FDA (IND 117175) in a “study may 
proceed” determination for our current study (IRB protocol 5644) which uses a dose of 46 ng (5 nCi). 
 
Provide survey questions, questionnaires, interview and focus group guides, references/citations, etc., as 
separate attachments.  
 
 
 
2 
Provide details of where data will be collected. Examples: Online, OSU campus, K-12 classrooms, U.S. 
parks, senior living communities in Denmark. 
 
 
 
 
All study visits to collect samples and data from subjects will take place in the Clinical Research Center, 
LPSC 407, in the Linus Pauling Institute. 
 
 
 
3 
Provide background justification: 
 
 
 
 
An estimated 95% of daily BaP exposure (270-700 ng, non-occupational; non-tobacco) is dietary1. PAHs, 
including BaP, are especially high in charcoal-broiled or smoked meats and cheeses and almost all foods 
contain appreciable amounts. Exposure to BaP, is associated with cancer of the lung, skin, stomach, ovary 
and testis in addition to non-cancer chronic disease such as asthma, cardiovascular disease and diabetes2. 
The fetus and infant are especially susceptible to PAH exposure. Even though PAHs are ubiquitous 
environmental pollutants of potential concern to human health, there is little or no information on the 
 
 
 


APPLICATION & PROTOCOL 
 
 
18 
 
 
 
 
HRPP Form | v. 4 March 2018 
 
pharmacokinetics of PAHs in humans and certainly no information on the impact of diet. With the 
utilization of AMS located at LLNL, interfaced with Ultra-High Pressure Liquid Chromatography (UPLC), it is 
possible to measure [14C]-isotopically-labeled BaP and metabolites over time in human plasma and urine 
following administration of micro-doses.  
The oral exposure slope factor for cancer risk (70 years, 70 Kg adult) for BaP using a linear, non-threshold 
model (EPA-IRIS) was, until recently4,18 is 7.3 mg/kg-day-1 but a recent review by EPA lowered that number 
to 1 mg/(kg-day). Cal/EPA uses a safety factor for age sensitivity (2.9 mg/kg-day-1). This risk assessment is 
based on high dose (1-100 mg/kg-day) exposures in rodents- 5-6 orders of magnitude higher doses than 
human exposures. This risk assessment may not adequately protect some populations. For comparison, 
our preliminary results show the plasma levels, as determined by AMS at Cmax (highest concentration 
obtained) after dosing individuals with 46 ng [14C]-BaP, were ~ 8 fM (femto(10—15) moles/L), or 107 lower 
than an in vitro study (50 nM) showing no adverse impact on hepatocytes. The sensitivity of AMS allows 
for micro-dosing with [14C]-BaP in humans with de minimus risk to determine [14C]-BaP and individual 
metabolites in the low fM range (2-20 femtograms/mL plasma). Our premise is- the best model for humans 
is humans. Utilizing PBPK models, we can provide a much more accurate estimate of BaP levels in human 
tissues following exposure at environmental levels, when dosed alone or subsequent to a week of 
consuming Brussels sprouts or DIM, as well as individual metabolites.  
 
Cruciferous vegetables (Brussels sprouts, broccoli, cauliflower, turnip, kohlrabi, kale, water cress, radish 
and bok choy), along with the phytochemical 3,3’-diindolylmethane (DIM) derived from cruciferous 
vegetables, have been shown to alter the metabolism of high dose environmental chemicals in preclinical 
animal models10,19.  There are multiple clinical trials ongoing or completed involving cruciferous vegetables, 
DIM or its precursor, indole-3-carbinol (I3C) (www.clinicaltrials.gov). The mechanism of action of DIM in 
alteration of BaP metabolism could occur by inhibition of CYPs involved in bioactivation, induction of CYPs 
and/or phase 2 enzymes (UGT, NQO, SULT, etc.) involved in detoxication (traditionally known as blocking 
mechanisms)10,19. Other than epidemiology studies, there have been no assessments of the potency and 
efficacy of DIM or Brussels sprouts impacting the pharmacokinetics (uptake, metabolism, elimination) of 
BaP or any environmental toxicant at truly environmentally relevant levels. It is important to note that this 
study is not testing any health benefits or claims of DIM or Brussels sprouts as we are not looking at any 
health endpoints in this study. The dose of BaP is almost a million fold lower than the dose producing 
cancer in animals and is in the low range of a safe daily lifetime exposure of 46-350 ng15 established by the 
World Health Organization. 
 
Background justification should support the objectives of the research as well as the knowledge that is 
anticipated from the research results. Explain the need for the study and what gap in knowledge the 
 
 
 


APPLICATION & PROTOCOL 
 
 
19 
 
 
 
 
HRPP Form | v. 4 March 2018 
 
results are expected to fill.  Summarize relevant existing data, literature, past and ongoing studies, and 
how your study ties in with these. 
 
Provide specific methods and procedures in a later section. 
4 
Is the study student-driven (for the purpose of a thesis, dissertation, or other)? 
☐ 
☒ 
 
SECTION 14 - Target Enrollment 
Yes 
No 
N/A 
1 
What is the target enrollment number? 
 
 
☐ 
Up to 50 people will be enrolled in this study. Our goal is for 7 subjects to complete the study. 
 
 
 
 
A target enrollment number is not applicable for studies limited to chart review or review of large, pre-
existing datasets, such as those originating from public health surveillance organizations. 
 
 
 
 
If the study is determined to be exempt, expedited, or eligible for flexibility in the application of the 
regulations, an approximate number is sufficient for the evaluation of risk. The PI will not be required to 
report enrollment numbers to the IRB over the course of the study. However, if the study involves more 
than minimal risk or is FDA-regulated, an exact number is required and cannot be exceeded without prior 
approval.  
 
 
 
FAQ What is the “total target” enrollment number? 
 
 
 
2 
Provide scientific justification for the target enrollment number: 
 
 
☐ 
 
We expect a high percentage of screen failure. If a large number of study enrollees qualify to participate in 
the study, we will stop enrolling subjects prior to reaching our maximum enrollment figure. 
 
 
 
SECTION 15 - Participant Demographics 
Yes 
No 
N/A 
1 
Age ranges  
Check all 
that 
apply 
 
 
1a 
0-7 
☐ 
 
 
1b 
8-17 
☐ 
 
 
1c 
18-89 
☒ 
 
 
1d 
90+ 
☐ 
 
 


APPLICATION & PROTOCOL 
 
 
20 
 
 
 
 
HRPP Form | v. 4 March 2018 
 
 
If the study is intended to be limited to adults, all enrolled participants must have attained the legal age to 
consent to research under the applicable law of the jurisdiction in which the research will be conducted.  
Not all states or countries consider 18 years to be the age of majority; in Oregon it is 18.  Describe nuances 
related to participant age in the inclusion and exclusion criteria sections below. Sample recruitment or 
consent language: “In order to be in this study you must be of legal age to consent, which is 18 in most 
states.” 
 
 
 
2 
Indicate all populations permitted to enroll who may need additional safeguards or for whom additional 
regulations may apply: 
 
 
 
2a 
Children 
☐ 
☒ 
 
 
Guidance on research with children 
 
 
 
2b 
Adults lacking capacity to consent 
☐ 
☒ 
 
2c 
Children in foster care or wards of the state 
☐ 
☒ 
 
Regulations related to enrolling children in foster care or wards of the state 
 
 
 
2d 
Pregnant women AND the study involves more than minimal risk OR a physical intervention 
☐ 
☒ 
☐ 
2e 
Fetuses and/or neonates 
☐ 
☒ 
 
2f 
Prisoners  
☐ 
☒ 
 
 
Guidance on research with prisoners. If in Oregon, submit an application to the Oregon Department of 
Corrections application. If outside of Oregon, contact the state DOC for instructions. 
 
 
 
2g 
Economically or educationally disadvantaged persons 
☒ 
☐ 
 
2h 
American Indians or Alaska Natives 
☒ 
☐ 
 
Guidance for research involving Tribal populations 
 
 
 
2i 
People in the European Union (regardless of citizenship) 
☐ 
☒ 
 
 
Contact the Office of Information Security (IS) if there is a plan to collect data from people who are in the 
EU. IS will determine the applicability of the EU’s General Data Protection Regulation and ensure 
compliance with this regulation when necessary. 
 
 
 
3 
Will any of the following OSU-affiliated groups be permitted to enroll: 
 
 
 


APPLICATION & PROTOCOL 
 
 
21 
 
 
 
 
HRPP Form | v. 4 March 2018 
 
3a 
Students currently enrolled in a class or lab instructed by a study team member 
☐ 
☒ 
 
3b 
Employees who report to or are otherwise supervised by a study team member  
☐ 
☒ 
 
3c 
Any of the study team members 
☒ 
☐ 
 
Guidance on Students and Employees as Research Subjects and self-experimentation. 
 
 
 
3d 
If “yes” to 3a, 3b, or 3c, provide scientific justification for permitting these individuals to enroll and a plan 
for mitigating the potential for actual or perceived coercion: 
 
 
☐ 
 
The PI is the only team member permitted to enroll in this study.  He will be subject to all eligibility 
screening and informed consent procedures described above and his participation will strictly adhere to 
the protocol. 
 
 
 
4 
Will people who do not speak or read English be permitted to enroll? 
☐ 
☒ 
 
4a 
If not, provide justification and information regarding the impact of the exclusion on the generalizability of 
the data: 
 
 
☐ 
 
We do not have the resources to translate documents into other languages or to provide translators over 
the course of the study. Given the nature of this study and the risks involved, it would not be appropriate 
to rely on limited English proficiency or informal translation by a friend or family member, nor would we 
be able to adequately assess comprehension of people with limited English proficiency. This study is not 
powered to create generalizations with a maximum of 7 subjects will complete this study. Therefore, these 
exclusions will not impact the generalizability of the data. 
 
 
 
5 
Are people of any sex, gender/gender identity eligible to participate? 
☒ 
☐ 
 
5a 
If not, who will be included/excluded and why? 
 
 
☒ 
 
 
 
 
6 
Are people of any race or ethnicity eligible to participate? 
☒ 
☐ 
 
6a 
If not, who will be included/excluded and why? 
 
 
☒ 
 
 
 
 
7 
List any inclusion criteria not addressed above and explain why this is a scientifically appropriate 
population for the study: 
 
 
☐ 
• 
Willing to defer blood donation for one month before, throughout, and one month after completion of 
 
 
 


APPLICATION & PROTOCOL 
 
 
22 
 
 
 
 
HRPP Form | v. 4 March 2018 
 
study activities 
• 
Willing to avoid consuming any non-study cruciferous vegetables, I3C or DIM supplements, smoked or 
cured meat or cheeses, or charcoal-grilled meats for 2 weeks prior to and during each study cycle. (gas 
grilled foods acceptable) 
• 
Health history review and physical assessment showing general good health, as determined by study 
physician.  Acceptable physical exam may have been conducted as part of protocol 8233 or 8554 if 
subject has not had significant changes in health status. 
 
8 
List any exclusion criteria not addressed above and explain why this is a scientifically appropriate 
population for the study: 
 
 
☐ 
 
• 
Adults aged 66 years or older –may have altered gut absorption and metabolism that differs from the 
21-65 year old population 
• 
Persons aged 18-20 years old – Prior to January 25, 2016, NIH defined adults as age 21 years and older. 
Our previous studies with BaP and DBC have used study populations aged 21-65, so we will continue to 
use this age range for scientific comparison 
• 
Women who are not post-menopausal or have not had surgical sterilization - to eliminate any 
possibility for fetal exposure 
• 
Smoker (tobacco or other substances) in past 3 months or living with smoker – excessive PAH exposure 
• 
Use of smokeless tobacco in past 3 months- excessive PAH exposure 
• 
Regular use of medications that affect gut motility or nutrient absorption (e.g. cholestyramine, 
sucralfate, orlistat, pro- or anti-motility agents) – altered gut absorption and metabolism 
• 
History of gastrointestinal surgery (e.g. bariatric surgery, cholecystectomy) or gastrointestinal disorder 
(e.g. Crohn’s disease, celiac disease, IBS, or colitis) – altered gut absorption and metabolism 
• 
Current or history of kidney or liver disease – altered PAH metabolism 
• 
Prior high-dose 14C exposure from medical tests. (micro-dose 14C exposure not exclusionary) – 
excessive 14C exposure and potentially high background levels that would interfere with AMS detection 
of 14C-BaP and metabolites  
• 
Occupational PAH exposure (e.g. roofers, asphalt pavers, fire-fighters, etc.) – excessive PAH exposure 
• 
Regular use of indole-3-carbinol or DIM dietary supplements  - altered PAH metabolism 
• 
Allergy or intolerance to Brussels sprouts or similar foods 
 
 
 


APPLICATION & PROTOCOL 
 
 
23 
 
 
 
 
HRPP Form | v. 4 March 2018 
 
SECTION 16 - Identification and Recruitment of Participants 
Yes 
No 
N/A 
1 
How will potential participants be identified and recruited? 
 
 
 
 
We will recruit subjects through postings in OSU Today, Craigslist, local regional and local media, and flyer 
advertisements placed on the OSU campus and throughout the Corvallis area. We also anticipate recruiting 
from the LIFE registry maintained by the Center for Healthy Aging Research (CHAR) at OSU. With the 
exception of contacting individuals on the LIFE registry, only subjects requesting information about the 
study will be contacted, and no subjects will be prospectively contacted by researchers without contact 
first being initiated by the individual.  
 
In situations that potential subjects respond to an abbreviated version of the full text recruitment posting 
(e.g. OSU Today’s 75-word limit for postings), the nurse coordinator can provide the full text of the 
recruiting flier via phone or email if more information is requested. Prior to study enrollment, the 
coordinator may also respond to general inquiries about study logistics (location, number of visits, study 
activities, the basic study schedule and type of specimen collected). 
 
 
 
Information on Recruitment of Research Participants 
 
 
 
 
Letters of support are generally required for studies that involve vulnerable populations. However, the IRB 
may request that you provide letters of support or permission under additional circumstances to ensure 
that appropriate safeguards are in place and/or that the study is feasible. Examples of supporting 
documents include school district permission forms or letters from local organizations attesting to 
feasibility or cultural appropriateness of international studies. 
 
 
 
Attach advertisement or other recruitment material (including content of electronic posts or email). 
 
 
 
2 
Confirm that the recruitment materials include the following information: 
 
 
 
2a 
Study title 
☒ 
☐ 
 
2b 
Name of the Principal Investigator 
☒ 
☐ 
 
2c 
A clear statement that this is research 
☒ 
☐ 
 
2d 
Contact information for study personnel 
☒ 
☐ 
 
3 
If no to any of the above, provide justification for the omission of the item(s): 
 
 
☐ 


APPLICATION & PROTOCOL 
 
 
24 
 
 
 
 
HRPP Form | v. 4 March 2018 
 
 
 
 
 
SECTION 17 - Informed Consent 
Yes 
No 
N/A 
 
“Respect for persons requires that subjects, to the degree that they are capable, be given the opportunity 
to choose what shall or shall not happen to them. This opportunity is provided when adequate standards 
for informed consent are satisfied.” Belmont Report, 1979 
 
 
 
 
Attach all consent forms, verbal consent guides, research information sheets, or other documents used for 
obtaining consent or notifying people of study participation. 
 
 
 
Information on Resources for the Consent and Assent Process 
 
 
 
SECTION 17.1 - Obtaining Consent 
Yes 
No 
N/A 
Information on Elements of informed consent 
 
 
 
1 
Will consent be obtained from all participants? 
☒ 
☐ 
 
2 
Are you seeking a waiver of the requirement of one or more elements of consent? 
☐ 
☒ 
 
 
3 
If yes, which of the criteria below does this study meet? Check all that apply.  
 
 
☒ 
3a 
The research involves no more than minimal risk to the subjects 
☐ 
☐ 
 
3b 
The waiver of consent or omission of one or more the elements of consent will not adversely affect the 
rights and welfare of the subjects 
☐ 
☐ 
 
3c 
The research could not practicably be carried out without the waiver or alteration 
☐ 
☐ 
 
3d 
Study is exempt or eligible for a flexible application of the regulations, and the waiver or alteration will not 
adversely affect the rights (such as FERPA) and welfare of the subjects. 
☐ 
☐ 
 
4 
Whenever appropriate, will the subjects be provided with additional pertinent information after 
participation? 
☐ 
☒ 
 
5 
Does the research involve deception? 
☐ 
☒ 
 
6 
If yes, review the guidance on research involving deception and provide all required information, including 
justification, and describe any debriefing process:  
 
 
☒ 
 
 
 
 
 
Deception occurs as the result of investigators providing false or incomplete information to participants for 
the purpose of misleading research participants.   
 
 
 


APPLICATION & PROTOCOL 
 
 
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HRPP Form | v. 4 March 2018 
 
SECTION 17.2 - Written Consent 
Yes 
No 
N/A 
 
There is no IRB-related requirement for signed consent forms if the study is exempt or eligible for 
regulatory flexibility. However, other laws or regulations, such as FERPA, may require that a signature be 
obtained. 
 
 
 
1 
Will participants be asked to sign written consent forms? 
☒ 
☒ 
☐ 
2 
If not, which of the criteria below does this study meet? Check all that apply. 
 
 
☐ 
2a 
The only record linking the subject and the research would be the informed consent form and the principal 
risk would be potential harm resulting from a breach of confidentiality. Each subject (or legally authorized 
individual) will be asked whether the subject wants documentation linking the subject with the research, 
and the subject's wishes will govern; 
☐ 
 
 
2b 
The research presents no more than minimal risk of harm to subjects and involves no procedures for which 
written consent is normally required outside of the research context; or 
☐ 
 
 
2c 
Study is exempt or eligible for a flexible application of the regulations. 
☐ 
 
 
2d 
Written consent will be obtained for the primary research activities but not for eligibility screening. 
☒ 
 
 
3 
Will participants be provided with a copy of their signed consent form or a written notification or 
explanation regarding the research? 
☒ 
☐ 
☐ 
SECTION 17.3 - Consent Process 
Yes 
No 
N/A 
1 
Indicate where and when consent will be obtained (e.g., in a location that protects the participants’ 
privacy, prior to involvement in any study activities): 
 
 
☐ 
Skip to 
section 
17.4 
 
Consent will be obtained in the Clinical Research Center (LPSC 407). The nurse coordinator will verbally 
review the informed consent document at the screening visit prior to any study activities taking place. We 
will offer subjects an opportunity to voice any questions or concerns, to take time to consult others (family 
members, health care providers), or do any other research that would help them understand the study 
activities before they sign the consent form. Except for telephone screening, no study activities will take 
place before written consent is obtained. 
 
Discussions regarding consent with potential subjects and acquisition of consent will take place in a private 
location with measures taken to ensure privacy (closed doors, periods of time between appointments with 
other subjects). 
 
 
 


APPLICATION & PROTOCOL 
 
 
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HRPP Form | v. 4 March 2018 
 
 
2 
Will consent be obtained in a web-based environment? 
☐ 
☒ 
 
2a 
Will there be a mechanism provided for participants to directly and privately communicate questions or 
concerns to a study team member?  
☐ 
☐ 
☒ 
2b 
If no, explain why: 
 
 
☒ 
 
 
 
 
3 
Explain how comprehension of consent information will be assessed and what questions will be asked of 
the participants to determine comprehension of the study information: 
 
 
☐ 
 
We will ask subjects to briefly, in their own words, describe the details of the study, required activities, and 
their understanding of the risks involved. 
 
 
 
 
Agreement without understanding is not informed consent. Open-ended questions are one useful tool for 
assessing comprehension. Examples: What questions can I answer for you? To ensure that you understand 
what the study involves, would you please tell me what you think we are asking you to do? In your own 
words, can you tell me what the biggest risk to you might be if you enroll in this study? 
 
 
 
SECTION 17.4 - Parental Permission 
Yes 
No 
N/A 
1 
If children may be enrolled in the research, provide a plan for obtaining consent from parents or legal 
guardians:   
 
 
☒ 
Skip to 
section 
17.5 
 
 
 
 
2 
Are you requesting that the requirement for parental permission be waived because (a) the research 
involves no more than minimal risk AND (b) the target population includes children in education settings 
(e.g., K-12 settings, 4-H programs, etc.)?  
☐ 
☐ 
 
3 
Are you requesting that the requirement for parental permission be waived because (a) the research 
involves no more than minimal risk AND (b) the target population includes college or university students 
who are not yet 18 years of age?  
☐ 
☐ 
 
4 
If you are asserting that the requirement for obtaining parental permission is not a reasonable 
requirement to protect children in this study, describe the alternative mechanism for safeguarding the 
rights and welfare of these participants (e.g., notification to parents with an opt-out period): 
 
 
☐ 
 
 
 
 


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27 
 
 
 
 
HRPP Form | v. 4 March 2018 
 
5 
If children the target population is children in foster care or wards of the state, describe the plan and 
process for addressing the potential for changes in guardianship over time and for ensuring that ongoing 
consent is in place from the current guardian: 
 
 
☐ 
 
 
 
 
SECTION 17.5 - Non-English Speakers 
Yes 
No 
N/A 
1 
If participants who do not speak English may be enrolled, describe the investigator’s language proficiency 
in the participants’ native language (conversational, fluent, do not speak the language) and provide 
information regarding the use of a translator, if one will be utilized: 
 
 
☒ 
Skip to 
section 
17.6 
 
 
 
 
Attach all documents that participants will see translated into the language they speak and understand. 
 
 
 
 
Indicate whether you will use a translator and/or an interpreter and explain their qualifications.  Consider 
issues of confidentiality related to using a translator or interpreter and describe instructions that they will 
receive with respect to any sensitive information. If the translator is not a native speaker of the language, 
is not a professional translator, or does not have a master’s degree in languages, provide back translations 
of the documents into English. 
 
 
 
SECTION 17.6 - Education Records 
Yes 
No 
N/A 
Directory information 
 
 
 
1 
If the study involves the collection of individually identifiable education records (e.g., grades, 
assignments), beyond directory-level information, confirm that consent will be obtained in writing or in an 
authenticated environment (valid login credentials required). If the education records will be de-identified 
before they are accessed by the researchers, check “N/A” and skip to 17.7. 
☐ 
 
☒ 
Skip to 
section 
17.7 
2 
If the study involves the collection of education records (e.g., grades, assignments), beyond directory-level 
information, confirm that the following FERPA-required information appears in the consent form: 
 
 
 
2a 
Data to be released (e.g., course grades, assignments, GPA, video-recordings of class activities, etc.) 
☐ 
☐ 
 
2b 
To whom it will be released (e.g., researchers, funding agency, publications, etc.) 
☐ 
☐ 
 
2c 
For what purpose the data is being released  
☐ 
☐ 
 
2d 
A field for the student/participant to include the date consent was given  
☐ 
☐ 
 


APPLICATION & PROTOCOL 
 
 
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SECTION 17.7 - Capacity to Consent 
Yes 
No 
N/A 
1 
If adult participants with diminished or fluctuating capacity to consent will be enrolled, address the 
following areas: 
 
 
☒ 
Skip to 
section 
18 
1a 
Describe how capacity for consent will be determined if some or all participants lack capacity to consent: 
 
 
 
 
 
 
 
1b 
If a participant’s capacity to consent may decline during the study (e.g., beginning stages of dementia), 
explain the plan for ongoing assessment of the participant’s ability to understand that they are 
participating in a study: 
 
 
 
 
 
 
 
1c 
If a participant may regain capacity to consent after being enrolled in the study through a surrogate 
consent process, describe the plan for assessing capacity to consent and the consent process: 
 
 
 
 
 
 
 
1d 
Describe the procedure for identifying a surrogate decision maker for a participant unable to consent: 
 
 
 
 
 
 
 
SECTION 18 - Assent 
Yes 
No 
N/A 
 
The responses in this section should demonstrate an understanding of the target population and the 
nature of assent. 
 
 
 
 
Check both “yes” and “no” for obtaining assent and requesting a waiver of assent when the plan is to 
obtain assent for at least one study activity but not others. Complete the entire section and provide 
clarifying details in the description of the process below. 
 
 
 
Information on Assent and Research with Children 
 
 
 
1 
Will children and/or people who cannot provide consent be enrolled (e.g., individuals lacking capacity to 
consent)? 
☐ 
☒ 
Skip to 
section 
19 
 
2 
Provide a description of the assent process:  
 
 
☐ 
 
 
 
 


APPLICATION & PROTOCOL 
 
 
29 
 
 
 
 
HRPP Form | v. 4 March 2018 
 
3 
Indicate who will discuss the study with the child and, if not the parent, describe their training in 
presenting research in a clear and age-appropriate fashion:   
 
 
☐ 
 
 
 
 
4 
If children enrolled in this study may reach the age of majority (18, in Oregon) before their study 
participation ends, describe the plan and process for obtaining their consent to continue: 
 
 
☐ 
 
 
 
 
5 
Will a written assent document or explanation of research be provided to children? 
☐ 
☐ 
 
Written assent form or verbal assent guide unless requesting a waiver. 
 
 
 
6 
Will a written signature be obtained from children prior to enrollment? 
☐ 
☐ 
 
7 
Will the assent process be strictly verbal (no written document)? 
☐ 
☐ 
☐ 
8 
Are you seeking a waiver of the requirement to obtain assent? 
☐ 
☐ 
 
9 
If yes, check the appropriate reasons below:  
 
 
☐ 
Skip to 
section 
19 
9a 
The ages, maturity, or psychological state of the children to be enrolled make them incapable of providing 
assent; or 
☐ 
☐ 
 
9b 
The intervention or procedure involved in the research holds out a prospect of direct benefit that is 
important to the health or well-being of the children and is available only in the context of the research; or 
☐ 
☐ 
 
9c 
The research involves no more than minimal risk to children, and the research could not practicably be 
carried out without the waiver of assent. 
☐ 
☐ 
 
SECTION 19 - Eligibility Screening 
Yes 
No 
N/A 
1 
Describe the eligibility screening process, including whether it will take place before or after written 
informed consent has been obtained and what will be done with the data if the individual is ineligible to 
proceed (“screen fails”): 
 
 
☐ 
 
Participants will be screened by telephone. A telephone screening guide with an eligibility checklist is 
attached. An overview of study description and activities will be described to individuals during telephone 
screening, and then subjects will be asked eligibility screening questions. Participants who qualify by 
telephone screening will be scheduled for a screening visit for in-depth written consent and health 
screening. Subjects that are not eligible based on their responses to the telephone screening questions will 
 
 
 


APPLICATION & PROTOCOL 
 
 
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HRPP Form | v. 4 March 2018 
 
be thanked for their interest and told that they do not qualify to participate in the study. Any personal 
information gathered will be shredded or deleted immediately.   
 
We seek a waiver for the telephone screening portion of the recruitment to be able to collect screening 
information over the telephone prior to the screening visit to make the best use of participant and study 
team time. The telephone screening guide describes the process of obtaining verbal consent for the 
eligibility screening questions. If the subject is eligible for a screening visit, the telephone screening guide is 
filed in the subject’s research record to document the phone screening consent along with the signed 
informed consent form that is subsequently obtained at the screening visit. 
 
Screening visit (60 minutes) 
The nurse coordinator will review the informed consent document including study activities, schedule and 
diet restrictions, answer questions, and provide further information as requested. After written consent is 
obtained, the nurse coordinator will collect demographic information, health history, height, weight, blood 
pressure and heart rate (see Health Assessment Form and Demographic Form). Female subjects will be 
asked to provide a spot urine sample for a pregnancy test. The study physician will perform a physical 
exam.  
Evaluation of eligibility 
The study physician will review Health Assessment information to assess eligibility to continue with the 
study. Subjects who qualify for this study will be notified of their eligibility and invited to participate. 
Subjects that do not qualify based on the screening visit health assessment will be notified of their 
ineligibility and if appropriate, referred to their primary care physician for follow-up. Their written 
consent, telephone screening document, screening visit data will be retained and protected for 
confidentiality. 
Subjects who were previously eligible for IRB protocol 8233 (Benzo[a]pyrene Ultralow Dose-Response 
Study) or IRB protocol 8554 (Ultralow Dose PAH Binary Mixture Study) will be potentially eligible for this 
study without an additional physical exam. All other screening activities, eligibility criteria, and obtaining 
written consent apply (e.g. telephone screening, health assessment, etc.). Any changes in health or 
medication since the previous screening visit will be reviewed by the nurse coordinator, or if significant, by 
the study physician, to determine continued eligibility. If deemed necessary, subjects will undergo another 
physical exam. A subject may not simultaneously participate in this study and 8233 or 8554.  The study 
team will ensure that any subjects who have completed protocol 8233 or 8544 will have at least 3 weeks’ 


APPLICATION & PROTOCOL 
 
 
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HRPP Form | v. 4 March 2018 
 
washout period between 14C-BaP doses from either study. 
Please attach screening guide, eligibility checklist, or similar document. 
 
 
 
SECTION 20 - Methods and Procedures 
Yes 
No 
N/A 
1 
Provide a description of the methods and procedures to be followed during this research project: 
 
 
 
 
All study activities will take place in the Clinical Research Center in the Linus Pauling Science Center, room 
407. 
Screening visit (60 minutes) 
The nurse coordinator will review the informed consent document including study activities, schedule and 
diet restrictions, answer questions, and provide further information as requested. After written consent is 
obtained, the nurse coordinator will collect demographic information, health history, height, weight, blood 
pressure and heart rate (see Health Assessment Form and Demographic Form). Female subjects will be asked
to provide a spot urine sample for a pregnancy test. The study physician will perform a physical exam. 
Fasting is not required for this visit. 
Cruciferous vegetable intake survey 
Subjects will be asked to complete the Arizona Cruciferous Vegetable Food Frequency Questionnaire8 before
they begin the first cycle. The time frame of the questionnaire will cover the previous 3 months prior to the 
first study cycle (excluding diet restriction period) to obtain baseline levels of cruciferous vegetable intake. 
Diet restrictions 
Subjects will be asked to avoid consuming any non-study cruciferous vegetables, I3C or DIM supplements, 
smoked or cured meat or cheeses, or charcoal-grilled meats for 2 weeks prior to and during each study cycle.
Gas-grilled foods are allowed. Subjects will be provided a list of cruciferous vegetables and condiments to 
avoid. 
Subjects will be asked to confirm they have followed the dietary restrictions before study cycle activities 
begin. Subjects who indicate that they have not followed the diet restrictions for 2 weeks will be allowed to 
have up to two dietary lapses with subsequent washout extension before they will be automatically removed
from the study due to lack of compliance.  
Study cycles (3 total): 
Subjects will be asked to complete a 3-day food diary covering the 3 days prior to each study cycle and 
 
 
 


APPLICATION & PROTOCOL 
 
 
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HRPP Form | v. 4 March 2018 
 
another diary covering the 48 hours of each study cycle. Administration of this diary in our current study (IRB
protocol 5644) showed that, on average, volunteers decreased their dietary BaP exposure by 35-54 ng/day20
The results will be used to estimate dietary intake of PAHs using the latest data from the Joint FAO/WHO 
Expert Committee on Food Additives (JECFA, http://www.food.gov.uk/multimedia/pdfs/poly-aromatic-
hydrocarbons.pdf, accessed 11-7-2016). 
For all 3 cycles: Subjects will fast overnight (no food or drink besides water) before Day 1 of each cycle. 
Subjects will be asked to provide a spot urine sample for baseline analysis and then to empty their bladders 
completely. Female subjects’ urine will also be used for a urine pregnancy test, and test results must be 
negative to proceed with study activities. The results of these pregnancy tests will not be revealed to the 
subject in compliance with the Oregon Health Authority, Laboratory Compliance Section.  
Cycle 1: [14C]-BaP capsule only 
The IV catheter will be placed in an appropriate vein in the forearm or antecubital region by the nurse 
coordinator. Subjects will swallow a capsule containing the [14C]-BaP with 100 mL water. Prior to micro-
dosing with [14C]-BaP, a time zero blood sample of 20 mL will be collected with 10 mL analyzed for 
background plasma levels of BaP (and 62 additional PAHs) with GC-MS/MS19 and the remaining 10 mL 
analyzed for [14C]-BaP and metabolites as with subsequent time points. 
Blood will be sampled at 0, 0.25 0.5, 1.0, 1.5, 2, 3, 4, 8, 24, and 48 hours (11 draws total, 8-9 of which come 
from the catheter). The catheter will remain in place for blood draws through hour 4. After the 4 hour 
blood draw, subjects will have the choice of having the catheter removed and returning for the 8 hour 
blood draw by straight stick, or they can keep the catheter in place and remain on-site until after the 8 
hour blood draw. The subjects will be monitored by the nurse coordinator between blood draws. The 8 
(possibly), 24, and 48 hour blood draws will be done with straight stick phlebotomy. No more than three 
(3) skin punctures will be made in an attempt to draw blood at each visit. The first blood draw of this cycle 
will be 20 mL and then subsequent blood draws will be 10 mL.  
Subjects will be instructed to collect all urine during the entire 48-hour study cycle in containers provided 
by the study team. 
Two hours after swallowing the capsule, a standardized breakfast will be provided, after which subjects 
may resume normal eating and drinking. Snacks or fluids will be provided prior to the standardized 
breakfast if the study team determines it is necessary.  
 


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HRPP Form | v. 4 March 2018 
 
Cycles 2 and 3:  [14C]-BaP capsule with Brussels sprouts and  [14C]-BaP capsule  with DIM 
Visit 0 (20 minutes): Seven days before the capsule is taken, subjects will come to the CRC for a spot urine 
collection (analyzed for DIM an β-estradiol metabolites) and 25 ml blood sample (analyzed for background 
BaP and 62 other PAHs, DIM, β-estradiol and metabolites.) They will pick up their study Brussels sprouts or 
DIM capsules as described below: 
Brussels sprouts: Subjects will be provided 7 days’ servings of frozen, pre-cooked Brussels sprouts. 
Each serving will be about 50 grams (about ½ cup) of frozen Brussels sprouts. Study team members 
will record serving weights before providing to subjects and serving weights will be standardized as 
much as possible. Subjects will be instructed to consume one serving with dinner (defrost, warm 
and season, if desired) during the 7 days prior to the study cycle.  
DIM capsules: Subjects will be provided 7 days’ worth of BioResponse DIM® 150 capsules. They will 
be instructed to take 2 capsules (300 mg total) each evening with dinner during the 7 days prior to 
the study cycle.  
The IV catheter will be placed in an appropriate vein in the forearm or antecubital region by the nurse 
coordinator. Prior to micro-dosing with [14C]-BaP, a time zero blood sample of 25 mL will be collected with 10
mL analyzed for background plasma levels of BaP (and 62 additional PAHs) with GC-MS/MS21 and the 
remaining 15 mL analyzed for DIM as well as β-estradiol and metabolites. Fifteen mL will be taken at the 48 
hour time point to determine what changes may have occurred in blood and urine levels of DIM and 
estrogens. Subjects will swallow a capsule containing the [14C]-BaP with 100 mL water. For the DIM study 
cycle, subjects will also take 2 capsules (300 mg BioResponse DIM®) with the [14C]-BaP capsule.  
Blood will be sampled at 0, 0.25 0.5, 1.0, 1.5, 2, 3, 4, 8, 24, and 48 hours (11 draws total, 8-9 of which come 
from the catheter). The catheter will remain in place for blood draws through hour 4. After the 4 hour 
blood draw, subjects will have the choice of having the catheter removed and returning for the 8 hour 
blood draw by straight stick, or they can keep the catheter in place and remain on-site until after the 8 
hour blood draw. The subjects will be monitored by the nurse coordinator between blood draws. The 8 
(possibly), 24, and 48 hour blood draws will be done with straight stick phlebotomy. No more than three 
(3) skin punctures will be made in an attempt to draw blood at each visit.  
Subjects will be instructed to collect all urine during the entire 48-hour study cycle in containers provided 
by the study team. 
Two hours after swallowing the capsule, a standardized breakfast will be provided, after which subjects 
may resume normal eating and drinking. Snacks or fluids will be provided prior to the standardized 


APPLICATION & PROTOCOL 
 
 
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HRPP Form | v. 4 March 2018 
 
breakfast if the study team determines it is necessary.  
Summary of samples collected for Brussels Sprouts and DIM cycles 
Time point 
Total blood 
collected (mL) 
Urine 
-7 days 
25 
Spot 
0 (background) 
25 
Spot 
0.25 – 24 hours 
90 
(9 x 10 mL) 
Total urine (0-48 hours) 
48  hours 
15 
 
The total amount of blood collected for the BaP-only cycle is 120 mL.  The total amount of blood collected 
for the Brussels sprouts and DIM cycles is 155 mL per cycle. 
Subjects who indicate that they have not consumed the Brussels sprouts or DIM capsules as instructed will 
be allowed to have up to two lapses with subsequent washout and dietary restriction extension before 
they will be automatically removed from study participation due to lack of compliance. 
There will be at least three weeks’ washout period between cycles. Previous multiple micro-dosing of the 
same individual has shown that after 3 weeks there is no detectable [14C] in plasma or urine, validating the 
choice of 3 weeks as adequate for a “washout period”6,7. Extending the washout period will not adversely 
impact the data collected from the subjects but will minimize the subject’s exposure to PAHs. 
Subjects who have participated in IRB protocol 8233 (Benzo[a]pyrene Ultralow Dose-Response Study) or 
IRB protocol 8554 (Ultralow Dose PAH Binary Mixture Study) will participate in only the [14C]-BaP plus DIM 
and [14C]-BaP plus Brussels sprout cycles if they have complete the 50 ng [14C]-BaP-only cycle within the 
prior 12 months. There is no set order to the Brussels sprouts or DIM cycles. 
Subjects will be asked to defer blood donation for one month before, throughout, and for one month after 
completion of the study. At any point during the study, subjects will be referred to their physician if the 
study physician or nurse consider this advisable.  
Processing of samples: 
Blood samples will be centrifuged to obtain plasma and peripheral blood mononuclear cells (PBMCs). The 
[14C]-BaP and metabolites will be extracted directly from plasma by liquid/liquid extraction with ethyl 
acetate. The urine will be pooled over the time periods pre-capsule (baseline), 0 – 12, 12-24, and 24-48 


APPLICATION & PROTOCOL 
 
 
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HRPP Form | v. 4 March 2018 
 
hours. After volumetric quantitation of each pool of urine, 12 mL will be collected, 4 mL will be adjusted to 
pH 5 and half treated with β-glucuronidase/sulfatase prior to extraction with ethyl acetate. The plasma and 
urine extracts will be blown down under argon, sealed in amber vials and shipped to LLNL where they will 
be injected onto an Ultra-Pressure Liquid Chromatograph (UPLC) interfaced via a “moving wire” into the 
AMS22. We will be able to determine femto (10-15) g/mL levels of BaP and BaP metabolites (by co-elution 
with unlabeled standards available from the OSU Superfund Research Center PAH repository). The time-
course of blood and urine levels of parent BaP and metabolites will be used to construct a pharmacokinetic 
model5. In addition, DNA isolated from PBMCs at 0 hr and 48 hr will be counted directly on the AMS to 
check for levels of covalent DNA binding. 
DIM levels in blood and urine will be measured as follows: Triplicate samples from each time point or 
pooled urine samples will be spiked with [2H2]DIM internal standard and incubated 20 hours at 37°C with 
β-glucuronidase/arylsulfatase. Samples will then be extracted twice with t-butyl methyl ether, solvent 
evaporated with nitrogen stream, and DIM levels determined. We will utilize the recently developed 
LC/ESI-MS/MS-SRM assay9 from Dr. Stephen Hecht’s (a collaborator on the NIH grant funding this work) 
group as a biomarker of both DIM and Brussels sprouts consumption.  
The levels of β-estradiol and metabolites (2-, 4- and 16α-hydroxylated, conjugated and total) is assessed by 
a UPLC-tandem mass spectrometry method11. Briefly, 2 mL of serum is divided into equal fractions with 1 
treated with glucuronidase/arylsulfatase for deconjugation. A liquid-liquid extraction with MTBE is 
performed and the estrogens derivatized with pyridine-3-sulfonyl chloride, re-extracted with MTBE, 
evaporated to dryness under nitrogen and then taken up in 20% methanol in water prior to injection onto 
a UPLC column interfaced to a TSQ mass spectrometer by electro-spray ionization. The identity of each 
metabolite will be determined by UPLC retention time and SRM-MS11.  Dr. Richard van Breemen, Director 
of the Linus Pauling Institute, has expertise with this assay23 and is available for consultation if needed. 
 
 
 
 
 
 
 


APPLICATION & PROTOCOL 
 
 
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HRPP Form | v. 4 March 2018 
 
Summary of sample analyses for Brussels sprouts and DIM cycles 
Time point 
DIM 
blood 
DIM 
urine 
Estrogen 
blood 
Estrogen 
urine 
14C-BaP 
blood 
14C-BaP 
urine 
Background PAH 
blood 
-7 days 
x 
x 
x 
x 
 
 
x 
0 
x 
x 
x 
x 
x 
x 
x 
0.25 – 24 
hours 
x 
x 
 
 
x  
x 
pooled 
 
48  hours 
x 
X 
24-48 
hr pool 
x 
X 
24-48 hr 
pool 
x 
x 
24-48 hr 
pool 
 
 
If the study involves accessing student education records, list all data to be used (e.g. course grades, 
assignments, GPA, video-recordings of class activities, etc.) 
 
 
 
 
Identify any surveys or questionnaires that are being tested or validated instruments that have been 
modified for the purposes of this study. 
 
 
 
Identify any novel or modified experimental activities that are being tested the purposes of this study. 
 
 
 
 
Specific information related to the use of drugs, devices, biologics, food, biospecimens, and radiation will 
be requested later in this document. 
 
 
 
2 
If any of the activities would be conducted regardless of the research, briefly describe those activities here: 
 
 
☒ 
 
 
 
 
 
Example: Grant is funding the expansion of an existing training program. Research will be conducted to 
compare outcomes between participants from the original program and those participating in the 
expanded program. In this scenario, the program would be administered regardless of the research 
question and should be briefly described in this section. 
 
 
 
3 
Describe the qualifications that study team members possess to safely and appropriately conduct the 
study activities: 
 
 
 
 
Williams, PhD in Biochemistry, is a Toxicologist with over 40 years of experience working with Polycyclic 
Aromatic Hydrocarbons (PAHs) and has directed similar human studies involving micro-dosing of PAHs at 
OSU.  
 
 
Uesugi, RN, the Clinical Research Nurse Coordinator (nurse coordinator) has extensive experience in 
 
 
 


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HRPP Form | v. 4 March 2018 
 
clinical research coordination, laboratory research, science communication for the lay public, and project 
management. In addition to being a registered nurse, Ms. Uesugi has completed a certified phlebotomy 
training course, intravenous therapy training, and a clinical research coordinator (CRC) training course. 
 
Siddens has performed carcinogen and radioisotope handling over the course of 32 years, including 15 
years with the study PI. Siddens is trained and approved to handle extreme carcinogens and participates in 
OSU’s medical surveillance program. As the person in charge of the LPI extreme carcinogen facility it is her 
responsibility to dilute extreme carcinogens such as benzo[a]pyrene to concentrations considered safe for 
handling per the OSU EHS guidelines.  Siddens also maintains chemical and ionizing isotope inventories. 
Siddens is trained in proper shipping and handling of biological and hazardous materials. For this protocol, 
Siddens will perform handling of extreme carcinogens, dilute carcinogen solutions as well as BaP capsule 
preparation.  Siddens was trained to carry out the capsule preparation protocol by Dr. Erin Madeen, a 
former graduate student in the Williams lab and person responsible for capsule preparation on previous 
IRBs. Madeen was a pharmacy technician before entering graduate school. The training first entailed 
observing Madeen prepare capsules for several cycles. Under Madeen’s guidance Siddens prepared a set 
of capsules. Capsules were evaluated for the proper level of 14C-BaP with liquid scintillation counting. This 
was repeated over several weeks to ensure consistency over time. 
 
 
4 
Will participants be audio or video recorded for research purposes? 
☐ 
☒ 
 
5 
If “yes”, indicate whether being recorded is required in order to participate and explain this in the consent 
document or guide: 
 
 
☐ 
 
 
 
 
6 
Does the study involve conducting research activities online? 
☐ 
☒ 
 
7 
Is the study designed to be implemented in phases, where fully describing one phase is dependent upon 
the outcome of another?  
☐ 
☒ 
 
IRB approval must be obtained prior to initiating each phase. 
 
 
 
SECTION 21 - Compensation 
Yes 
No 
N/A 
1 
Describe any compensation or incentives for participants: 
 
 
☐ 
 
Subjects will receive $125 for the BaP-only cycle and $150 each for the DIM and Brussels sprouts cycles for 
a total of $425 for the 3 cycles or $300 if only doing the DIM and Brussels sprouts cycles. Subjects who 
 
 
 


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HRPP Form | v. 4 March 2018 
 
discontinue the study early will be paid an amount pro-rated to the percentage of total blood samples 
completed. The amount will be determined by multiplying the number of study blood samples completed 
by $11.36. 
 
Subjects also receive up to $10 worth of breakfast foods and beverages on day 1 of each cycle. 
 
Include details concerning the conditions under which research participants would receive partial payment 
or no payment at all (e.g., withdrawing early from the study) 
 
 
 
SECTION 22 - Costs 
Yes 
No 
N/A 
1 
Describe any costs to participants that are associated with the study (e.g., parking, travel, etc.):  
 
 
☐ 
 
Subjects are responsible for transportation to and from the study site. A parking space outside of LPSC is 
reserved for study subjects during their visits. 
 
 
 
This section should not include costs incurred by the study team or the study. 
 
 
 
SECTION 23 - Education Records 
Yes 
No 
N/A 
 
Education Record is defined by FERPA as a range of information about a student that is maintained in 
schools in any recorded way, such as handwriting, print, computer media, video or audio tape, film, 
microfilm, and microfiche. 
 
 
 
1 
Does the study involve the use of student education records? 
☐ 
☒ 
Skip to 
section 
24 
 
1a 
If yes, list all data to be used (e.g. course grades, assignments, GPA, video-recordings of class activities, 
etc.): 
 
 
 
 
 
 
 
2 
Are any of the education records related to OSU students? 
☐ 
☐ 
 
3 
How will education records will be accessed or obtained (e.g., provided by class instructor; request will be 
submitted to the Office of the Registrar; etc.)? 
 
 
 
 
 
 
 
Information on Feasibility Determinations and Data Requests through the Office of the Registrar 
 
 
 


APPLICATION & PROTOCOL 
 
 
39 
 
 
 
 
HRPP Form | v. 4 March 2018 
 
SECTION 24 - Drugs or Biologics 
Yes 
No 
N/A 
Guidance and decision trees on Drugs, Biologics, and Dietary Supplements 
 
 
 
1 
Are one or more drugs or biologics being studied as part of this project?  
☒ 
☐ 
Skip to 
section 
25 
 
2 
Drug Name (include generic and trade name, if applicable): 
 
 
 
[7-14C]-benzo[a]pyrene (BaP), specific activity 27 µCi/µmol 
 
 
 
3 
Approval Status (e.g., FDA Approved, FDA Approved/Unapproved Use, not FDA approved): 
 
 
 
 
not approved for therapeutic use; this protocol is an amendment to FDA IND 117175 (see IRB Protocol 
8233 for FDA correspondence) 
 
 
 
4 
Has an IND application been submitted to the FDA? 
☒ 
☐ 
 
5 
If no, provide justification: 
 
 
 
 
 
 
 
6 
Chemical formula: 
 
 
 
C20H12 
 
 
 
7 
Dosage strength(s): 
 
 
 
50 ng 
 
 
 
8 
Rationale for choosing the drug or substance dose: 
 
 
 
 
The impact of diet and/or supplements on the pharmacokinetics of a PAH when an individual is exposed to 
an environmentally relevant defined dose has never been determined. This information will be very useful 
to regulatory agencies in order to incorporate this important variable into the risk assessment models for 
PAH mixtures that utilizes the Relative Potency Factor (RPF) approach, derived from animal studies24. BaP 
is the reference compound and has an RPF of 1. The accuracy of the RPF approach is based on the 
assumption that the interaction between all PAHs is additive (same Mechanism of Action or MOA) and that 
high-dose animal data (fed semi-synthetic defined diets) can model human exposure at environmentally 
relevant levels (orders of magnitude lower than the animal studies). If cruciferous vegetables and their 
 
 
 


APPLICATION & PROTOCOL 
 
 
40 
 
 
 
 
HRPP Form | v. 4 March 2018 
 
phytochemical components can impact the uptake, metabolism and/or elimination of BaP, this will have a 
significant impact on the validity of the RPF approach. DIM is an OTC commercially available and common 
supplement which has GRAS status. This study is intended to evaluate the effect on structure or function of 
the body (rate of metabolism and elimination of micro-doses of [14C]-BaP). 
9 
Method/route of administration: 
 
 
 
oral in a food-grade cellulose capsule 
 
 
 
10 
Mechanism of action: 
 
 
 
 
BaP is not a therapeutic, so the mechanism of action described involves the current understanding of BaP 
carcinogenesis. The most well accepted mechanism for BaP carcinogenesis involves metabolic activation25. 
Bioactivation to the ultimate carcinogen is initiated by epoxygenation at the 7,8-position. The epoxide is 
hydrolyzed by the action of the enzyme epoxide hydrolase and a second epoxygenation produces the 
ultimate mutagenic and carcinogenic metabolite, the BaP-7,8-dihydrodiol-9,10-epoxide. The (+)-anti-BaP-
7,8-dihydrodiol-9,10-epoxide metabolite is the most mutagenic and carcinogenic form of BaP. The 
metabolite is formed by oxidative metabolism by cytochrome P450 enzymes (CYPs) enzymes, primarily in 
the liver (also to some degree in lung and GI). The epoxide is chemically unstable and has been shown to 
react with the N2 position in guanine in DNA which can lead to mutations in genome sequence. To date we 
have not detected any of this [14C]-BaP metabolite (or tetrol hydrolysis products) by UPLC-AMS in plasma 
or any covalent DNA adducts in PMBCs. 
 
 
 
11 
Known drug interactions: 
 
 
 
Not applicable at this microdose 
 
 
 
12 
Manufacturer/Sponsor: 
 
 
 
American Radiolabeled Inc. (ARC, custom synthesis) 
 
 
 
13 
Manufacturer/Sponsor Location:  
 
 
 
St. Louis, Missouri 
 
 
 
If manufactured on site at OSU, provide details of facilities and restricted access. 
 
 
 
14 
Name of supplier: 
 
 
 
Same as Manufacturer (custom synthesis) 
 
 
 


APPLICATION & PROTOCOL 
 
 
41 
 
 
 
 
HRPP Form | v. 4 March 2018 
 
15 
Summarize preclinical and early human studies (for studies that are required to have an investigational 
new drug (IND) number): 
 
 
 
 
BaP is one of the most extensively studied PAH environmental contaminants. BaP is a skin carcinogen in 
the rodent 2-stage model involving dermal application and promotion by TPA1,2. In addition to dermal 
exposures, BaP has been documented as an animal carcinogen following oral or inhalation exposures. 
Target tissues include liver, forestomach, esophagus, auditory canal and oral cavity. Occupational 
exposures in humans are associated with increased incidences of cancers of the lung, skin and bladder2.  
 
Animal studies in mouse and rat confirm the carcinogenic potential of BaP when administered by the 
oral route, a mimic of human exposure2. Dose-dependent appearance of tumors can be observed in the 
forestomach, esophagus, tongue and larynx in a somewhat reliable manner. A summary of animal 
studies in which BaP was administered by the oral route is provided in the table below, the dose 
information was converted to mg/kg for ease of comparison. The summary only includes studies which 
evaluated untreated control animals as a negative control. 
 
Animal Studies with Orally Administered Benzo[a]pyrene 
 
Species 
Dose 
(mg/kg) 
Route; 
Regimen 
Duration 
Tumor 
Observations 
Reference 
(all in Ref 2) 
Mouse,A/J 
 
0 
550 
3,350 
 
Oral, 
Diet 
 
260 days 
Forestomach 
tumors 
0/21 (0%) 
5/25 (20%) 
27/27 (100%) 
Weyand et al., 
1995 
Chem Res Toxicol 
8(7): 949-954 
Mouse, B6C3F1 
 
0 
5 
25 
100 
 
Oral, 
Diet 
  
2 years 
Forestomach 
tumors 
1/48 (2%) 
3/47 (6%) 
36/46 (78%) 
46/47 (98%) 
Culp et al., 1998 
Carcinogenesis 
19(1): 117-124 
Mouse,Swiss 
 
0 
50 
Oral 
2X/week, 
4 weeks 
 
27 weeks 
Forestomach 
tumors 
0/10 (0%) 
10/10 (100%) 
Badary et al., 
1999 Eur J Canc 
Prev. 85 435-440 
 
 
 


APPLICATION & PROTOCOL 
 
 
42 
 
 
 
 
HRPP Form | v. 4 March 2018 
 
Mouse, Muta 
 
0 
75 
125 
 
Oral, 
5 consec. 
days 
 
41 weeks 
Forestomach 
tumors 
0/8 (0%) 
10/10 (100%) 
10/10 (100%) 
Hakura et al., 
1998 Regul 
Toxicol Pharmacol 
27(3): 273-279 
Rat, Sprague 
Dawley 
 
0 
6 
39 
Oral, 
1x/9 days 
5X/week 
 
Lifespan 
Combined 
tumors 
3/64 (4.7%) 
3/64 (4.7%) 
10/64 (15.6%) 
Brune et al., 1981 
J Canc Res Clin 
Oncol 102(2): 
153-157 
Rat Crl:CD 
 
0 
63 
Oral, 
1x/week 
8 weeks 
 
49 weeks 
Mammary 
Tumors 
1/30 (3%) 
11/30 (37%) 
El-Bayoumy et 
al.,1995 
Carcinogenesis 
16(2):431-434 
 
The mouse study of Culp et al., 1998 (see above Table) utilized the lowest exposure with 5 mg/kg (a 
dose 100,000 times greater than the dose in our microdose studies) which did not produce a significant 
increase in tumor incidence. This is similar to the rat study of Brune et al., 1981 (see above Table) in 
which a dose of 6 mg/kg did not result in an increase in tumors when animals were monitored for their 
lifetime.  
 
16 
Will an FDA-approved drug be administered for an indication, dose, route of administration, or subject 
population that is different from what has been approved for the marketed product?  If “yes”, explain and 
provide justification and safety information:  
☐ 
☒ 
 
 
 
 
 
17 
Provide the plan for the storage, dispensing, handling, inventory control, and disposal of investigational,  
FDA-approved drugs, and/or biologics:  
 
 
 
 
Preparation Location: The lab where the capsules are prepared (LPSC 383) is not a radiopharmacy.  
Because these capsules are created solely for the purposes of this study and are not to be considered a 
therapeutic drug, they are not made to GMP standards but will be prepared with the highest quality, 
consistency and precision possible. Room 383 is a locked, secure laboratory, and no other activities occur 
in this space besides those related to BaP handling and capsule preparation. Siddens and Williams are the 
only persons with keys to access this space.  
 
 
 


APPLICATION & PROTOCOL 
 
 
43 
 
 
 
 
HRPP Form | v. 4 March 2018 
 
Capsules intended for human use will be prepared in a clean hood dedicated solely to capsule preparation.  
Concentrated 14C-BaP stock solution is not diluted in the same area as capsule preparation. The hood 
where capsule preparation is performed will be surveyed for radioactivity by taking swipes and evaluating 
with liquid scintillation counting. The capsule preparation hood will be sterilized with bleach and alcohol, 
and all work surfaces will be covered with fresh, plastic backed laboratory bench paper.  All pipettes are 
calibrated, dedicated to this procedure, and only used with sterile, filter pipette tips. All Hamilton syringes 
were purchased new, checked for accuracy, and dedicated to this project.    
Material storage & preparation: Prior to use, empty Solaray® capsules and pharmaceutical grade lactose 
monohydrate NF (Spectrum Chemical Mfg. #61-1730890) are stored in an airtight bag in a gasket sealed 
plastic box, in a cabinet in a lab that does not utilize scintillation-detectable radioactivity or human tissues. 
This box contains all microdosing supplies in an area separated from traditional laboratory supplies. 
The [14C]-BaP is shipped as a concentrated solution (0.10 mCi/mL; specific activity = 27 nCi 14C/nmol BaP = 
0.103 nCi/ng) in toluene. This concentrated solution is stored in sealed containers as received from the 
supplier at -80°C in a secure carcinogen laboratory in LPSC 383. In order to ensure radiochemical purity 
(greater than or equal to 98% for the purified concentrated stock) and to prepare a diluted sample suitable 
for human consumption, the compound is collected as a single peak from an HPLC run. The identity of the 
compound is confirmed by co-elution with a non-radioactive standard.  
A working stock solution will be prepared by diluting the 0.10 mCi/mL [14C]-BaP concentrated solution. The 
stock solution will contain 50 ng [14C]-BaP /25 µL = 2 ng/µL (5.4 nCi 14C/25 µL = 0.2 nCi/µL). For example, 
to make 4 mL of stock solution, 8 µL of the 0.10 mCi/mL solution will be aliquoted into a clean vessel. 
Toluene is carefully evaporated off, and the [14C]-BaP aliquot resolubilized into 4 mL 95% food grade 
ethanol. The radioactivity will be checked with a liquid scintillation counter and adjusted to the target 
concentration if needed. 
The stock solution will be aliquoted into clean 2 mL amber glass vials and stored under argon at -80°C. Each 
stock solution is checked for ≥ 95% [14C]-BaP radioisotope purity on a quarterly schedule throughout the 
study. Stock solutions will be checked for both purity and concentration on UPLC using UV detection for 
BaP and radioisotope detection for [14C].  
Capsule preparation, verification and storage:  Siddens and Uesugi have been trained to prepare the 
capsules. As an added safety measure, a second trained study team member will also be present during 
capsule preparation for quality control to verify capsules are produced per specified SOPs.  
Each capsule will contain only the [14C]-BaP and lactose as an excipient.  Empty vegetarian capsules, size 0, 


APPLICATION & PROTOCOL 
 
 
44 
 
 
 
 
HRPP Form | v. 4 March 2018 
 
composed of vegetable cellulose, will be opened and held in a microtube rack. The empty capsules will be 
filled with lactose. The 25 μL aliquot of either stock solution will be applied to the lactose with a calibrated 
pipet fitted with a sterile filter tip. The ethanol is allowed to evaporate, and then the capsules are sealed 
with their caps. 
Five (5) capsules will be prepared in each batch:  Up to two (2) subjects may participate in a study cycle per 
week and three (3) capsules will be used for quality control verification.  
 
Capsules for quality control: Immediately after preparation, 3 of the 5 capsules will each be 
dissolved in 5 ml ultrapure water and 15 ml scintillation cocktail and counted on a liquid 
scintillation counter. Results will be emailed directly to the director of OSU Radiation Safety (RSO). 
Once the RSO has determined that the three evaluated capsules are within 10% variance and 10% 
error, the results are emailed to Siddens or Uesugi. Siddens will then contact Williams and Uesugi 
that the cycle(s) may proceed. If the capsules are not given RSO approval, a new set of capsules 
will be prepared and the subject(s) will be rescheduled if needed. 
 
Capsules for subjects: Two capsules will be stored in sealed vials in the dark in a zipper-lock plastic 
bag with silica desiccant at -20°C until subject consumption. The bag will be labeled appropriately 
(see sample label). Any capsules not used within 1 week will be discarded. 
Dispensing: Capsules will be transported to the Clinical Research Center (407 LPSC) in sealed vials within 
the labeled zipper-lock plastic bag.  The bag will be stored within a plastic box for transportation to the 
clinic. 
 
One (1) capsule containing 50 ng [14C]-BaP will be administered to the subject with 100 mL of water by the 
nurse coordinator at the start of the study cycle. 
 
Inventory control: Information including number of capsules, date of preparation, and operator are 
recorded immediately after capsules are prepared. Date of consumption and disposal of test capsules are 
recorded on day 1 of the cycle. If test capsules do not pass approval by the OSU radiation safety officer, 
the information is still recorded and a new set of capsules will be prepared. 
Disposal: Capsules that are not needed, expired or rejected for human use will be disposed of in the 
radiochemical dry waste at Oregon State University.  
 


APPLICATION & PROTOCOL 
 
 
45 
 
 
 
 
HRPP Form | v. 4 March 2018 
 
Please see IRB Protocol 8233 for lactose, capsule, and [14C]-BaP quality assurance documents. 
18 
Does the use of the test article involve a route of administration or dosage level, use in a subject 
population, or other factor that significantly increases the risks (or decreases the acceptability of the risks) 
associated with its use? If “yes”, explain: 
☐ 
☒ 
 
 
As noted above, the use of [14C]-BaP is not intended to be therapeutic. The great majority of exposure 
(>95%) of the larger molecular weight PAHs, such as BaP, is through the diet in a variety of foods including 
breads and cereals, grains, vegetables and smoke-cured or barbequed meats2. Dietary intakes of total 
PAHs in the U.S./North America have been estimated at 160-3,000 ng/day with BaP alone at 270-700 
ng/day. In Asia, dietary levels of total PAHs are estimated at 55,000 ng/day2. A 2005 report from the 
FAO/WHO Joint Expert Committee on Food Additives and Contaminants listed a mean BaP daily dietary 
intake of 270 ng (70 Kg individual) with 700 ng as a high-level intake1. The European Union maximum limit 
for BaP in smoked meats is 5,000 ng/Kg fresh weight. The dose of 50 ng would be the equivalent of 
approximately 10 g of smoked meat at the EU allowable limit. Compiling all of the animal data, a Virtually 
Safe (Lifetime) Dose (VSD) of 42-350 ng/person/day has been established as the best estimate for a 
lifetime exposure to BaP producing no more than 1 cancer per million people2-4. Therefore, based on the 
chemical mass involved in microdosing (significantly lower than background exposure and levels 
determined to be VSD), this study poses de minimus risk to subjects.  
 
 
 
 
Potential attachments triggered by this section: 
• 
Investigator brochure 
• 
Approved labeling 
• 
Package insert 
• 
Documentation of quality or purity or Certificate of Analysis 
• 
“Safe to Proceed” from the FDA 
• 
Correspondence from the FDA 
• 
Letter from the FDA or industry sponsor setting forth the IND number 
 
 
 
SECTION 25 - Dietary Supplements 
Yes 
No 
N/A 
 
A dietary supplement is a product taken by mouth that is intended to supplement the diet and that 
contains one or more "dietary ingredients". The "dietary ingredients" in these products may include: 
• 
Vitamins 
• 
Minerals 
• 
Herbs or other botanicals 
• 
Amino acids 
 
 
 


APPLICATION & PROTOCOL 
 
 
46 
 
 
 
 
HRPP Form | v. 4 March 2018 
 
• 
Other substances found in human diet, such as enzymes 
 
In some cases, dietary supplements or substances generally recognized as safe (GRAS) are considered to be 
drugs when they are used to diagnose, cure, mitigate, treat, or prevent disease. Under FDA regulations, 
research that involves use of a drug other than the use of a marketed drug in the course of medical 
practice must have an Investigational New Drug (IND) Application, unless the study meets one of the 
exemptions from the IND requirement. 
Guidance and decision trees on Drugs, Biologics, and Dietary Supplements 
 
 
 
1 
Are one or more dietary supplements being studied as part of this project? 
☐ 
☒ 
Skip to 
section 
26 
 
2 
Name of dietary supplement (include generic and trade name, if applicable): 
 
 
 
 
3,3’-diindolylmethane (DIM) - This protocol involves the use of a dietary supplement (BioResponse DIM® 
150), but the supplement is not being studied.  
 
 
 
3 
Approval Status (e.g., FDA Approved, FDA Approved/Unapproved Use, not FDA approved): 
 
 
 
FDA Approved 
 
 
 
 
If a dietary supplement is being used in the study as a drug, the study is regulated by the FDA. Please see 
the Guidance on Drugs, Biologics, and Dietary Supplements for additional information. 
 
 
 
4 
Has an IND application been submitted to the FDA? 
☐ 
☒ 
 
5 
If no, provide justification: 
 
 
 
We are studying the metabolism of [14C]-BaP, not BioResponse DIM® 150. 
 
 
 
6 
Chemical formula: 
 
 
 
C17H14N2 
 
 
 
7 
Dosage strength(s): 
 
 
 
300 mg per day 
 
 
 
8 
Rationale for choosing the drug or substance dose: 
 
 
 


APPLICATION & PROTOCOL 
 
 
47 
 
 
 
 
HRPP Form | v. 4 March 2018 
 
 
BioResponse DIM® 150 (purchased locally) will be used as the standardized source of 3,3’-
diindolylmethane (DIM). We have chosen the BioResponse supplement, rather than purchasing and 
encapsulating DIM from a chemical supply company, as the oral bioavailability is significantly greater26 and 
it more accurately reflects human consumption.  
 
 
 
9 
Method/route of administration: 
 
 
 
 
Subjects will be instructed to take 300 mg (2 x 150 mg capsules) orally with dinner for 7 days prior to the 
study cycle. 
 
 
 
10 
Mechanism of action: 
 
 
 
 
In animal models, DIM is capable of inducing or inhibiting phase 1 (e.g., CYP1A1; CYP1B1) and phase 2 (e.g., 
GSTM1 or UGT1A10) enzymes known to metabolize BaP for elimination.  In human clinical trials (for 
prevention of breast cancer) it has been shown to increase the ratio of (2-hydroxy E2/16α-hydroxy E2). The 
2-hydroxy metabolite is sometimes referred to as the “good estrogen” and 16α-hydroxy as the “bad 
estrogen”10. CYP1B1 is capable of metabolizing estrogen to 4-hydroxy-estrogen which is a “catechol” 
capable of producing oxidative stress at high levels.  DIM actually does not impact CYP1B1 markedly and 
most reports from animal studies indicate inhibition (which would be protective). 
 
 
 
11 
Known drug interactions: 
 
 
 
 
It is possible that DIM could impact the metabolism of other substrates for these enzymes.  However, 
CYP1A1 and CYP1B1 (required for formation of carcinogenic metabolites) rarely are involved in metabolism 
of drugs. This fact and our exclusion criteria with respect to use of therapeutic drugs makes drug 
interaction unlikely.  There are no known drug interactions in humans taking DIM reported in the 
literature.  In addition, the impact of DIM would be transient as it has a half-life in humans of a few hours. 
Any induction or inhibition of enzymes would only last 1-3 days as these enzymes turnover fairly rapidly. It 
is possible that there could be a transient change in estrogen metabolite levels in women taking DIM. 
 
 
 
12 
Manufacturer/Sponsor: 
 
 
 
BioResponse, LLC 
 
 
 
13 
Manufacturer/Sponsor Location:  
 
 
 
Boulder, Colorado 
 
 
 
14 
Name of supplier: 
 
 
 


APPLICATION & PROTOCOL 
 
 
48 
 
 
 
 
HRPP Form | v. 4 March 2018 
 
BioResponse, LLC, purchased locally. 
 
 
 
15 
Summarize preclinical and early human studies (for studies with an IND): 
 
 
☐ 
n/a 
 
 
 
16 
Will an FDA-approved drug be administered for an indication, dose, route of administration, or subject 
population that is different from what has been approved for the marketed product?  If “yes”, explain and 
provide justification and safety information:  
☐ 
☒ 
 
 
 
 
 
17 
Provide the plan for the storage, dispensing, handling, inventory control, and disposal of the dietary 
supplement:  
 
 
 
 
 
 
 
18 
Does the use of the test article involve a route of administration or dosage level, use in a subject 
population, or other factor that significantly increases the risks (or decreases the acceptability of the risks) 
associated with its use? If “yes”, explain: 
☐ 
☒ 
 
 
 
 
 
 
Potential attachments triggered by this section: 
• 
Investigator brochure 
• 
Approved labeling 
• 
Package insert 
• 
Certificate of Analysis or other documentation of quality/purity 
• 
“Safe to Proceed” from the FDA 
• 
Correspondence from the FDA 
• 
Letter from the FDA or industry sponsor setting forth the IND number 
 
 
 
SECTION 26 - Medical Devices 
Yes 
No 
N/A 
 
A medical device is an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, 
or other similar or related article, including a component part, or accessory which is: 
• 
recognized in the official National Formulary, or the United States Pharmacopoeia, or any supplement 
to them, 
• 
intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, 
or prevention of disease, in man or other animals, or 
 
 
 


APPLICATION & PROTOCOL 
 
 
49 
 
 
 
 
HRPP Form | v. 4 March 2018 
 
• 
intended to affect the structure or any function of the body of man or other animals, and which does 
not achieve any of its primary intended purposes through chemical action within or on the body of 
man or other animals and which is not dependent upon being metabolized for the achievement of any 
of its primary intended purposes. 
Guidance and decision trees on medical devices 
 
 
 
1 
Are one or more medical devices being studied as part of this project? 
☐ 
☒ 
Skip to 
section 
27 
 
2 
Indication if data related to the safety or efficacy of the device will be collected: 
 
 
 
 
 
 
 
3 
Rationale for choosing the device to be used:  
 
 
 
 
 
 
 
4 
Device description: 
 
 
 
 
 
 
 
 
The device description can include: 
• 
pictures of the device (where applicable);  
• 
physical, chemical and/or biological processes/principles used by the device to generate device output, 
if applicable;  
• 
physical and biological characteristics of the device output, if applicable;  
• 
explanation of the user interface and/or how the device interacts with other devices or with the user 
(medical professional and/or patient);  
• 
explanation of the materials used in the device;  
• 
a brief explanation of how the device is manufactured (where necessary);  
• 
discussion of the mechanism of action and how the device and/or, if applicable, device output is used;  
• 
for an IVD, detailed technical description of your device including instruments, reagents, components, 
software, principles of operation, and accessories (if there are changes to a previously cleared or 
approved device, then you should describe these changes);  
• 
discussion of the scientific basis for development of the device or an explanation of expected clinical 
utility;  
 
 
 


APPLICATION & PROTOCOL 
 
 
50 
 
 
 
 
HRPP Form | v. 4 March 2018 
 
 
In addition to pictures and a written description, other information about the clinical use of the device, 
such as a surgical technique guide or video of how the device is used in the clinical setting, may be helpful. 
5 
Proposed Intended Use/Indications for Use: 
 
 
 
 
 
 
 
 
Use description can include: 
• 
identification of the disease or condition the device is indicated to prevent, mitigate, screen, monitor, 
treat, or diagnose;  
• 
identification of the target population;  
• 
part of the body or type of tissue to which applied or with which the device is interacting;  
• 
frequency of use;  
• 
physiological use;  
• 
Statement of whether investigators intend to commercialize or market the device; statement of 
whether the device is intended for prescription and/or over-the-counter use;  
 
For an IVD device, this information should include a detailed draft of the intended use of the device 
including the intended use population, the analyte/condition to detect, and the assay methodology. 
 
 
 
6 
Is there an intent to commercialize or patent the device? 
☐ 
☐ 
 
 
If there is commercialization intent or if investigators hold IP rights or interests in this device, it is 
considered a financial interest that should be disclosed in the conflict of interest section of the protocol. 
Additional disclosures may be required in the consent form. 
 
 
 
7 
Will the device(s) be stored in a locked environment under secure control with limited access and in an 
area of the PI’s control? 
☐ 
☐ 
 
8 
Will proper instructions on the use of the device will be provided to the subjects?  
☐ 
☐ 
 
9 
Will a log be kept regarding the receipt, use, and/or dispensing of the device and the disposition of 
remaining devices at the conclusion of the investigation? 
☐ 
☐ 
 
10 
Will the device be labeled in accordance with the FDA’s requirements? 
☐ 
☐ 
 
 
Label that will be placed on the device; including an indication of single-use or directions for sterilization 
between uses. 
 
 
 


APPLICATION & PROTOCOL 
 
 
51 
 
 
 
 
HRPP Form | v. 4 March 2018 
 
SECTION 27 - Food or Beverages 
Yes 
No 
N/A 
If food or food extract will be used as a drug, complete the drug section above instead. 
 
 
 
 
21CFR172: Food Additives Permitted For Direct Addition To Food For Human Consumption (FDA approved)  
21CFR182: Substances Generally Recognized As Safe (FDA affirmed)  
21CFR184: Direct Food Substances Affirmed As Generally Recognized As Safe (FDA affirmed)  
21CFR186: Indirect Food Substances Affirmed As Generally Recognized As Safe (FDA affirmed)  
FEMA GRAS LIST: Flavor & Extract Manufacturers Association, Flavor Ingredient Library (FDA consulted and had no 
questions)  
EAFUS: Everything Added to Food in the United States. Inclusion on this list does not indicate approval or affirmation 
– it simply provides the references and regulations pertaining to a food ingredient 
 
 
 
SECTION 27.1 - Food as Courtesy or Compensation 
Yes 
No 
N/A 
1 
Does the study involve providing participants with commercially purchased food intended as a courtesy or 
compensation? 
☒ 
☐ 
Skip to 
section 
27.2 
 
2 
If the study involves providing participants with commercially purchased food intended as a courtesy or 
compensation, will allergen information (clear labeling or menu with ingredients listed) be provided to the 
participants? If no, explain why: 
☒ 
☐ 
 
 
 
 
 
SECTION 27.2 - Food as Intervention 
Yes 
No 
N/A 
1 
Does the study involve participants ingesting, tasting, or smelling a food or beverage, or a component 
thereof for the purpose of research? 
☒ 
☐ 
Skip to 
section 
28 
 
2 
Name of food, beverage, or component thereof: 
 
 
 
Brussels sprouts 
 
 
 
3 
Supplier (e.g., manufacturer name, grocery store, restaurant): 
 
 
 
Local grocery store 
 
 
 
4 
Is this study a taste and food quality evaluation or consumer acceptance study? 
☐ 
☒ 
 


APPLICATION & PROTOCOL 
 
 
52 
 
 
 
 
HRPP Form | v. 4 March 2018 
 
5 
Will participants consume wholesome foods without additives? 
☒ 
☐ 
 
21CFR172: Food Additives Permitted For Direct Addition To Food For Human Consumption (FDA approved) 
 
 
 
6 
Will the food or beverage consumed contain only ingredients that are at or below the level and for a use 
found to be safe by the Food and Drug Administration? 
☒ 
☐ 
☐ 
7 
Will the food or beverage consumed contain only agricultural chemicals or environmental contaminants at 
or below the level found to be safe (or approved) by the Environmental Protection Agency or the Food 
Safety and Inspection Service of the U.S. Department of Agriculture? 
☒ 
☐ 
☐ 
8 
Has there been a determination by the FDA that the product is Generally Recognized as Safe (GRAS)? 
☐ 
☒ 
 
9 
If yes, provide GRAS number: 
 
 
☒ 
 
 
 
 
10 
Has the determination of GRAS been self-affirmed as a result of published safety data? 
☐ 
☐ 
☒ 
11 
Is the food, beverage, or component food-grade and intended for use in humans? If yes, provide 
documentation. If no, explain and indicate how safety for use in humans is known and attach 
documentation that demonstrates substantial equivalence to ingredients found in the food supply: 
☒ 
☐ 
 
Brussels sprouts are a commonly consumed whole food. 
 
 
 
Certificate of Analysis from the manufacturer; package insert 
 
 
 
All GRAS substances are food-grade. The same substance at another grade is not GRAS. 
 
 
 
12 
Risks to subjects are minimized by ensuring that the proposed products are food-grade. If product is not 
food-grade, compare the analysis to the same product in the USP Food Chemicals Codex and provide an 
assessment of whether the proposed product is substantially equivalent: 
 
 
☒ 
 
 
 
 
13 
Provide the plan for the storage and handling of the food:  
 
 
 
 
The Brussels sprouts used in this study will be commercially frozen and purchased at a local grocery store. 
We will re-package them into individual daily serving portions and weigh portions in the OSU Moore Family 
Center kitchen in Milam Hall. Subjects will receive 7 days’ worth of frozen Brussels sprouts and instructed 
to thaw, gently warm, season as desired and consume each evening with dinner for 7 days prior to the 
study cycle. Study team members handling and preparing the Brussels sprouts will have a current Oregon 
 
 
 


APPLICATION & PROTOCOL 
 
 
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Food Handler’s License and will follow the kitchen preparation and sterilization procedures as outlined in 
the Oregon Health Authority, Division 150, and Food Sanitation Rule. 
 
GMP certificate or food-grade certificate that indicates that the product can be lawfully used in the US 
food supply 
Documentation that the product is an approved food additive (21 CFR 172) 
Safety data if GRAS status is self-affirmed 
 
 
 
SECTION 28 - Radiation 
Yes 
No 
N/A 
The Radiation Safety Officer will review this submission. 
 
 
 
1 
Does the study involve exposing participants to radiation? 
☒ 
☐ 
Skip to 
section 
29 
 
2 
Will any participant be asked to undergo an x-ray procedure (including radiographic and DEXA) while in 
this study?   
☐ 
☒ 
 
2a 
All x-ray procedures are for research use only, and will not be used for medical screening or diagnosis. 
☐ 
☐ 
 
2b 
If diagnostic x-ray scans are performed for medical screening, and all procedures are routine, standard, 
clinical procedures. 
☐ 
☐ 
 
2c 
All participants receiving a diagnostic radiation procedure would have the same procedure for clinical 
reasons even if they were not in this study. 
☐ 
☐ 
 
3 
Will radioactive materials (including nuclear medicine, metabolic, nutrition, toxicity, or drug studies) be 
administered to any participants as part of this study?   
☒ 
☐ 
 
3a 
All procedures involving administration of radioactive materials are routine standard, clinical procedures 
prescribed by a physician. 
☐ 
☒ 
 
3b 
All participants receiving a radioactive material would have the same procedure for clinical reasons even if 
they were not in this study. 
☐ 
☒ 
 
4 
Summarize the “authorized users” training and experience in the use of (ionizing) radiation-emitting 
devices and/or radioactive materials with human participants: 
 
 
 
 
PI/Program Director Williams oversees all radioisotope activities in his laboratory and has made use of 
radioisotopes his entire career.  His experience includes use of many carcinogens, drugs and 
phytochemicals labeled with a variety of different isotopes covering a range of doses in the laboratory and 
in animals. This is the fifth human subject study he has conducted as PI using ultra low dose 14C-labeled 
carcinogens administered to human subjects to study carcinogen metabolism at everyday levels of 
exposure. 
 
 
 


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Lisbeth Siddens has worked at OSU for over 30 years as a laboratory technician and has worked on a 
variety of procedures utilizing isotope-labeled chemicals. Recent work has focused primarily on 3H- and 
14C-labeled carcinogens. Siddens has previously done radiation compliance for other OSU faculty and is 
currently doing so for the Williams laboratory.   She is also approved by chemical safety for handling of 
extreme carcinogens so her experience is ideally suited for this study. Siddens cross-trained with 
McQuistan and Madeen, former study team members involved in carcinogen and isotope handling, record 
training, stock preparation and capsule preparation for this study. 
 
 
Sandra Uesugi, RN has previous laboratory experience handling 14C-labeled radioisotopes. 
 
 
 
 
Uesugi is approved to assist Siddens with capsule preparation for study subjects providing quality control 
and to ensure that a second trained individual is always present to assist and confirm and verify capsules 
are produced per specified SOPs.  Uesugi has also been trained by Siddens to prepare BaP capsules in the 
event that Siddens is not available to prepare capsules for this study. 
5 
Will ionizing or radiation-emitting devices/procedures or drugs be used or evaluated as part of this 
research protocol? 
☐ 
☒ 
 
6 
For each x-ray machine and associated procedure, indicate the total number of exposures per single study 
and per complete research protocol.  A single study is comprised of all procedures performed on a 
participant during a single visit/session. 
 
 
☒ 
6a 
Device or procedure name: 
 
 
 
 
 
 
 
6b 
Total exposures per participant, per study visit: 
 
 
 
 
 
 
 
6c 
Total exposures per participant, per protocol: 
 
 
 
 
 
 
 


APPLICATION & PROTOCOL 
 
 
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7 
For each radioactive material, indicate the activity (mCi) per single dosage, and the total number of 
dosages per single study and per complete research protocol.  A single study is comprised of all dosages 
received by the participant during a single visit/session. 
 
 
☐ 
7a 
Radioactive material name: 
 
 
 
[7-14C]-benzo[a]pyrene (BaP), specific activity 27 µCi/µmol 
 
 
 
7b 
mCi dosage: 
 
 
 
0.0000054 
 
 
 
7c 
Total dose per participant, per study visit: 
 
 
 
1 
 
 
 
7d 
Total exposure per participant, per protocol: 
 
 
 
 
3 (or 2- if subject has completed Protocol 8233 or Protocol 8554 within the past 12 months, they will 
complete only the Brussels sprouts and [14C]-BaP  cycle and DIM and [14C]-BaP cycle, not [14C]-BaP -only 
cycle) 
 
 
 
8 
Radioactive drug(s) prepared on-site will be prepared, assayed, tested, and labeled in accordance with the 
FDA’s requirements? 
☒ 
☐ 
 
9 
Radioactive drug(s) prepared on-site will be prepared, assayed, tested, and labeled in accordance with an 
Radioactive Drug Research Committee’s (RDRC) requirements? 
☐ 
☒ 
 
SECTION 29 - Biological Samples 
Yes 
No 
N/A 
1 
Does the study involve the collection or receipt of biological samples? 
☒ 
☐ 
Skip to 
section 
30 
 
1a 
If yes, indicate what biological samples will be received or collected: 
 
 
 
Blood and urine 
 
 
 
2 
Will samples be obtained prospectively from living individuals? 
☒ 
☐ 
 
3 
Where possible, risks should be minimized by using procedures already being performed on the subjects 
for diagnostic or treatment purposes. Check all that apply: 
☒ 
☐ 
 


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3a 
Samples are being collected separately from any clinically indicated procedure or another approved study 
☒ 
☐ 
 
3b 
Study involves taking additional samples during clinically indicated procedure or another approved study 
☐ 
☒ 
 
3c 
Study involves using samples leftover from a clinically indicated procedure or another approved study 
☐ 
☒ 
 
4 
If blood samples will be collected, provide the maximum volume to be collected in an 8-week period and 
the frequency of collection: 
 
 
☐ 
 
The maximum amount of blood collected in an 8 week period is 310 mL. The [14C]-BaP only cycle involves 
120 mL of blood collection.  The amount collect for the Brussels sprouts and DIM cycles are each 155 mL. 
The total amount of blood collected from each subject is 430 mL (1 cycle at 120 and 2 at 155 mL) or 310 
mL if they are only doing Brussels sprouts and DIM cycles (2 x 155 mL/cycle). 
 
 
 
 
Guidance on Minimal risk blood draw 
 
 
 
5 
Will any clinical lab testing be conducted? If yes, describe the purpose of the tests and whether results will 
be disclosed to participants and/or their treating physician: 
☒ 
☐ 
 
 
We will conduct a urine pregnancy test on female subjects at the screening visit and on day 1 of each cycle 
to ensure no potential for fetal exposure to [14C]-BaP.  A positive test result will exclude subjects from 
further study participation. Results of these tests will neither be disclosed to subjects nor their physician.   
 
 
 
6 
Will the human biological material be tested/collected in a CLIA-certified lab? 
☐ 
☒ 
☐ 
If yes, attach the CLIA certificate 
 
 
 
 
Results from lab tests, including urine pregnancy tests, cannot be disclosed to participants unless the lab 
conducting the test is CLIA-certified. For more information, please see the OSU Guidance for CLIA 
Certification: http://research.oregonstate.edu/irb/clia-certification-guidance  
 
 
 
 
 
Yes 
No 
N/A 
7 
Will the study involve genetic testing? 
☒ 
☐ 
 
7a 
Will test results be disclosed to the participant or their physician? 
☐ 
☒ 
☐ 
7b 
Will disease risk be quantified, including the limits on certainty of the testing? 
☐ 
☒ 
☐ 
7c 
Will a change in a family relationship be disclosed, such as mistaken paternity? 
☐ 
☒ 
☐ 


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HRPP Form | v. 4 March 2018 
 
7d 
Does the participant or family member have the option not to know the results? If yes, how will this 
decision be recorded: 
☒ 
☐ 
☐ 
 
Subjects will not be contacted in the future as there will be no relevant genetic clinical data to share. The 
subject can indicate on the consent form whether or not s/he agrees to have a small number of genes 
(maximum 7) known to be involved in metabolism and excretion of BaP analyzed. The results will not be 
shared as there is no established disease risk. 
 
 
 
7e 
Could other clinically relevant information be uncovered by the study? If yes, explain how (or if) disclosure 
of this information will occur: 
☐ 
☒ 
☐ 
 
 
 
 
7f 
Do any practical limitations exist on the participant's right to withdraw from the research, withdraw data, 
and/or withdraw DNA? If yes, explain: 
☐ 
☒ 
☐ 
 
 
 
 
7g 
Is the participant permitted to participate in the study if they decline to participate in the genetic testing? 
☒ 
☐ 
☐ 
8 
Will samples be stored for future studies?  
☒ 
☐ 
Skip to  
8e 
 
8a 
Indicate how long samples will be retained, how they will be stored, and what they will be used for: 
 
 
 
 
Samples and data will be identified only by an anonymous code. After analysis for this study, the coded 
samples will be stored in LPSC 389 at OSU indefinitely unless not allowed by subjects. Data will be stored 
securely on password protected computers or in locked file cabinets in LPI.  If subjects decline permission 
to store samples beyond the scope of this study, their samples will be properly discarded after analysis. 
Samples and data will only be used in future PAH-related studies. 
 
 
 
8b 
The information in the consent form should convey the disease, condition, or specific field of study for 
future projects. Explain whether and how participant permission will be sought for future studies of 
existing samples: 
 
 
 
 
As stated in the consent form, we will not contact subjects for permission to use their samples and data in 
future projects.  The consent form includes a section for subjects to give permission to use their samples 
and data in future projects without being contacted for consent. They may withdraw permission at any 
point during the study. 
 
 
 
8c 
Indicate whether participants will be contacted by researchers in the future for the purpose of updating 
information: 
 
 
 


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No 
 
 
 
8d 
Indicate whether and how participants can opt out of any sharing or future use of their sample: 
 
 
 
 
The consent form includes a section for subjects to give permission to use their samples and data in future 
projects without being contacted for consent. They may change their answer at any point during the study.  
Since the AMS analysis at LLNL is the primary method of analysis for this study, subjects will not be offered 
the option to opt out of sharing their sample with LLNL. 
 
 
 
 
The Biological Safety Officer will review this portion of the submission unless the materials are exempt 
from biosafety review 
 
 
 
8e 
Provide location(s) of material handling, manipulation, and storage at OSU (i.e., building and room): 
 
 
 
Samples will be collected in LPSC 407. Processing and storage will take place in LPSC 389. 
 
 
 
8f 
Provide the names of all personnel who will be working with biological materials: 
 
 
 
Lisbeth Siddens and Sandra Uesugi 
 
 
 
 
All personnel who will be working with biological materials must have current Blood-borne 
Pathogens Training and any required vaccinations. Information about current status accessed from the 
EH&S website 
 
 
 
 
SECTION 30 - Privacy and Confidentiality 
Yes 
No 
N/A 
 
Many of the terms used in this section are defined in the glossary under the heading “Privacy, 
Confidentiality, and Identifiers”.  
 
 
 
1 
Privacy, in the context of a research protocol, means respecting an individual’s right to be free from 
unauthorized or unreasonable intrusion, including control over the extent, timing, and circumstances of 
obtaining personal information from or about them. Explain how privacy will be respected when 
identifying and recruiting potential participants:  
 
 
☐ 
 
With the exception of contacting individuals on the LIFE registry maintained by the Center for Healthy 
Aging Research (CHAR) at OSU, only subjects requesting information about the study will be contacted, 
and no subjects will be prospectively contacted by researchers without contact first being initiated by the 
individual. We will protect email correspondence by deleting after the subject has completed the study, is 
removed, withdraws from the study, or has been found to not qualify. Telephone and in-person screenings 
will take place in a private location with time between subject visits to maintain privacy. 
 
 
 
 


APPLICATION & PROTOCOL 
 
 
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We will immediately destroy notes taken during telephone screening conversations with excluded 
subjects. We will securely retain records from subjects who are excluded from the study after being 
enrolled. 
2 
Will direct and/or indirect identifiers be requested or recorded? 
☒ 
☐ 
 
3 
If no, will all data be collected anonymously or provided to researchers without identifiers? 
☐ 
Skip to 
section 
31 
☐ 
☒ 
4 
List the direct identifiers (e.g., names, social security numbers, addresses, telephone numbers, student ID, 
medical record number, mTurk ID, photographs, video recording):  
 
 
☐ 
Name, address, email address, telephone number, date of birth 
 
 
 
5 
Indicate whether identifiers or codes will be retained that could link the identity of the participant to the 
sample: 
 
 
☐ 
 
Samples will be labeled only with codes. Only study team members will have access to study samples.  If a 
student employee is hired to assist with processing of de-identified study samples, s/he will always be 
supervised by Siddens, Uesugi or Williams. 
 
 
 
6 
List the indirect identifiers (e.g., combination of demographic and other variables such as gender, race, 
ethnicity, age, zip code, company affiliation, class standing, department, audio recording): 
 
 
☐ 
 
Age, gender, race, ethnicity – this data will be collected on forms containing only subject codes, not direct 
identifiers 
 
 
 
7 
Describe the steps that will be taken to minimize the chances of a breach of confidentiality during and 
after data collection (e.g., coding system, pseudonyms, etc.) 
 
 
☐ 
 
Only the nurse coordinator will have access to the document linking identifiers to subject code numbers. 
Personal information collected during telephone screening, the consent documents, and compensation 
acknowledgement form will be the only documents containing direct identifiers. We will store this 
information separately from coded data.  These documents will be stored in a locked file cabinet in a 
secure office.  Direct identifiers will be stored in hard-copy only. 
 
 
 
 
Details of data security will be collected in later section. 
 
 
 
8 
Will a copy of the consent form, test results, or other research study information be placed in the 
participants’ record (e.g., medical, personnel, or education record)? 
☐ 
☒ 
 
SECTION 31 - Record Retention 
Yes 
No 
N/A 
1 
Will the Principal Investigator store research records in a secure and audit accessible manner for a 
☒ 
☐ 
 


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minimum of three years post-study termination? 
2 
If not, provide justification for early destruction: 
 
 
☒ 
 
 
 
 
3 
Will the student researcher also store research records after the study has closed? 
☐ 
☐ 
☒ 
3a 
Will the records stored by the student contain individually identifiable information? 
☐ 
☐ 
☒ 
4 
If the study is FDA-regulated, confirm the PI will also comply with the following relevant records retention 
requirements: 
 
 
☐ 
4a 
In accordance with 21 CFR 312 (drugs), an investigator or sponsor shall retain the records and reports for 2 
years after a marketing application is approved for the drug; or, if an application is not approved for the 
drug, until 2 years after shipment and delivery of the drug for investigational use is discontinued and FDA 
has been so notified. 
☒ 
☐ 
☐ 
4b 
In accordance with 21 CFR 812 (devices), an investigator or sponsor shall maintain the records required by 
this subpart during the investigation and for a period of 2 years after the latter of the following two dates: 
The date on which the investigation is terminated or completed, or the date that the records are no longer 
required for purposes of supporting a premarket approval application or a notice of completion of a 
product development protocol. 
☐ 
☐ 
☒ 
5 
Will a link between study code numbers and direct identifiers be retained after data collection is 
complete? 
☐ 
☒ 
☐ 
6 
If yes, explain why this is necessary and state how long the link will be retained: 
 
 
☐ 
 
 
 
 
7 
If audio and/or video recording, indicate whether these files will be destroyed after transcripts and/or 
coding is verified. If A/V files will be retained, provide justification for retention: 
 
 
☒ 
 
 
 
 
8 
Will data be stored for future studies?  
☒ 
☐ 
Skip to 
next 
section 
 
8a 
Indicate how long data will be retained, how it will be stored, and what it will be used for: 
 
 
 
See section 29 
 
 
 
8b 
The information in the consent form should convey the area of study for future projects. Explain whether 
and how participant permission will be sought for future studies of existing data: 
 
 
 


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8c 
Indicate whether participants will be contacted by researchers in the future for the purpose of updating 
information: 
 
 
 
 
 
 
 
8d 
Indicate whether and how participants can opt out of any sharing or future use of their data: 
 
 
 
 
 
 
 
SECTION 32 – Sharing Data and Biological Samples  
Yes 
No 
N/A 
1 
Will data and/or samples be shared with individuals or entities external to OSU (e.g., made public, shared 
with sponsor, sent to collaborators, given to people at the site of research, etc.)? 
☒ 
☐ 
Skip to 
section 
33 
 
1a 
Why and with whom?  
 
 
 
 
A portion of the de-identified coded study samples will be forwarded to LLNL for analysis with no personal 
identifying information contained within the shipment, so there is no risk of loss of confidentiality with the 
mailing of samples nor the analysis of samples at LLNL.  Data returned to OSU will be identified only be de-
identified codes, so there is no risk of loss of confidentiality. 
 
 
 
1b 
Will shared data and/or samples be individually identifiable? 
☐ 
☒ 
 
1c 
Will data security plan at the external site match or exceed the OSU data security plan? 
☒ 
☐ 
☐ 
1d 
If the data security plan at the external site will not match or exceed the OSU data security plan, explain: 
 
 
 
 
 
 
 
1e 
Describe how security will be maintained in transit: 
 
 
☐ 
 
A portion of the de-identified coded study samples will be forwarded to LLNL for analysis with no personal 
identifying information contained within the shipment, so there is no risk of loss of confidentiality with the 
mailing of samples nor the analysis of samples at LLNL.  Data returned to OSU will be identified only be de-
identified codes, so there is no risk of loss of confidentiality. 
 
 
 
2 
If the study is federally funded, provide the plan to comply with federal data sharing requirements: 
 
 
☐ 
 
Oregon State University adheres to the NIH Grants Policy Statement on Availability of Research Results: 
Publications, Intellectual Property Rights, and Sharing Research Resources as described in 
https://grants.nih.gov/grants/policy/nihgps_2013/nihgps_ch8.htm#_Toc271264947. Specifically, material 
transfers would be made with no more restrictive terms than in the Simple Letter Agreement or the 
UBMTA and without reach through requirements. Should any intellectual property arise which requires a 
 
 
 


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patent, we would ensure that the technology remains widely available to the research community in 
accordance with the NIH Principles and Guidelines document. We do not anticipate generating and unique 
genetic animal or biological reagents (e.g., plasmids). All publications and presentations of results will be 
made available to interested researchers. The centralized data management organization facilitating the 
publication of data to the NIEHS Chemical Effects in Biological Systems Knowledge Base for public 
availability of Program data. The bioinformatics software updates will be released in the Bioinformatics 
Resource Manager (BRM) software as version 2.2. BRM is a client-server application, and account 
registration is required to store each user’s personal data securely on remote servers. We also want to 
ensure our AMS data with human carcinogen micro-dosing, is available to EPA as quickly as possible. We 
intent to provide EPA ORD, NCEA, IRIS with password protected access to de-identified clinical data at the 
earliest possible time. 
3 
Will the intent to share data be disclosed to research participants as part of the consent process? If not, 
provide justification: 
☒ 
☐ 
 
 
 
 
 
SECTION 33 – Publication 
Yes 
No 
N/A 
1 
Could participants be identifiable in publication or presentation (e.g., results will be reported using direct 
quotes, group or tribe name, company name and position title) 
☐ 
☒ 
 
2 
Will manuscripts, presentation materials, theses, or dissertations be stored in Scholars Archive? 
☒ 
☐ 
 
3 
Will individually identifiable data or specimens be stored in an archive or repository? If yes, describe: 
☐ 
☒ 
 
 
 
 
 


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SECTION 34 - Data Security 
 
 
 
Use this matrix to determine the data security level 
and related requirements for this study. 
Breach of confidentiality poses what level of risk? 
No Risk 
Minimal Risk 
Greater than Minimal Risk 
Are data and/or subjects: 
 
De-Identified or 
anonymous? 
Level 1 
Level 1 
Level 2 
 
Identifiable or 
coded? 
Level 1 
Level 2 
Level 3 
 
 
 
 
 
 
 
Complete only the subsection for the appropriate level of data security below. 
 
 
 
SECTION 34.1 - Level 1 
Yes 
No 
N/A 
1 
Will the following security requirements be met:  
• 
Information will be shared and stored in a manner that provides access only to authorized individuals.  
• 
If information is stored on a computer, the system will have fully patched operating systems and 
applications, and current antivirus software with current virus definitions. Information may be stored 
in cloud-based servers. 
☐ 
☐ 
 
2 
If not, provide justification: 
 
 
☐ 
 
 
 
 
 
3 
Will the following security recommendation be met:  
• 
A plan for routine back-ups of all data will be in place 
☐ 
☐ 
 
4 
Outline any additional safeguards that will be taken:  
 
 
☐ 
 
 
 
 
 
SECTION 34.2 - Level 2 
Yes 
No 
N/A 
1 
Will the following security requirements be met:  
• 
Information will be shared and stored in a manner that provides access only to authorized individuals.  
• 
Data will not be disclosed to additional parties without prior IRB approval specifically authorizing the 
☒ 
☐ 
 


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disclosure.  
• 
If information is stored on a computer, the system will have fully patched operating systems and 
applications, and current antivirus software with current virus definitions.  
• 
Information may be stored on cloud servers licensed by OSU. A plan for routine back-ups will be in 
place.  
• 
If subjects will be asked to use a third-party website or application, or if a cloud-based server will be 
used, the researchers will review the data security plan with the Information Security Office before 
initiating the study. Exceptions include servers and software licensed by OSU. 
2 
If not, provide justification: 
 
 
☐ 
 
 
 
 
3 
Will the following security recommendation be met:  
• 
Computers will have firewalls in place. 
☒ 
☐ 
 
4 
Outline any additional safeguards that will be taken:  
 
 
☐ 
 
 
 
 
 
SECTION 34.3 - Level 3  
Yes 
No 
N/A 
1 
Will the following security requirements be met:  
• 
Information will be shared and stored in a manner that provides access only to authorized individuals.  
• 
Data will not be disclosed to additional parties without prior IRB approval specifically authorizing the 
disclosure.  
• 
If information is stored on a computer, the system will have fully patched operating systems and 
applications, and current antivirus software with current virus definitions.   
• 
When feasible, information will be stored in a local system of record (e.g., local server, approved 
cloud).  
• 
All mobile computer systems or portable storage media will be encrypted with at least the 256-bit 
encryption common in operating systems and encoding devices sold in the United States.  
• 
If the data are coded, and there is a linked list of codes and identifiers, this list will be stored separately 
from all coded data.   
• 
Identifiable information will not be stored on student researchers’ computers after the study has 
ended, unless justified elsewhere in this section and approved by the IRB.  
• 
Computers must have host-based firewalls enabled in addition to being behind a networked firewall 
context.  
• 
A plan for routine back-ups of all data must be in place, with the appropriate security mechanisms for 
☐ 
☐ 
 


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that data, including encryption and physical security addressed.  
• 
The researchers will review the data security plan with the Information Security Office before 
initiating the study. 
2 
If not, provide justification: 
 
 
 
 
 
 
 
3 
Outline any additional safeguards that will be taken:  
 
 
☐ 
 
 
 
 
 
Researchers using cloud-based servers, or third party websites or applications, that are not licensed by 
OSU, and those collecting level 3 data can minimize delays by consulting with the Information Security 
Office prior to submitting the application materials to the HRPP for review. 
 
 
 
SECTION 35 - Mandatory Reporting 
Yes 
No 
N/A 
Under Oregon state law, all OSU employees are mandatory reporters. 
 
 
 
Reporting requirements related to child abuse or neglect.   
 
 
 
Reporting requirements related to sexual assault or misconduct 
 
 
 
What is the impact of mandatory reporting legislation on IRB-approved research? 
 
 
 
 
What do I do if a research participant tells me about an experience with sexual harassment or sexual 
violence? 
 
 
 
1 
Study includes collection of information regarding child abuse or neglect OR it is reasonable to expect that 
child abuse or neglect could be observed or revealed to the researchers 
☐ 
☒ 
 
2 
Study includes collection of information regarding sexual harassment or sexual violence OR it is 
reasonable to expect that such information could be revealed to the researchers 
☐ 
☒ 
 
3 
Study includes collection of information regarding harm to self or others OR it is reasonable to expect that 
such information could be observed or revealed to the researchers 
☐ 
☒ 
 
4 
Researchers plan to report information regarding harm to self or others and this is disclosed to potential 
participants as part of the consent process 
☐ 
☐ 
☒ 
5 
If yes to any of the above items in this section, describe the relevant training that study team members 
have, or will receive, to minimize risks to participants and comply with the reporting requirements: 
 
 
☒ 
 
 
 
 


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SECTION 36 - Certificate of Confidentiality 
Yes 
No 
N/A 
Certificate of Confidentiality 
 
 
 
1 
A Certificate of Confidentiality has been automatically deemed issued because this study is NIH-funded 
and includes individually identifiable data 
☒ 
☐ 
☐ 
2 
A Certificate of Confidentiality from the NIH has been obtained or will be sought for this study because it 
includes the collection of individually identifiable, “sensitive” data 
☐ 
☐ 
☒ 
SECTION 37 - Risks 
Yes 
No 
N/A 
 
Minimal risk means that the probability and magnitude of harm or discomfort anticipated in the research 
are not greater in and of themselves than those ordinarily encountered in daily life or during the 
performance of routine physical or psychological examinations or tests. 
 
 
 
 
It is not sufficient to describe the risks as “minimal” without identifying what those risks are. Include risks 
of potential harm that are physical, mental/emotional, legal, financial, insurance, employment, or social 
and reputational risks.  
 
 
 
 
In all cases where participants are known to the investigators, there is the chance of a breach of 
confidentiality.  However, if there is no potential for harm associated with such a breach, it need not be 
listed in this section.  The ways in which the potential for a breach of confidentiality will be minimized 
should be articulated in the anonymity and confidentiality section.  
 
 
 
 
Investigators should consider risks to entire groups under study (e.g., tribes, ethnic or racial groups, 
economic classes).   
 
 
 
1 
Does the study involve greater than minimal risk to adult participants? 
☒ 
☐ 
 
2 
If children will be enrolled, which of the following four federal categories applies (check “yes” only once for 
2a – 2d): 
 
 
☒ 
2a 
Research does not involve greater than minimal risk to children. 
☐ 
☐ 
☒ 
2b 
Research involves more than minimal risk to children but the study holds prospect of direct benefit to the 
participants. 
☐ 
☐ 
☒ 
2c 
Research involves more than minimal risk to children and there is no prospect of direct benefit to 
participants, but the study likely to yield generalizable knowledge about the participants’ disorder or 
condition. 
☐ 
☐ 
☒ 
2d 
Research is not otherwise approvable under the federal regulations but the study presents an opportunity 
to understand, prevent, or alleviate a serious problem affecting the health or welfare of the participants. 
☐ 
☐ 
☒ 
3 
Describe all reasonably foreseeable risks to study participants:  
 
 
☐ 


APPLICATION & PROTOCOL 
 
 
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HRPP Form | v. 4 March 2018 
 
 
BaP: The International Agency for Research on Cancer (IARC) has determined that BaP is a Class 1 known 
human carcinogen.  
Radiation: The total radiation dose of 16.4 nCi for the 3 dose cycles of [14C]-benzo[a]pyrene (10.8 nCi if 
only doing 2 dose cycles) is equivalent to about 60 minutes of natural background radiation. The risk from 
the ultra-low doses in this study is negligible. 
Blood Sampling: Risks of blood sampling include pain, bruising, and in rare instances, infection.  Some 
individuals can become lightheaded or nauseated.  
Blood Loss:  The total amount of blood collected from each subject is 420 mL (120 mL for the [14C]-BaP 
only cycle and 155 each for the Brussels sprouts and DIM cycles) or 310 mL if only doing the Brussels 
sprouts and DIM cycles. The maximum amount of blood collected in an 8 week period is 310 mL. 
Food allergens:  Foods and beverages provided during this study may contain allergens.   
Foodborne illness: As with any perishable foods, the Brussels sprouts may spoil if improperly stored or 
may become contaminated. 
Confidentiality/anonymity:  Loss of confidentiality or anonymity is a potential risk.  
 
 
 
 
4 
Describe all steps taken to minimize risks: 
 
 
 
 
BaP: Humans are exposed to PAHs, including BaP, from a number of sources, the highest being 
occupational and smoking, so we are excluding these populations. In the general population, the greatest 
BaP exposure is through diet (9.5-43.5 ng/day inhalation; 1 ng/day water; 160-1,600 ng/day diet).  The 
dietary restrictions during this study are intended to offset the total 100 ng BaP consumed in 2 study 
cycles. This is equivalent to less than or equal to 4 ng/day over the 25 day (minimum) study period. We 
estimate that following our dietary restrictions will reduce subject daily dietary exposure to BaP by 35-54 
ng/day. Therefore, subjects are not exposed to an increased risk of cancer.  
Radiation: The risk from the ultra-low doses in this study is negligible.  
Blood Sampling: A qualified research nurse or certified phlebotomist will perform blood draws and carry 
out all necessary precautions to reduce the risk of injury to subjects. Subjects will be encouraged to 
hydrate with 1-2 glasses of water before blood draws to minimize risk of syncope or lightheadedness. 
Blood Loss:  While the risk of negative impact due to blood loss is negligible, subjects will be asked to 
refrain from blood donation one month before the study until one month after completion of the final 
 
 
 


APPLICATION & PROTOCOL 
 
 
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cycle.  
Food Allergens: Ingredient lists and packaged foods with clearly labeled allergen information will be 
provided to subjects upon request. Subjects will be asked to notify the study nurse of any food allergies 
before ordering breakfast. 
Foodborne illness: Subjects will be instructed to store Brussels sprouts frozen and only thaw immediately 
before consumption. Study team members handling the Brussels sprouts will have Oregon Food Handler’s 
Licenses, and the study Brussels sprouts will be repackaged in a facility compliant with Oregon Health 
Authority, Division 150, Food Sanitation Rule. 
Confidentiality/anonymity:  Protection efforts are described in the Privacy and confidentiality section 
 
Consider whether it is appropriate to provide participants with contact information for one or more 
resources during the recruitment or consent process (e.g., CAPS if OSU students, EAP if OSU employees, 
suicide prevention hotlines, address of local shelters, etc.). 
 
 
 
5 
If the study is greater than minimal risk, attach a Data and Safety Monitoring Plan or provide the following 
information:  
 
 
☐ 
Skip to 
section 
38 
5a 
Definition of an adverse event for this study: 
 
 
 
DSMP is attached 
 
 
 
5b 
Definition of a serious adverse event for this study: 
 
 
 
 
 
 
 
5c 
Provide a plan for managing adverse events: 
 
 
 
 
 
 
 
5d 
Summarize any reporting requirements and timelines: 
 
 
 
 
 
 
 
5e 
Indicate if there are any individual or overall study stopping rules: 
 
 
 
 
 
 
 
5f 
Provide the plan for reporting adverse events or unanticipated problems (e.g., breach of confidentiality, 
incarcerated participant, or an unresolved complaint):  
 
 
 
 
 
 
 
5g 
If the potential harm related to physical, psychological, or financial risks is greater than minimal, describe 
 
 
 


APPLICATION & PROTOCOL 
 
 
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the plan for paying for related costs to participants: 
 
 
 
 
NIH guidance on data and safety monitoring 
 
 
 
SECTION 38 - Benefits 
Yes 
No 
N/A 
1 
Describe benefits to the individual participants, to society, and to science: 
 
 
 
 
This study is not designed to be of benefit to individual subjects. Potential benefits to society include 
essential information to aid regulatory agencies with respect to how environmental PAHs, such as BaP, at 
environmentally relevant levels of exposure are taken up by the G.I. (96% of carcinogenic PAH exposure in 
humans is dietary), metabolized and excreted from the body. That information can be used in modeling 
risk assessment rather than high-dose animal studies. This will provide a mechanism for improvement of 
public health. 
 
 
 
SECTION 39 - Training and Oversight 
Yes 
No 
N/A 
 
CITI training is required and should not be included in this section. This section pertains to all other training 
required to conduct the study, such as training study team members to collect data or samples. 
 
 
 
1 
Is the PI the only member of the study team? 
☐ 
Skip to 
section 
40 
☒ 
 
2 
Describe the plan for confirming or providing training related specifically to the study activities  and for 
supervising all study team members: 
 
 
 
 
Williams is responsible for the conduct and oversight of the study, for ensuring that privacy/confidentiality 
of subjects is maintained and that all individuals working on the study are properly trained to perform their 
role on the study. 
 
 
 
3 
Describe the plan for training related specifically to obtaining informed consent and maintaining 
confidentiality: 
 
 
 
 
Nurse coordinator Uesugi will obtain informed consent from study subjects.  She has completed a clinical 
research coordinator (CRC) training course and will be responsible for maintaining confidentiality. 
 
 
 
4 
Explain how oversight of study team members will be handled during PI absences (sabbaticals, non-
contract months, etc.): 
 
 
 
 
Extended absence of the PI is not anticipated because the PI will not use sabbatical leave during the study, 
is appointed at 1.0 FTE (9-month) and a tenured faculty member. A certified phlebotomist may 
occasionally be employed to collect blood samples as a back-up to Uesugi. 
 
 
 


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SECTION 40 - Principal Investigator’s Assurance Statements 
Yes 
No 
N/A 
 
I understand Oregon State University’s policies concerning research involving human participants and I 
attest: 
 
 
 
 
• 
that the information contained in this document is accurate and complete 
☒ 
 
 
 
• 
that research activities will not begin until an approval or acknowledgement has been issued 
☒ 
 
 
 
• 
to the scientific merit and importance of this study 
☒ 
 
 
 
• 
to the competency and availability of the study team member(s) to conduct the project 
☒ 
 
 
 
• 
that facilities, equipment, and personnel are adequate to conduct the research 
☒ 
 
 
 
Furthermore, I agree to: 
 
 
 
 
• 
comply with all HRPP and IRB policies, decisions, conditions, and requirements 
☒ 
 
 
 
• 
accept responsibility for every aspect of the conduct of this study 
☒ 
 
 
 
• 
adhere to all aspects of the protocol, once approved 
☒ 
 
 
 
• 
obtain approval prior to amending or altering the study, when required by institutional policy  
☒ 
 
 
 
• 
report in accord with institutional policy, any adverse event(s) and/or unanticipated problem(s) 
☒ 
 
 
 
• 
inform the HRPP if PI or another member of the study team leaves OSU or otherwise changes 
institutional affiliations 
☒ 
 
 
 
• 
notify the HRPP office immediately of the development of any potential conflict of interest not already 
disclosed and, when applicable, report to an external IRB 
☒ 
 
 
 
• 
accept and fulfill all expectations and responsibilities required by the FDA if the study is regulated by 
21 CFR 312 (drugs) or 812 (devices) 
☒ 
 
☐ 
 
I understand that if OSU has deferred oversight to an external IRB, I am responsible for ensuring that the 
content of the OSU file matches the external IRB’s file within 30 days of any approvals, changes, or other 
actions 
☐ 
 
☒ 
SECTION 41 - Attachments 
Check all that apply: 
☐ Assent document(s) or guide(s) 
☒ Certificate of Analysis or other documentation of quality/purity 
☐ Certificate of Confidentiality 
☐ CLIA certificate 
☒ Consent document(s) or guide(s) 
☐ Copy of curriculum if the study intervention is a workshop or a class 
☐ Data and Safety Monitoring Board Charter or Report 


APPLICATION & PROTOCOL 
 
 
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HRPP Form | v. 4 March 2018 
 
☒ Data and Safety Monitoring Plan 
☐ Department of Corrections application 
☐ Documentation that the product is an approved food additive (21 CFR 172) 
☐ External IRB document(s) 
☐ External study document(s) 
☐ FDA Correspondence 
☐ FDA “Safe to Proceed” letter  
☐ GMP certificate or food-grade certificate that indicates that the product can be lawfully used in the US food supply 
☐ Grant or contract if not already in Cayuse 
☐ IND or IDE Application for Investigational New Drug or Device 
☐ Investigator brochure 
☒ Label for investigational drug or device 
☐ Letter from the FDA or industry sponsor setting forth the IND number 
☐ Letter(s) of support or permission 
☐ Package insert 
☒ Recruitment materials 
☒ References or citations 
☐ Safety data if GRAS status is self-affirmed 
☒ Screening or eligibility checklist(s) or document(s) 
☐ Surveys, questionnaires, interview or focus group guide(s) 
☐ Translated document(s) 
☐ Tribal Council Resolution or other appropriate supporting documentation from the appropriate Tribal authority 
Additional attachments: 
☒ Food diary 
☒Demographics form 
☒Cruciferous vegetable list 
☒Health assessment form 
☒Cruciferous vegetable food frequency questionnaire (FFQ) 
☒BioResponse DIM 150 label 
☒Brussels sprouts preparation instructions 
☐ 
☐ 


APPLICATION & PROTOCOL 
 
 
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☐ 
 
 
PI should email completed application and all relevant attachments to IRB@oregonstate.edu 
 
 


 
David E. Williams, PhD 
Page 1 of 1 
 
 
Statistical Analysis Plan 
 
Pharmcokinetic parameters were evaluated for linearity using a best fit modeling approach. First, 
pharmacokinetic parameters were evaluated for significant change as a functin of dose using a standard 
linear regression model including a fit y-intercept.  Slopes were compared using a t-test and an alpha 
value of 0.05. If the parameter changed as a function of dose, we further evaluated the parameter with 
a linear regression model, with k as the slope through the origin and a Michaelis-Menten model, which 
assumes saturation at Vmax and an affinity constant K, to individual parameters (p) as a function of 
extermal [14C]-BaP dose.  The Baysesian information criterion (BIC) was used to judge the best-fit model 
and provide evidence of linear or saturable pharmacokinetics. 
 


 
RESEARCH CONSENT FORM 
 
Study Title: Ultralow Dose PAH Binary Mixture Study 
Principal Investigator: David E. Williams, PhD 
Study team: Douglas Aukerman, MD, Sandra Uesugi, RN, Lisbeth Siddens, Jamie Pennington 
Sponsor: National Institutes of Health, National Institute of Environmental Health Sciences 
Version: August 31, 2018 
 
 
SUMMARY 
 
We are inviting you to take part in a research study. You do not have to be in the study if you do 
not want to.  You can also decide to be in the study now and change your mind later.  
 
This study is about a common pollutant called benzo[a]pyrene or BaP. The purpose of this 
research study is to better understand how our bodies absorb and eliminate BaP. 
 
If you take part in this study, we will ask you to complete two 48-hour study cycles. You will be 
asked to provide blood and urine samples.  During one cycle, you will receive a dose of BaP 
alone, and in the second cycle, you will receive a dose of BaP with phenanthrene, another 
common pollutant related to BaP. 
 
The most serious risks related to being in this study are ultralow dose exposure to BaP, a known 
carcinogen, and potential bruising or discomfort from the blood draws. 
 
We plan to make the results of this study public, but we will not include your name. 
 
We would like you to ask us questions if there is anything about the study that you do not 
understand. You can contact the Nurse Coordinator Sandra Uesugi, RN at 541-737-3594 or 
sandra.uesugi@oregonstate.edu or the Principal Investigator Dr. David Williams at 541-737-
3277 or david.williams@oregonstate.edu. 
 
You can also contact the Human Research Protection Program with any concerns that you have 
about your rights or welfare as a study participant. This office can be reached at (541) 737-8008 
or by email at IRB@oregonstate.edu . 
 
There are more details about the study in the following pages. 
 
 


 
 
STUDY DETAILS 
1. WHY AM I BEING INVITED TO TAKE PART IN THIS STUDY? 
You are being invited to take part in this study because you are a healthy non-smoking adult 
aged 21-65. If you are female, you must be post-menopausal or surgically sterile. 
 
2. WHAT WILL HAPPEN IF I TAKE PART IN THIS RESEARCH STUDY?   
This research study involves a screening visit and two study cycles. We will ask you to take a    
50 ng dose of BaP during each cycle with and without 1250 ng phenanthrene, another PAH 
commonly found in smoked foods.  All the visits will take place in the Clinical Research Center 
(CRC) - Room 407 in the Linus Pauling Science Center at OSU. 
Screening visit (60 minutes) 
We will review the study activities, schedule and diet restrictions, and answer any of your 
questions before obtaining your written consent.  We will collect demographic information, 
health history, height, weight, blood pressure and heart rate.  If you are female, you will be asked 
to provide a urine sample for a pregnancy test. The study physician will perform a physical exam 
and review your health history. Fasting is not required for this visit.   
If you were eligible for our previous Benzo[a]pyrene Ultralow Dose-Response Study (IRB Study # 
8233), you may not need another physical exam if you have not had any significant changes to 
your health or medication. All other screening activities will be conducted. 
Two study cycles (48 hours, 4 visits per cycle)*: 
For each study cycle, we will ask you to participate in these study activities:  
Food Diaries: We will ask you to record all food and beverages that you consume during the 3-
days before each study cycle and during the 48-hour study cycle. 
Diet restrictions: We will ask you to follow these restrictions for 2 weeks before and through 
the end of each cycle (16 days): 
1. Avoid eating any smoked meats and cheeses 
2. Avoid eating any charcoal grilled meats (gas-grilled meat is ok) 
3. Avoid eating cruciferous vegetables and condiments (see list) 
4. Avoid taking any supplements that contain indole-3-carbinol (I3C) or 3,3’-
diindolylmethane (DIM) 
Overnight Fast:  We will ask you to not eat or drink anything besides water for at least 8 hours 
before the first morning of each study cycle.  We will provide breakfast on the first morning of 
each cycle, 2 hours after you swallow the BaP capsule.  You will be able to order your own 
breakfast food and beverage from a menu, and ingredient information can be provided if you 
have any food allergies or dietary restrictions. 
 


 
Study visits: 
Visit 1 - (0-4-hour time points, 4.5 hours): On the first morning of each cycle, we will ask you to 
provide a urine sample and to empty your bladder.  If you are female, we will also do a urine 
pregnancy test at the start of each study cycle. The study nurse will measure your weight and 
then place an IV catheter in a vein in your inner elbow.   
We will draw a baseline blood sample and then provide a BaP or BaP + phenanthrene capsule 
for you to swallow with water (time 0 hours).  The study nurse will draw a blood sample at 0.25 
0.5, 1.0, 1.5, 2, 3, 4 hours from the IV catheter.  You will have the choice to keep the IV catheter 
in place until the 8 hour blood draw or have it removed after 4 hours.  You will need to remain 
near the CRC if you choose to keep the IV catheter until the 8-hour time point. 
Visit 2 – (8 hour time point, 15 minutes): If you chose to have the IV catheter removed after 4 
hours, you can leave the building. We will ask you to return to the CRC at the 8-hour time point 
for a straight needle stick blood draw. 
Visit 3 – (24-hour time point, 15 minutes): We will ask you to return to the CRC at the 24-hour 
time point for a straight needle stick blood draw. 
Visit 4 – (48-hour time point, 15 minutes): We will ask you to return to the CRC at the 48-hour 
time point for a straight needle stick blood draw. 
We will collect a total of 120 mL (8 Tbsp.) of blood in each cycle. 
Urine collection: We will ask you to collect all of your urine for 48 hours in containers that we 
provide.  We will also provide a discrete soft-sided cooler bag for transportation. You can store 
any collected urine samples at room temperature in the bag until you return for your next visit. 
We will ask you to return any filled containers at the next visit until the end of the cycle. The 
longest you will need to store any samples is 24 hours between Visits 3 and 4. 
Washout period:  We will wait at least 3 weeks between study cycles to allow your body to 
completely eliminate each BaP dose.   
*Participants of Ultralow Dose-Response Study (IRB protocol 8233): If you completed the 50 
ng BaP dose cycle within the past 12 months, you will only participate in the BaP plus 
phenanthrene dose cycle in this study to minimize your risks.  
Storage and future use of data and samples: We may indefinitely store a portion of your blood 
and urine for possible future studies.  The samples will be coded with no identifying personal 
information. Because it is not possible for us to know what studies may be a part of our future 
work, we ask that you give us permission now to use your samples and data without being 
contacted about each future study.  Future use of your samples will be limited to studies about 
health effects of pollution. We will not pay you for the use of your sample or data.  If you agree 
now to future use of your samples but decide in the future that you would like to have them 
removed from research tests, please contact Dr. David E. Williams, Oregon State University, 473 
Linus Pauling Science Center, Corvallis, OR 97331, 541-737-3277.  


 
We will be destroying all identifying information when data collection is complete. Once the 
identifying information is destroyed, we will not be able to remove your information from the 
larger dataset. 
______You may store my information and/or samples for use in future studies. 
Initials 
______You may not store my information and/or samples for use in future studies. 
Initials 
 
During this study some of your blood will be used to study 1-7 specific genes. A gene is the code 
(DNA) present in each cell in your body and controls the behavior of that cell. We are interested 
in studying the genes that control the way BaP is handled in the body. This will help us 
understand if these genes increase or decrease the uptake, metabolism or excretion of BaP.  
 
______You may use my samples for gene analysis. 
Initials 
______You may not use my samples for gene analysis. 
Initials 
 
Future contact: We may contact you in the future for another similar study.  You can ask us to 
stop contacting you at any time. 
Study Results: We will share any published results of the study with you if you request.  
3. WHAT ARE THE RISKS AND POSSIBLE DISCOMFORTS OF THIS STUDY? 
BaP: The International Agency for Research on Cancer (IARC) has determined that BaP is a Class 
1 known human carcinogen. The amount of BaP you will take in this study is extremely small. It 
is less than you may eat already every day in your diet, especially in cooked meat. For example, 
one grilled hamburger could contain as much or more PAHs than the amount you will take in 
this study.  The diet restrictions are designed to help reduce additional exposure to BaP and 
other PAHs during the study cycles, and your cancer risk is not increased by participating in this 
study. The US EPA and IARC have evaluated phenanthrene and determined it not to be a 
carcinogen. 
Radiation: In order to track the BaP in your blood and urine samples, it contains a carbon-14 
label.  Carbon-14 emits very low levels of radiation. The total amount of radiation that you will 
receive in the 2 cycles is equivalent to 40 minutes of natural background radiation. At this level, 
the risks associated with radiation exposure are negligible and no higher than your everyday 
exposure.  
Blood Sampling:  The risks of having blood drawn from your arm include some pain when the 
needle goes in and a small risk of bruising, inflammation or infection at that site.  Please alert 
the study nurse if you notice any symptoms during or after each study cycle. 
Some people get lightheaded, nauseous, or faint.  You are less likely to have these problems if 
you drink 1-2 glasses of water in the evening and morning before your study visits.   


 
The American Red Cross recommends that you do not donate more than 1 pint (32 
tablespoons) of blood within a 2-month period.  We request that you do not donate blood for 
at least one month after completing the final study cycle. 
Food allergens:  We will provide breakfast on the first day of each cycle and will provide clearly 
labeled packaged foods or ingredient lists if requested.  Please notify the study nurse if you 
have any food allergies or diet restrictions. 
Confidentiality and Privacy: There is a risk that we could accidentally disclose information that 
identifies you. 
4. WHAT ARE THE BENEFITS OF THIS STUDY? 
This study is not designed to benefit you directly.  This study may help scientists and environmental 
regulatory agencies better understand the health effects of PAHs. Your participation will contribute 
to our scientific body of knowledge for risk assessment of an important group of environmental 
contaminants. 
5. WHAT OTHER OPTIONS DO I HAVE IF I DO NOT TAKE PART IN THIS STUDY? 
Participation in this study is voluntary.  If you qualify for the study, you may choose to not 
participate. There are no alternative study activities if you choose to not participate.  
 
6. WHAT SHOULD I DO IF I WANT TO STOP BEING IN THE STUDY? 
If you decide to participate, you are free to withdraw at any time without penalty. If you choose 
to withdraw from this project before it ends, the researchers may keep samples and 
information collected about you, and this information may be included in study reports. 
7. WHO WILL SEE THE INFORMATION I GIVE?  
The information you provide during this research study will be kept confidential to the extent 
permitted by law.   Research records will be stored securely.  Regulatory agencies, the Food and 
Drug Administration, the National Institute of Environmental Health Sciences and Oregon State 
University employees may access or inspect records pertaining to this research as part of 
routine oversight or university business.  Some of these records could contain information that 
personally identifies you. 
 
Some of your coded blood samples will be sent to outside laboratories for analysis. Outside 
laboratories will only have samples identified by code and will not have access to the key 
connecting your name to the code.  
 
If we contacted you through the Center for Healthy Aging Research (CHAR) LIFE Registry, we 
will be providing CHAR with any updates to your contact information. We will also tell them 
whether or not you chose to participate in this research study. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This website will not include information that can identify you. At most, the 
website will include a summary of the results. You can search this website at any time. 


 
 
Most people outside of the study team will not see research information that includes your 
name. This includes people who try to get your information using a court order. We could give 
out this information if you gave us permission.  
 
8. WHAT HAPPENS IF I AM INJURED?  
Oregon State University has no program to pay for research-related injuries.  If you think that 
you have been injured as a result of being in this study, please contact the study team 
immediately.  
9. WILL I BE PAID FOR BEING IN THIS STUDY? 
You receive $125 for each study cycle. The total amount you will receive for completing 2 cycles is 
$250 or $125 if you only complete 1 cycle. If you withdraw early from the study, your payment 
will be prorated to the proportion of blood samples provided. For example, if you complete 9 out 
of 11 blood samples in a cycle you will receive $102.27 ($11.36/sample).  
 
10. WILL IT COST ME ANYTHING TO BE IN THIS STUDY?  
You are responsible for transportation to the OSU campus.  We will provide convenient free 
parking during your study visits. 
 
11. WHAT WILL HAPPEN IF THE RESEARCHERS THINK THAT I SHOULD NO LONGER BE IN THE 
STUDY? 
We may take you off the study early if you do not follow study instructions, if the investigator 
stops the study, or if you develop serious side effects.  
 
 
12. WHAT DOES MY SIGNATURE ON THIS CONSENT FORM MEAN? 
Your signature indicates that you acknowledge that this study has been explained to you, that your 
questions have been answered, and that you agree to take part in this study.  You will receive a 
copy of this form. 
 
 
Participant Name: 
 
 
 
 
 
 
 
 
 
Participant Signature:  
 
 
 
 
 
 
 
 
Date Signed:  
 
 
 
 
 
Name of Person Obtaining Consent:  
 
 
 
 
 
 
Signature of Person Obtaining Consent: 
 
 
 
 
 
 
Date Signed: