Systematic Evidence Map of Noncancer Health Endpoints and Exposures to Polychlorinated Biphenyl (PCB) Mixtures [CASRN 1336-36-3]


*>EPA

United States

Environmental
Protection Agency

EPA/600/R22/201F | March 2023 | www.epa.gov/research

A Systematic Evidence Map of
Noncancer Health End points and
Exposures to Polychlorinated
Biphenyl (PCB) Mixtures

Office of Research and Development

Center for Public Health & Environmental Assessment

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A EPA

EPA/600/R-22/201F

A Systematic Evidence Map of Noncancer Health Endpoints and
Exposures to Polychlorinated Biphenyl (PCB) Mixtures

[CASRN 1336-36-3]

March 2023

Center for Public Health and Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Washington, DC

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DISCLAIMER

This document has been reviewed by the U.S. Environmental Protection Agency, Office of
Research and Development and approved for publication. Any mention of trade names, products, or
services does not imply an endorsement by the U.S. government or the U.S. Environmental
Protection Agency. EPA does not endorse any commercial products, services, or enterprises.

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CONTENTS

AUTHORS | CONTRIBUTORS | REVIEWERS	vii

EXECUTIVE SUMMARY	x

1.	INTRODUCTION	1-1

2.	METHODS	2-1

2.1.	LITERATURE SEARCH	2-1

2.2.	ELECTRONIC APPROACHES USED TO REFINE A LARGE DATABASE	2-1

2.3.	LITERATURE SCREENING	2-5

2.3.1.	Title and Abstract Screening of the Literature	2-5

2.3.2.	Full-Text Screening of the Literature	2-6

3.	RESULTS AND DISCUSSION	3-1

3.1.	LITERATURE SEARCH AND SCREEN	3-1

3.1.1.	Literature Searches (2015-2021)	3-1

3.1.2.	Electronic Prioritization for Manual Review	3-3

3.1.3.	Literature Screening	3-4

3.2.GENERAL	CONSIDERATIONS	3-5

3.2.1.	Human Studies	3-6

3.2.2.	Nonhuman Mammalian Studies	3-8

3.3.	ORGAN/SYSTEM DATABASE SUMMARIES	3-9

3.3.1.	Cardiovascular	3-16

3.3.2.	Dermal	3-21

3.3.3.	Developmental	3-23

3.3.4.	Endocrine	3-26

3.3.5.	Gastrointestinal	3-30

3.3.6.	Hematopoietic	3-32

3.3.7.	Hepatobiliary	3-35

3.3.8.	Immune	3-40

3.3.9.	Metabolic	3-46

3.3.10.	Musculoskeletal	3-50

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3.3.11. Nervous System	3-53

3.3.12.Ocular	3-69

3.3.13.	Reproductive	3-71

3.3.14.	Respiratory	3-83

3.3.15.	Urinary System	3-86

4. CONCLUSIONS	4-1

REFERENCES	R-l

APPENDIX A. QUALITY ASSURANCE FOR A SYSTEMATIC EVIDENCE MAP FOR

POLYCHLORINATED BIPHENYL (PCB) MIXTURES: EVALUATION OF NONCANCER HEALTH
ENDPOINTS AND EXPOSURES	A-l

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TABLES

Table 1. Populations, exposures, comparators, outcomes (PECO) criteria 1-3

Table 2. Electronic prioritization of literature for hazard identification 3-3

Table 3. Overview of the databases available for selected endpoint categories by organ/system 4-3

FIGURES

Figure 1. Illustration of electronic prioritization approaches 2-3

Figure 2. Chronology of prioritization approaches applied to PCB literature search results 2-5

Figure 3. Literature search flow diagram for PCBs 3-2

Figure 4. Overview of Human and Other Mammalian Studies Across Organs/Systems 3-9

Figure 5. Overview of Human Studies by Organ/System and Population 3-10

Figure 6. Overview of Human Studies by Organ/System and Study Design 3-11

Figure 7: Overview of Human Studies by Organ/System and Exposure Metric 3-12

Figure 8. Overview of Nonhuman Mammalian Studies by Organ/System and Species 3-13

Figure 9. Overview of Nonhuman Mammalian Studies by Organ/System and Exposure Route 3-14

Figure 10. Overview of Nonhuman Mammalian Studies by Organ/System and Exposure

Duration/Lifestage 3-15

Figure ll:Overview of Human and Other Mammalian Cardiovascular Studies 3-17

Figure 12:Overview of Human and Other Mammalian Dermal Studies 3-22

Figure 13: Overview of Human and Other Mammalian Developmental Studies 3-25

Figure 14. Overview of Human and Other Mammalian Endocrine Studies 3-27

Figure 15. Overview of Human and Other Mammalian Gastrointestinal Studies 3-31

Figure 16. Overview of Human and Other Mammalian Hematopoietic Studies 3-33

Figure 17. Overview of Human and Nonhuman Mammalian Hepatobiliary Studies 3-36

Figure 18. Overview of Human and Other Mammalian Immune Studies 3-43

Figure 19. Overview of Human and Other Mammalian Metabolic Studies 3-47

Figure 20. Overview of Human and Other Mammalian Musculoskeletal Studies 3-51

Figure 21. Overview of Human and Other Mammalian Nervous System Studies 3-55

Figure 22. Overview of Nonhuman Mammalian Studies of Nervous System Endpoints by

Lifestage of Exposure and Lifestage at Endpoint Evaluation 3-56

Figure 23. Overview of Human Studies of Nervous System Endpoints by Endpoint Category and

Exposure Lifestage 3-58

Figure 24. Overview of Nonhuman Mammalian Studies of Nervous System Endpoints by

Endpoint Category and Lifestage of Exposure 3-60

Figure 25. Overview of Human and Other Mammalian Ocular Studies 3-70

Figure 26. Overview of Human and Other Mammalian Reproductive Studies 3-73

Figure 27. Overview of Human and Other Mammalian Respiratory Studies 3-84

Figure 28. Overview of Human and Other Mammalian Urinary System Studies 3-87

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ABBREVIATIONS

ACTH

adrenocorticotropic hormone

ALT

alanine aminotransferase

AOP

adverse outcome pathway

AhR

aryl hydrocarbon receptor

AST

aspartate aminotransferase

ATSDR

Agency for Toxic Substances and



Disease Registry

BUN

blood urea nitrogen

BW

body weight

CASRN

Chemical Abstracts Service registry



number

CERCH

Center for Environmental Research and



Children's Health

CNS

central nervous system

CPAD

Chemical and Pollutant Assessment



Division

CPHEA

Center for Public Health and



Environmental Assessment

CYP450

cytochrome P450 CYP1A2

DoCTER

Document Classification and Topic



Extraction Resource

EPA

Environmental Protection Agency

EPM

elevated plus maze

EZM

elevated zero maze

FVC

forced vital capacity

FEV1

forceful exhalation

GGT

gamma-glutamyltransferase

GSH

glutathione

HAWC

Health Assessment Workspace



Collaborative

HDL

low high-density lipoprotein

HERO

Health and Environmental Research



Online

HF

heart failure

HPA

hypothalamus-pituitary-adrenal

HPT

hypothalamus-pituitary-thyroid

IGT

impaired glucose tolerance

i.p.

intraperitoneal

IR

insulin resistance

i.v.

intravenous

IARC

International Agency for Research on

Cancer

IHD	ischemic heart disease

IRIS	Integrated Risk Information System

MCH	mean corpuscular hemoglobin

MCV	mean corpuscular volume

ML	machine learning

MetS	metabolic syndrome

MOA	mode of action

MI	myocardial infarction

NCI	National Cancer Institute

NHANES	National Health and Nutrition

Examination Survey

NK	natural killer cells

NLP	natural language processing

NTP	National Toxicology Program

ORD	Office of Research and Development

OW/OB	overweight/obesity

PCBs	polychlorinated biphenyls

PCDFs	polychlorinated dibenzofurans

PECO	populations, exposures, comparators,

and outcomes

PK	pharmacokinetic

QA	Quality Assurance

QAPP	Quality Assurance Project Plan

RBCs	red blood cells

SD	standard deviation

SE	standard error

SEMs	systematic evidence maps

SGOT	serum glutamic oxaloacetic

transaminase, also known as AST

SGPT	serum glutamic pyruvic transaminase,

also known as ALT

TCDD	2,3,7,8-tetrachlorodibenzo-p-dioxin

TK	toxicokinetics

TSCATS	Toxic Substances Control Act Test

Submissions

TSH	thyroid stimulating hormone

T4	thyroxine

T3	triiodothyronine

WOS	Web of Science

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AUTHORS | CONTRIBUTORS | REVIEWERS

Authors

Laura M. Carlson. PhD. (Lead Author)
Krista Christensen. Ph.D. (Lead Author)
Geniece M. Lehmann. Ph.D. (Lead Author)

Office of Research and Development, Center for
Public Health and Environmental Assessment
(CPHEA)

Xabier Arzuaga. Ph.D.
Evan Coffman. Ph.D.
Rachel M. Shaffer. Ph.D.
Erin E. Yost. Ph.D.

Contributors

Robvn Blain
Michael S. Bloom
Pam Factor-Litvak

Brandall Ingle
Todd A. lusko

Aileen F. Keating

Carolyn R. Klocke

Pamela I. Lein

Cvnthia Lin
lohn D. Meeker
Pradeep Raian
Larrv Robertson
Sharon K. Sagiv

Alexander Sergeev
Kelly Shipkowski

ICF, Reston, VA

George Mason University, Fairfax, VA

Mailman School of Public Health, Columbia
University, New York, NY

ICF, Reston, VA

University of Rochester School of Medicine and
Dentistry, Rochester, NY

Department of Animal Science, Iowa State
University, Ames, IA

Department of Molecular Biosciences, University of
California, Davis School of Veterinary Medicine,
Davis, CA

Department of Molecular Biosciences, University of
California, Davis School of Veterinary Medicine,
Davis, CA

ICF, Reston, VA

University of Michigan, Ann Arbor, MI

Pradeep Rajan LLC, Chapel Hill, NC

University of Iowa, Iowa City, IA

Center for Environmental Research and Children's
Health (CERCH), School of Public Health, University
of California, Berkeley, CA

Ohio University, Athens, OH

ICF, Reston, VA

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Raauel A, Silva
Samantha Snow
Michal Toborek
loanne Tr gpvci ch

ICF, Reston, VA
ICF, Reston, VA

University of Miami, Miami, FL
ICF, Reston, VA

Executive Direction

Wayne Cascio, M.D (CPHEA Director)	Office of Research and Development, Center for

V. Kay Holt, M.S. (CPHEA Deputy Director)	Public Health and Environmental Assessment

Samantha Jones, Ph.D. (CPHEA Associate Director)	(CPHEA)

Kristina Thayer, Ph.D. (CPAD Director)

Steve Dutton, Ph.D. (HEEAD Director)

Andrew Kraft, Ph.D. (CPAD Associate Director)

Ravi Subramaniam, Ph.D. (Acting CPAD Senior Advisor)

Paul White, Ph.D. (CPAD Senior Science Advisor)

Andrew Hotchkiss, Ph.D. (Branch Chief)

Janice Lee, Ph.D. (Branch Chief)

Elizabeth Radke-Farabaugh, Ph.D. (Branch Chief)

Viktor Morozov, Ph.D. (Branch Chief)

Garland Waleko, M.S. (Acting Branch Chief)

Production Team

Ryan Jones (HERO Technical Lead)	Office of Research and Development, Center for

Andrew Shapiro (HAWC Technical Lead)	Public Health and Environmental Assessment

Dahnish Shams (Project Management Team)	(CPHEA)

Avanti Shirke (Project Management Team)

Jessica Soto-Hernandez (Project Management Team)

Vicki Soto (Project Management Team)

Shane Thacker (HERO Lead Developer)

Sean Watford (HERO/HAWC Team)

Reviewers

This report was peer reviewed by independent, expert scientists external to EPA convened by Versar under
contract EP-C-17-023 (Order No. 68HERH21F0354).

Andreas Kortenkamp, Ph.D.	Brunei University, London United Kingdom

John C. Lipscomb, Ph.D. DABT, FATS	CTEH, LLC, North Little Rock, AR

Cynthia V. Rider, Ph.D.	Division of National Toxicology Program,

National Institute of Environmental Health Sciences,
Durham, NC, USA

Questions regarding the content of this report should be directed to the EPA Office of Research and
Development (ORD) Center for Public Health and Environmental Assessment (CPHEA) website at
https: / / ecomments.epa.gov/

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Acknowledgments:

The authors would like to thank Maryjane Selgrade for preliminary review of studies related to immune and
hematopoietic health endpoints and Francesca Branch and Catheryne Chiang for internal review of the draft
report, and Jessica Soto-Hernandez for document production and publishing. The authors would also like to
thank the following ICF staff for assistance in (1) literature searching, literature prioritization, and database
support (Steven Black, Michelle Cawley, Grace Cooney, Tom Feiler, Jeremy Frye, Kaitlin Geary, Pam Hartman,
Cara Henning, Josiah McCoy, Rachel McGill, Kristen McKinley, Alicia Murphy, Blake Reilly, Delaney Reilly,
Nicole Vetter, Arun Varghese, Ashley Williams, River Williams); (2) creating Tableau visualizations (Courtney
Lemeris]; (3) screening studies (Carlye Austin, Steven Black, Natalie Blanton, Canden Byrd, Kathleen Clark,
Tyler Cromer, Ryan Cronk, Jon Davis, Katie Duke, Sorina Eftim, Anna Engstrom, Susan Goldhaber, Ali
Goldstone, Lindsey Green, Kate Helmick, Angela Hensel, Chelsea Hunter, Audrey Ichida, Allison Killius, Alex
Kliminsky, Gillian Laidlaw, Ellen Lee, Camryn Leib, Jessica Levasseur, Alex Lindahl, Yi Lu, Kristen Magnuson,
Maureen Malloy, Sophie McComb, Rachel McGill, Emma Meyer, Devon Morgan, Revathi Muralidharan, Alicia
Murphy, Ed Murray, Sean Robins, Johanna Rochester, Amanda Ross, Pam Ross, Alessandria Schumacher,
Kendall Scott, Jennifer Seed, Karen Setty, Codi Sharp, Robert Shin, Catherine Smith, Parnian Soleymani,
Deshira Wallace, Jared Wang, Ashley Williams, River Williams, Jennifer Yourkavitch, Maricruz Zarco]; and (4)
technical editing (Tara Hamilton, Penelope Keller, Whitney Mitchell).

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EXECUTIVE SUMMARY

Assessing health outcomes associated with exposure to polychlorinated biphenyls (PCBs) is
important given their persistent and ubiquitous nature. PCBs are classified as a Group 1 carcinogen,
but the full range of noncancer health effects that could result from exposure to PCBs has not been
systematically summarized and evaluated. This review compiles and organizes human and other
mammalian studies of noncancer health endpoints measured with exposure to PCB mixtures to
identify areas of robust research, as well as areas of uncertainty and research needs.

A protocol was developed that describes the systematic review methods, including the
literature search strategy and the Populations, Exposures, Comparators, and Outcomes (PECO)
criteria used to facilitate subsequent screening and categorization of literature into a systematic
evidence map of PCB exposure and noncancer health endpoints across 15 organs/systems. A
comprehensive literature search yielded 62,599 records. After a prioritization step that included
machine learning and natural language processing, 17,037 studies were manually screened at the
title and abstract level. An additional 900 studies identified by experts or supplemental searches
were also included, for a total of 17,937 studies reviewed. After full-text screening of 3,889
references, 1,586 studies met PECO and were included in the database. Relevant study details such
as the PCB congeners measured or administered, organs/systems and endpoints assessed,
exposure duration, and species were extracted into literature summary tables. Summary data are
available online as interactive visuals with downloadable metadata.

We identified 637 mammalian toxicological studies evaluating endpoints in a variety of
species exposed for different durations and at different life stages and 953 epidemiological studies
conducted among diverse populations. Although human and other mammalian data are abundant
for some organs/systems (e.g., hepatobiliary, nervous system, and reproductive), other endpoints
of great public interest (e.g., cardiovascular disease, autism) have not been extensively studied in
the context of exposure to PCB mixtures. Furthermore, despite many years of research, sparse data
exist for inhalation and dermal exposures, which are highly relevant human exposure routes.
Robust research is available to inform PCB hazard assessments for most organs/systems, but the
amount of data to inform associations with specific endpoints differs. This evidence map provides a
foundation for future systematic reviews and noncancer hazard assessments of PCB mixtures and
for strategic planning of research to address areas of greater uncertainty.

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1. INTRODUCTION

Polychlorinated biphenyls (PCBs) are halogenated organic pollutants consisting of 209
congeners varying in the number and position of chlorine atoms substituted on biphenyl rings.

PCBs were produced as technical mixtures (e.g., Aroclors) containing numerous individual
congeners. Mixtures of these congeners were used as dielectric fluids in capacitors and
transformers, as lubricants, and as additives in a variety of other products, including paints and
caulk. PCB production was banned in the United States in 1979 fU.S. EPA. 19791 and in most of the
world by the time the Stockholm Convention was adopted in 2001 fSCPOP. 20081. Even so, because
of their widespread use, disposal, and resistance to degradation, these chemicals are pervasive in
the environment and biota.

Humans are exposed to PCBs throughout their lifetimes, including prenatally and during the
early postnatal period through breastfeeding (van den Berg etal.. 2017). with continuing exposure
through multiple routes including diet and inhalation (Weitekamp etal.. 20211. Occupational
exposure historically occurred during production or use of PCBs and PCB containing products
fWolff. 19851. and may still occur, for example through maintenance, repair, or recycling of old PCB
containing products or disturbance of construction materials containing PCBs (Okeme and
Arrandale. 2019: Herrick et al.. 20071. The general population can be exposed to PCBs by ingesting
contaminated food (especially fish from contaminated waters), and by inhaling contaminated air, in
both indoor and outdoor settings, especially at locations which still use electrical equipment and/or
building and construction products containing PCBs. The issue of potential inhalation exposure to
PCBs in contaminated buildings, including some schools, is an environmental health topic that has
received much attention from the US Environmental Protection Agency fU.S. EPA. 2019. 2015.
20121.

The PCB mixtures associated with each exposure pathway differ from each other and from
the original technical mixtures due to differential degradation of the individual congeners in the
environment over time, variable partitioning of PCB congeners in environmental compartments,
and differences in toxicokinetics. Another factor contributing to differences between modern
environmental PCB mixtures and technical mixtures is the ongoing, inadvertent PCB production
that occurs during certain manufacturing processes, such as pigment production fZhao etal..
2020a: Vorkamp. 2015: Hu and Hornbuckle. 2010). Therefore, humans are exposed to different
environmental mixtures of PCBs from different sources (Ampleman et al.. 2 015: Hornbuckle and
Robertson. 2010) that have distinct congener compositions from the original produced mixtures.
Furthermore, the composition of an exogenous environmental PCB mixture is subject to change
after uptake into the human body as different congeners are metabolized and eliminated at
different rates. Consequently, relating measures of PCB congeners in biological matrices to their

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corresponding environmental source mixtures can be challenging, which complicates traditional
risk assessment fChristerisen etal. 20211.

Associations between PCB exposure and cancer and noncancer health endpoints have been
reported in both human epidemiological and experimental animal studies (IARC. 2015: ATSDR.
20001. Of the 209 congeners, approximately 12 are considered "dioxin like," meaning that they bind
to the aryl hydrocarbon receptor (AhR) and can interact with biological systems through the same
mode of action as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (van den Berg et al, 2006: Poland et
a] ). The remaining "nondioxin-like" congeners have also been reported to be associated with

health endpoints; however, the specific hazards, dose-response relationships, and modes of action
are variable and not as clearly understood for these PCBs. National and international health
agencies have assessed PCB toxicity, including cancer (IARC. 2015: U.S. EPA. 19961 and noncancer
endpoints fATSDR, 2000: U.S. EPA. 1994.19931. The International Agency for Research on Cancer
(IARC) has classified PCBs as Group 1 carcinogens flARC. 20151. However, the most comprehensive
review of the potential effects of PCB exposure to date was conducted by the Agency for Toxic
Substances and Disease Registry (ATSDR) fATSDR. 2011. 20001. These reviews identified several
noncancer outcomes sensitive to PCB exposure, including dermal, ocular, immune, thyroid, liver,
reproductive, developmental, and neurodevelopmental effects (ATSDR. 2000). New research since
ATSDR's assessments suggests the potential for additional health hazards, notably metabolic and
cardiovascular effects. Furthermore, the full database of PCB literature has not previously been
reviewed using systematic methods with the intent to identify most of the available data informing
potential noncancer health hazards of exposure to PCB mixtures.

Systematic evidence maps (SEMs) are a useful tool to gain appreciation for the size and
content of a literature database fThaver etal. 20221. SEMs are used as analysis tools, which "do not
seek to synthesize evidence but instead to catalog it, utilizing systematic search and selection
strategies to produce searchable databases of studies along with detailed descriptive information"
(Elsevier. 2017). In this approach, systematic review methods are used, including a targeted search
of the literature guided by Populations, Exposures, Comparators, and Outcomes (PECO) criteria
(see Table 1) and subsequent study categorization and development of visualizations to "map" the
contents of the database. The resulting map can be used to evaluate the data available to inform
specific questions that could be of interest for future systematic reviews.

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Table 1. Populations, exposures, comparators, outcomes (PECO) criteria3

PECO
element

Description of Studies Included

Populations

Human: Adults and/or children with exposure to PCBs at anv life stage.

Animal: Nonhuman mammalian animal species (whole organism) exposed during anv life stage
(during any period from in utero through adulthood). Studies including evaluations of transgenic
animals only (i.e., with no evaluations of exposure-response relationships in wild-type animals)
were considered "Potentially Relevant Supplemental Material."

Exposures

Human: Any exposure to PCBs (in vivo) as determined by controlled exposure, measured PCB
concentration in contact medium (e.g., food, air, dust), biomarkers of exposure (e.g., serum PCB
levels), or occupation in a job involving exposure to PCBs (e.g., electric capacitor manufacturing).
The following exposure assessment methods/exposure contexts were considered "Potentially
Relevant Supplemental Material" in the absence of biomarker measurements or estimates
derived using scientifically sound methods: Yusho/Yu-Cheng patient status; consumption offish
(or marine mammals or other wildlife); and residential proximity to a PCB-contaminated site.

Animal: One or more oral (gavage, diet, drinking water, intragastric), inhalation (aerosol, vapor,
or particle; whole-body or nose-only), dermal (occlusive, semiocclusive, nonocclusive), or
injected (intravenous, subcutaneous, intraperitoneal) treatment(s) with any clearly quantified
dosage of PCB congeners or PCB mixtures administered to a whole animal (in vivo).

Studies were considered "Potentially Relevant Supplemental Material" if they used only routes of
administration not listed above (e.g., intratracheal instillation, intracisternal injection) or
evaluated only combinations of PCBs with other exposures (e.g., metals).

Comparators

Human: A referent or comparison population that is unexposed or exposed at lower levels of
PCBs, or exposed to PCBs for shorter periods of time, or cases versus controls, or a repeated
measures design. However, worker surveillance studies are considered to meet PECO criteria
even if no statistical analysis using a referent group is presented. Case reports and case series
were considered "Potentially Relevant Supplemental Material."

Animal: A concurrent control group exposed to vehicle-onlv treatment or untreated control.

Outcomes

Human: Anv examination of survival, bodv weight, or development, or of the structure or
function of dermatological, cardiovascular, endocrine, gastrointestinal, hematological,
hepatobiliary, immune, nervous, ocular, musculoskeletal, urinary, respiratory, or reproductive
cells, tissues, or systems.

Animal: Anv examination of survival, bodv weight, or development, or of the structure or
function of dermatological, cardiovascular, endocrine, gastrointestinal, hematological,
hepatobiliary, immune, nervous, ocular, musculoskeletal, urinary, respiratory, or reproductive
cells, tissues, or systems.

In general, endpoints related to clinical diagnostic criteria, disease outcomes, histopathological
examination, or other apical/phenotypic outcomes are considered to meet PECO criteria and are
prioritized for evidence synthesis while endpoints such as observations of cellular structure, gene
expression, cell signaling, or other similar biochemical measures are considered "Potentially
Relevant Supplemental Material."

aPECO criteria are based on those presented in U.S. EPA (2019).

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This evidence map's main objective is to summarize available noncancer health endpoint
data for mammalian toxicological and human epidemiological studies of exposures to PCB mixtures.
By identifying health endpoints with databases sufficient to support evaluations of coherence
across evidence streams (i.e., from studies in humans and nonhuman mammals) and across
biologically related endpoints (e.g., endpoints linked through a common adverse outcome
pathway), we can highlight the databases with the highest likelihood of supporting an analysis of
causal relationships with exposure to PCB mixtures for future systematic reviews. Conversely, by
identifying areas with poorer databases, this evidence map can also be used to inform future
research efforts on topics that have been insufficiently studied.

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2. METHODS

2.1. LITERATURE SEARCH

A protocol was developed that describes the literature search strategy and PECO criteria
used to facilitate subsequent screening and categorization of literature into a SEM of PCB exposure
and noncancer health endpoints fU.S. EPA. 20191. The protocol was registered in 2019 via Zenodo
(https://doi.org/10.5281/zenodo.3585771). Peer-reviewed literature was identified by searching
PubMed (National Library of Medicine), Web of Science (Clarivate Analytics), and, prior to 2019,
Toxline (National Library of Medicine). The literature search strategy relied on terms describing
PCB mixtures and individual congeners (e.g., "polychlorinated biphenyls," "Aroclor," "PCB,"
"tetrachlorobiphenyl") to gather information on exposure to the chemicals of interest Additional
exposure terms were used to identify studies not indexed by the chemical name (e.g., "capacitor
manufacturing workers," "Yu-Cheng," "New York State Angler Cohort"). These search terms were
intentionally broad and did not prioritize studies in which exposure was quantified for individual
participants; this was considered during screening of the literature. The detailed search strategies
are presented in Table S1A, and a summary of search results is provided in Table SIB in
Supplementary File 1. A list of all references retrieved through the literature searches is provided in
Supplementary File 2, and search results by year are provided in Supplementary Files 3-9. The
original search, conducted in 2015, was not restricted by publication date or language
(Supplementary File 3). Literature search updates were conducted yearly through September 1,
2021 and were restricted to the 12-month period since the original search or the most recent
update (Supplementary Files 4-9). Each annual search update utilized the same search terms.
Records identified through the original literature search were prioritized electronically as
described below. Reference lists of health assessments published by federal, state, and international
health agencies were searched to identify seed references (described below), but additional
supplemental search strategies (e.g., citation mapping) were not applied. Twenty-five references
were identified through recommendation by technical experts (see Table SIC).

2.2. ELECTRONIC APPROACHES USED TO REFINE A LARGE DATABASE

Screening a large number of candidate studies for inclusion is time-consuming when
conducted manually by human reviewers. Automation tools are available to reduce the human
effort needed for screening. For this review, natural language processing (NLP) and machine
learning (ML) techniques were employed to identify the most relevant literature for manual
screening. Studies were prioritized using DoCTER, a Document Classification and Topic Extraction
Resource fVarghese etal.. 20181. Details of the NLP and ML methods are described elsewhere

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fVarghese etal. 2019: Varghese etal. 20181. Briefly, 483 studies selected as having met the PECO
criteria for inclusion in this review (see Table 1) were designated as seed references (provided in
Table SID). Seed references are a set of relevant documents that are labeled and included in the
larger collection of unclassified documents. Seed references function as tracers in the document
prioritization process, helping identify documents with similar content For this review, seed
references were identified during problem formulation (U.S. EPA. 20151. which was largely on the
basis of a survey of references cited in health assessments published by federal, state, and
international health agencies, most notably ATSDR [20001. Seed studies were included in the
corpus of references identified by keyword searches and used to prioritize studies using an ML
method called supervised clustering. In Phase 1 of a two-phased prioritization approach, titles and
abstracts of all references identified by keyword searches, along with the seed references, were
represented as a mathematical matrix using an NLP transformation and then organized into groups
of references with semantic similarity (i.e., "clusters") using algorithms as depicted in Figure 1A.
Two clustering algorithms (k-means, nonnegative matrix factorization) were applied using cluster
sizes of 10, 20, or 30 references for a total of 6 different clustering approaches. Reference clusters
that included seed references were identified as illustrated in Figure IB.

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Figure 1. Illustration of electronic prioritization approaches.

1A. Schematic illustration of electronic prioritization of literature depicting references clustered by similarity using
natural language processing. IB. Illustration depicting clusters containing relevant seed references (circled blue
clusters). Clusters were ranked by the number of seed studies included. 1C. Visualization of identified clusters.
Clusters were organized into groups (A-F) on the basis of the number of approaches that identified the cluster
such that Group A contains clusters that include seed references identified by six approaches and Group F
contains clusters that include seed references identified by a single approach. All references in the top four
groups (A-D) were manually screened for inclusion based on PECO criteria. Low scoring groups (E, F) were
subjected to additional machine learning approaches to capture relevant references for manual screening.

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In each of these six approaches, clusters were ranked in decreasing order of the number of
seed studies included in the cluster, and clusters were accepted in order until 90% of the total set of
seed studies was captured. A 90% threshold was selected because it provided an optimal balance
between the statistical measures of recall (fraction of relevant studies retrieved) and precision
(fraction of relevant studies among the retrieved studies) (Varghese etal. 2018). Higher thresholds
would have resulted in diminished precision and a considerably higher manual screening burden
given the size of the original literature database. This method was repeated for all six clustering
approaches; thus, a given study could have appeared in one of the accepted clusters (and thus
appear with the greatest fraction of the seed studies) in anywhere from zero to six of the
approaches. Clusters containing seed references were grouped by the number of approaches in
which they were identified (Groups A-F, Figure 1C). Studies that appeared in groups A-D
(representing 6, 5, 4, or 3 approaches, Figure 1C) were subjected to manual title and abstract-level
screening, as described in Section 2.3.1. Screened studies from Phase 1 were used to train the ML
model in Phase 2.

In Phase 2, a supervised ML algorithm (support vector machines; fVarghese et al. 201811
was used to predict relevance for those studies in the remaining groups of clusters that appeared in
one or two approaches (groups E and F, Figure 1C). Also included in this approach was one group of
studies excluded from initial clustering until abstracts were recovered and a second group of
studies with titles only. The training data set for this secondary analysis is distinct from the seed
references mentioned above and included all studies manually screened in Phase 1; the training
data set for supervised ML thus included examples of studies that met PECO and those that did not.
Studies predicted to be relevant in Phase 2 by the supervised ML algorithm were subjected to
manual title and abstract-level screening. Details of the DoCTER prioritization strategy are
presented in Table S1E, and a list of studies prioritized using DoCTER supervised clustering and ML
approaches is provided in Table S1F.

Because fewer references were identified in yearly search updates, alternative approaches
were used to prioritize the literature for screening (summarized in Figure 2). References identified
in 2016 were directly subjected to manual screening without electronic prioritization. References
identified after August 2016 were prioritized using SWIFT-Active Screener fSciome. 20231. a web-
based software application integrated with electronic prioritization using ML and statistical
approaches. For each literature update, manually reviewed studies were used to train the model,
which is updated iteratively, thus reducing manual screening efforts (Howard et al. 2020).

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, Up to 2015, 2016 , 2017 , 2018 , 2019 , 2020 , 2021 ,

Initial Literature Literature Search

Search Update

Up to 2015 ^P| 2016

All Studies Published
Up To August 2015

50,309 Studies
Identified

Electronic Prioritization using
DoCTER

(Supervised Clustering and
Machine Learning)

Studies Published
From August 2015 To
August 2016

1,818 Studies
Identified

No Electronic Prioritization
(Manual Review Only)

Literature Search
Updates

2017-2021

Studies Published
From August To August
For Each Year

1,756-2,402 Studies
Identified Per Year

Electronic Prioritization using
SWIFT-Active Screener
(Active Machine Learning)

Figure 2. Chronology of prioritization approaches applied to PCB literature
search results.

The initial 2015 literature search used DoCTER, an electronic prioritization approach described in Section 2.2 and in
ICF (2021). The literature updates from 2017-2021 utilized SWIFT-Active Screener, another electronic
prioritization program fully described in Sciome (2023).

2.3. LITERATURE SCREENING

2.3.1. Title and Abstract Screening of the Literature

Prioritized records were combined with smaller groups of records, including seed
references, records identified through literature search updates, and references suggested by
technical experts, into a single database. The literature was then manually screened in two steps to
determine whether individual studies sh ould be included or excluded as a primary source of health
endpoint data based on PECO criteria shown in Table 1. Step 1 consisted of title and abstract
screening, while Step 2 involved full-text screening (Section 2.3.2).

In Step 1, two trained screeners independently conducted a manual title and abstract
review using structured forms developed in DRAGON (a modular database with integrated
screening and literature evaluation tools developed for systematic review) (ICF. 2018) to identify
records that appeared to meet the PECO criteria. For citations with no abstract, articles were
screened based on title relevance. Screening conflicts were resolved by a third reviewer. Each study
was categorized to one of the following bins: "Relevant to Hazard Identification in Humans",
"Relevant to Hazard Identification in Animals" (nonhuman mammals only), "Potentially Relevant

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Supplemental Material", or "Not Relevant". Identification of studies "Relevant to Hazard
Identification in Humans" or "Relevant to Hazard Identification in Animals" was based on the
species of the population(s) exposed to PCBs. Studies identified as "Not Relevant" did not meet
PECO. "Potentially Relevant Supplemental Material" included toxicokinetic studies, studies
describing pharmacokinetic models for PCB congeners and mixtures, and mechanistic studies.
Additional records tracked as "Potentially Relevant Supplemental Material" included conference
abstracts, secondary data sources (e.g., reviews, agency assessments), non-English-language
studies, exposure studies unrelated to health endpoints, and human case reports or case series. The
tags used for study categorization are summarized in Tables S1G, S1H, and S1I. Categories of
"Potentially Relevant Supplemental Material" are shown in Table S1I.

References retrieved through August 2016 were screened and tagged using DRAGON.
Screening decisions and study metadata recorded in DRAGON (v. 03-25-2016) were recently
moved to a second generation, web-based systematic review platform rebranded as litstream™
fiCF, 2021). References identified in search updates after August 2016 were screened in SWIFT-
Active Screener until the software indicated a likelihood of 95% that all relevant studies had been
captured. This threshold is comparable to human error rates fBannach-Brown et al. 2018: Howard
et al, 2016: Cohen et al, 2006) and is used as a metric to evaluate ML performance. A summary of
literature prioritized using SWIFT-Active Screener is provided in Table SI J.

To validate the application of clustering and ML algorithms, a subset of nonprioritized
studies was also randomly selected for manual title and abstract-level review.

2.3.2. Full-Text Screening of the Literature

Records not excluded or considered "Potentially Relevant Supplemental Material" based on
the title and abstract advanced to full-text manual review using litstream. Full-text copies of these
potentially relevant records were retrieved and independently assessed by two screeners to
confirm eligibility according to the PECO criteria. Screening conflicts were resolved by a third
reviewer. Seed references, which had been identified as meeting PECO during problem formulation
flJ.S. EPA. 20151 were also included in the full-text screen to categorize these records.

In addition to confirming that studies met PECO criteria, the health endpoints investigated
in each study were identified using structured forms in litstream. Health endpoints were organized
into the following categories based on Thayer et al. (2022): Cardiovascular, Dermal, Developmental,
Endocrine, Gastrointestinal, Hematopoietic, Hepatobiliary, Immune System, Metabolic,
Musculoskeletal, Nervous System, Ocular, Reproductive, Respiratory, and Urinary System. These
organ/system categories were chosen because of their potential to include specific noncancer
health endpoints that could be affected by PCB exposure at levels relevant to those experienced in
the general population. Assignment of specific endpoints into each of the organs/systems was made
by one or more coauthors based on their primary areas of expertise. Some studies evaluated
multiple endpoints and so were assigned to multiple organs/systems. We recognize that there is
crosstalk among many physiological systems, which can complicate the categorization of endpoints;

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specific information on which endpoints are included in each organ/system is provided in Section
3.3. Studies focused entirely on cancer or frank toxicity, including mortality of unknown cause, and
wasting, although not the focus of this review, were considered "Potentially Relevant Supplemental
Material". Humans tend to be exposed to complex PCB mixtures that contain many congeners of
varied toxic potency and potential modes of action (U.S. EPA. 20151. Since the focus of this review is
on studies of mixtures that better reflect a typical human exposure scenario, toxicological studies in
which mammals were exposed only to individual PCB congeners or to mixtures comprising fewer
than four congeners were considered "Potentially Relevant Supplemental Material".

Based on the results for the full-text review, summary-level, sortable lists of relevant
literature were created for human and animal (nonhuman mammalian) studies for each
organ/system. Fundamental study design information (e.g., study population, exposure
assessment/design, PCB mixtures administered in nonhuman mammalian studies, health endpoints
evaluated) was extracted for each study in Microsoft Excel by one individual and independently
reviewed by at least one additional individual.

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3. RESULTS AND DISCUSSION

3.1. LITERATURE SEARCH AND SCREEN

3.1.1. Literature Searches (2015-2021)

The results of the literature searches and screens for literature published through August
31, 2021, are summarized in the Literature Flow Diagram presented in Figure 3. After duplicate
removal, 50,309 studies were identified from the initial literature search conducted in 2015. Yearly
literature search updates were conducted from 2016 to 2021, yielding between 1,756 and 2,402
unique studies per year, which added 11,390 studies. Thus, 61,699 studies were identified after
duplicate removal.

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2015-2021

Figure 3. Literature search flow diagram for PCBs.

Searches were conducted up to August 31, 2021, in PubMed, Web of Science, and, prior to 2019, also Toxline.
References were identified by technical experts or through supplemental searches, including seed references.
3Records were prioritized for screening using machine learning tools (DoCTER for references identified in 2015-
2016 database searches and SWIFT-Active Screener for 2017-2021).

4	Studies not meeting PECO criteria.

5	"Potentially Relevant Supplemental Material" includes conference abstracts, reviews, and non-English studies
that met PECO and studies on PECO-related topics (e.g., toxicokinetic or mechanistic studies).

6Four studies examined health endpoints in both humans and other mammals.

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3.1.2. Electronic Prioritization for Manual Review

Manual screening of the entire database was time and cost prohibitive because of the vast
number of studies. Therefore, electronic prioritization approaches were implemented to identify
studies most likely to meet the PECO criteria (see Table 1). Results and prioritization strategies are
summarized in Figure 2 and Table SIB.

As described above for the initial literature search conducted in 2015, both supervised
clustering and ML approaches were used to prioritize studies for manual screening. The number of
studies identified using electronic prioritization methods is summarized in Table 2.

Table 2. Electronic prioritization of literature for hazard identification

Study group3

Prioritization approach

Number of prioritized studies

2015 literature search (original search): 50,309 records retrieved - DoCTER Prioritization

Groups A-D (see Figure 1C)

DoCTER - Supervised

4,605

Clustering

Groups E-F (see Figure 1C)

DoCTER - Supervised

3,363

Clustering and ML

Studies with titles only

DoCTER-ML

3,209

Total number electronically prioritized - DoCTER

11,177

2017-2021 literature search updates

2017

SWIFT-Active Screener -

609

2018

Active ML

819

2019

855

2020

917

2021

842

Total number electronically prioritized - Active ML

4,042

aAs described in Section 2.2, titles and abstracts were organized into clusters based on semantic similarity using six
different approaches. Clusters were ranked by the number of seed studies included in each and organized into
groups (A-F) on the basis of the number of approaches that identified the cluster; Group A contains clusters that
include seed references identified by six approaches, and Group F contains clusters that include seed references
identified by a single approach. All references in Groups A-D were manually screened; Groups E and F were
subjected to additional machine learning approaches to prioritize references for manual screening. The bold
numbers are defined as "Total number electronically prioritized - Active ML".

Studies not manually reviewed included those not identified by any of the clustering
approaches or those identified by one or two approaches and predicted not to be relevant during
the ML phase. Collectively, clustering and ML approaches using DoCTER identified 11,177 studies
from the initial literature search conducted in 2015 as high priority studies for manual review.
Review of a randomly selected subset of nonprioritized studies demonstrated that less than 10% of
nonprioritized studies were relevant based on PECO criteria, indicating that these approaches
captured at least 90% of the literature relevant to informing associations between PCB exposure
and health endpoints. In 2016, all 1,818 unique studies were manually reviewed. Of the 9,572

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studies retrieved in 2017-2021, 4,042 studies were prioritized using SWIFT-Active Screener and
were manually screened. Thus, 17,037 (27.6%) of the 61,699 studies retrieved through literature
searches were manually reviewed.

3.1.3. Literature Screening

In addition to electronically prioritized studies, 900 other studies were manually reviewed.
These included 483 seed references (see Table SID) and 417 studies identified by technical experts
or through supplemental literature searches conducted to identify information on PCB
toxicokinetics or modes of action (see Tables SIC and S1K). The manual review thus included
17,937 studies. Of these, 3,889 were identified as potentially relevant and subjected to full-text
review and categorization by health endpoint. After full-text review and categorization, 1,586
studies were included in literature summary tables organized by organ/system, with one summary
table per system for human studies and a second for animal studies (nonhuman mammals only). A
total of 953 human studies and 637 nonhuman mammalian studies were evaluated for health
endpoints and exposure to PCBs.

Most studies evaluated more than one type of health endpoint, so the numbers of studies for
each system are not expected to sum to the total number of studies, nor are the numbers of studies
of each health endpoint expected to sum to the total number of studies for the relevant
organ/system. Furthermore, sometimes results from a single research project are reported in
multiple publications. Different publications might focus on different subsets of data, use different
statistical or other analytical approaches, or update results published from earlier stages of data
collection. For example, a study of women with and without endometriosis first described by Buck
Louis et al. (20051 was later reanalyzed using different statistical techniques (Roy et al, 2012:
Gennings et al, 2010). When the same results were reported in multiple publications or when some
publications reported results based on less complete data, we considered those data only as
reported in the most up-to-date or most complete publication. Even so, this multiplicity of
published reports is important to note when interpreting numbers of studies identified by the
literature search and screening process and evaluation of the adequacy of the database to support
hazard conclusions. To help readers navigate through the literature and understand the basis for
our study counts, we have developed interactive visualizations that allow for identification of the
individual references included for each organ/system

(https://hawcprd.epa.gov/summarv/assessment/lQQ5QQ282/visuals/: underlying data provided
in Table S1L). These visualizations can also be used to filter references by study design
characteristics of interest to generate customized reference lists and counts of studies that we do
not include in this report

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3.2. GENERAL CONSIDERATIONS

One potential use for this evidence map is to provide a starting point for future health
hazard assessments of PCB mixtures. Such assessments could include full systematic reviews of the
evidence for PCB effects on specific types of health outcomes. Because of the time and level of effort
required to develop a full systematic review, a practical preliminary step for prioritizing
organs/systems for systematic review is to identify health endpoints with databases that are
sufficiently large and informative to potentially support meaningful conclusions about causal
relationships with PCB exposure. This evidence map is designed to facilitate the identification of
such databases that could be further evaluated through subsequent systematic reviews, which
would include study evaluation and evidence synthesis and integration (U.S. EPA. 20191.
Determination of causal relationships between exposures and health effects forms the basis for
hazard identification, which is a fundamental step in human health risk assessment fNRC. 19831.
The following sections describing the databases for each organ/system include information on the
types of considerations important for establishing an exposure hazard for that system. One
consideration is the availability of information from human studies - while nonhuman mammalian
data can be useful to support findings from human studies and can help address gaps in the human
database (due, e.g., to the difficulty associated with measuring certain endpoints in humans), a lack
of nonhuman mammalian studies is not considered a limitation if human data are sufficient to
establish hazard. Other examples of considerations applicable for all organs/systems, described in
the remainder of this section, include the following: the number of studies and endpoints examined;
public health significance of the endpoints; exposure level, timing, and context; method of assessing
exposure and health endpoints; and occurrence of co-exposures. Considerations that are most
applicable for a specific organ/system are outlined in each organ/system summary section (e.g.,
validity and accuracy of a clinical diagnostic method for a certain health endpoint). For each
organ/system, these factors were considered to develop conclusions regarding the potential for
each database to support hazard identification.

Databases with the potential to inform coherence across biologically related endpoints are
more likely to support strong hazard conclusions than databases including evaluations of only
single endpoints in isolation. While a change in a single endpoint or biomarker of effect could be
due to random chance, changes in several related endpoints are less likely to occur solely for this
reason. In some instances, changes in multiple endpoints can indicate greater severity or
progression along a disease continuum or provide more insight into possible mechanisms/modes
of action. Therefore, throughout this review, information is often provided on the availability of
studies evaluating multiple, biologically related endpoints.

Exposure timing is one important consideration for assessing the potential sensitivity of
studies conducted in humans or other mammals. This is especially true for studies of potential
effects on development The developmental period is critical because it is the foundation for health
throughout an organism's lifetime. Adverse effects on development can occur because of chemical

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exposure during gestation, infancy, adolescence, or even early adulthood (e.g., the nervous system
continues to develop until around age 21 years in humans) fMakris etal. 2008: Adams et al. 20001.
For many endpoints, sensitive developmental windows can represent periods of important
biological progressions. The exact developmental period of vulnerability varies for different
endpoints, depending on the duration or timing of a given developmental process. The ability of a
human exposure measurement to correctly classify individuals with respect to their exposure
during an etiologically relevant period(s) will vary depending on the specific health endpoint,
exposure context and timing of measurement, and study population. Evaluating exposure during
the preconception, pregnancy, and perinatal periods presents unique challenges. For example, PCB
body burden changes with changes in maternal weight and body composition during pregnancy
and lactation; thus, the timing of sample collection is critical and should reflect an etiologically
relevant period for the endpoint of interest [e.g., (Bloom et al.. 2007)]. In addition, for many
endpoints, critical or sensitive windows of exposure have not been well characterized. However,
studies of exposures during those windows are important to optimize the sensitivity of the
database for identifying effects on those endpoints. Specific windows of susceptibility and the
existence of studies that evaluate exposures during those windows are discussed in the summary
sections for each organ/system.

3.2.1. Human Studies

Assessment of methodological features such as the study population, study design, exposure
and endpoint measurement, analytical methods, and completeness of reporting guide the
evaluation of human studies with respect to their validity and utility for assessing relationships
between health effects and chemical exposures. The most informative studies include an
appropriate sample of the target population (e.g., representative and of adequate size for the study
question), use sensitive and specific methods to assign exposure status and to measure health
endpoints, and use appropriate statistical techniques and design considerations to minimize
potential bias and confounding. For epidemiological studies, some general considerations apply
across all exposure types and organs/systems flJ.S. EPA. 20221: some specific examples particularly
relevant to the database of PCB studies are outlined here.

In terms of study population, general population samples might enable examination of
health endpoints observed at relatively lower levels of exposure compared with persons exposed
occupationally or through specific high-exposure events with relevant coexposures. Conversely,
occupational studies can provide valuable information regarding certain exposure contexts that are
not otherwise observed in epidemiology studies, such as high-level exposure or exposure via
inhalation or dermal routes, and thus can be useful for informing hazard when considered together
with other sources of evidence. In the PCB database, many studies have evaluated health endpoints
occurring among persons accidentally exposed to PCBs and their combustion by-products,
polychlorinated dibenzofurans (PCDFs) (Hutzinger etal. 1985). via contaminated rice bran oil, in
the Yusho (Japan, 1968) and Yu-Cheng (Taiwan, 1979) incidents. As described by ATSDR (20001

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and Kunita et al. (1985). PCDFs and dioxin-like PCBs could affect the same health endpoints
because they share a common mode of action mediated by the AhR. Such co-occurring exposures
are generally present in epidemiological studies and can complicate evaluation of health endpoints
if they are highly correlated with PCBs and the endpoint of interest in the study population. Other
issues that need consideration in the Yusho/Yu-Cheng group of studies include the ability to define
the exposed population (e.g., patient registries might be incomplete) and the magnitude of exposure
(e.g., many studies rely on self-reported oil use, and often the lag between exposure and its
measurement is considerable). Similar considerations of potential coexposures are important for
interpreting and generalizing the results of studies in consumers of PCB-contaminated fish, marine
mammals, or other wildlife. These dietary sources might contain PCBs in notable amounts, along
with both other pollutants (e.g., methylmercury) and beneficial nutrients (e.g., long-chain fatty
acids) (Paliwoda et al. 2016: Turvketal, 20121. Throughout this review, information on the study
population is considered in each database when determining the ability to generalize results to
other populations with different exposure scenarios.

The most common types of study design for human studies of PCB exposure were cohort
and cross sectional followed by case-control and other study designs. We note that while we
designated study design using these broad categories for the purpose of this review, study design
does not always fall cleanly into these bins. Prospective designs (e.g., cohorts or case-control
studies nested within cohorts) are advantageous in that the temporality of the exposure preceding
the outcome is ensured, in contrast to cross-sectional or typical case-control studies. For longer-
lived PCB congeners, exposure measurements made concurrently with outcome ascertainment may
adequately represent prior exposure status, but this is less certain for shorter-lived congeners
fChristensen et al. 20211. However, cohort designs might not be efficient when evaluating rare
health endpoints; in this case, other designs such as case-control studies are advantageous. As
described above, several studies evaluate health endpoints following unintended exposure to PCBs
and PCDFs in the Yusho and Yu-Cheng populations. Evaluation of these studies is complicated by
the fact that membership in respective health registries is often used to confer "exposed" status,
while measurements in biological tissues were taken at various time points after the exposure
occurred, sometimes concurrent with the endpoint measure and sometimes before or afterward.
For this review, studies of Yusho and Yu-Cheng are generally considered to be cohort studies, but
specific cases are noted when exposure measures are interpreted differently based on timing
relative to outcome ascertainment. Information on study design is considered in each database to
help determine whether the data can inform presence of causal links (considering, e.g., temporality)
between PCB exposure and evaluated endpoints.

Most human studies in the database characterized PCB exposure using measures of PCB
congeners or their metabolites in biological matrices. The most reported measurements were made
in plasma/serum collected from adults outside the context of pregnancy or lactation or, for studies
of mother-infant pairs, in maternal plasma/serum, umbilical cord plasma/serum, human milk, or

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child blood. PCB measurements in other tissues such as adipose tissue, placenta, or brain are much
less common. PCBs are lipophilic, although the degree varies by congener and generally increases
with increasing chlorination. This implies that the PCB content in lipid-rich tissues (such as milk) is
substantially higher and possibly easier to detect and quantify compared with lipid-poor tissues
(e.g., cord plasma/serum), especially in populations exposed to very low levels of PCBs. Throughout
this review, exposure measurement methods are broadly considered when describing the database
of human studies for each organ/system but would be evaluated in more detail at the study
evaluation step of a full systematic review.

Outcome ascertainment methods vary across studies; endpoints can be measured using
information from a variety of sources, including national databases (e.g., mortality data, cancer
registries), medical records, pathology reports, self-report, assessment by study examiners, and
biomarkers based on urine or blood samples. Suitability of the endpoint measure (including factors
such as reliability and validity in different populations or periods) will depend on the specific
health endpoint and study population. Many studies evaluate mortality rates, or cause-specific
mortality rates, as a health endpoint. This is particularly common in the PCB literature for
occupationally exposed populations. These estimates can provide valuable information when the
cause-of-death coding is likely to be sensitive and specific, and when an appropriate comparator
population is selected. Endpoint measurement methods are broadly considered when describing
the database of human studies for each organ/system but would be evaluated in more detail at the
study evaluation step of a full systematic review.

3.2.2. Nonhuman Mammalian Studies

Although using human data for risk assessment can reduce uncertainty, human data are
often unavailable for reasons including the ethical implications of permitting human chemical
exposures to reach levels associated with health effects. Therefore, laboratory animal studies are
commonly conducted to investigate a range of endpoints useful for determining whether a chemical
is likely to pose a hazard to human health (NRC. 1983). Evaluations of the utility of such studies for
hazard identification might consider study design and experimental conduct, including features like
reporting quality, internal validity, and study sensitivity flJ.S. EPA. 20221. The most informative
studies use accurate and valid methods to assess endpoints of interest and rely on appropriate
statistical techniques and design considerations to limit potential bias (e.g., blinding,
randomization, variable control) and to maximize sensitivity for detecting the endpoints of interest
[e.g..(Dishaw et al, 2020)].

Although human exposure to PCBs can occur through multiple routes, including dietary
intake, inhalation, and dermal contact fWeitekamp etal. 20211. few mammalian data are available
on health endpoints and inhalation and dermal exposures to PCBs. As described in (see Section 1),
PCB inhalation in contaminated buildings has been an area of great public health interest, especially
in the context of PCB exposure in schools (U.S. EPA. 2019. 2015. 2012). The scarcity of PCB data for
inhalation exposure represents one important area of uncertainty for risk assessment (U.S. EPA.

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2019: Lehmann et al.. 2015: U.S. EPA. 20151. Pharmacokinetic modeling approaches offer potential
utility for extrapolating dose-response data among exposure routes fFairmanetal.. 20201:
however, more research is needed to address the complexity and interactions of multiple PCB
congeners with unique toxicokinetic behavior and exposure pathways. Throughout this review,
information is provided on the routes of exposure addressed in the database for each organ/system
to provide an indication of the ease with which study results can be applied to various human
exposure scenarios.

3.3. ORGAN/SYSTEM DATABASE SUMMARIES

The available human and nonhuman mammalian studies for each organ/system will be
reviewed in Sections 3.3.1 through 3.3.15. Overview figures summarizing study design information
were generated from the interactive visualizations described in Section 3.1.3
(https://hawcprd.epa.gov/summary/assessment/100500282/visuals/] and will be referenced
throughout this report; they are highlighted briefly here. Figure 4 presents an overview of human
and nonhuman mammalian studies across the 15 organs/systems.

Evidence Stream

Organ/System

Human

Other Mammal

Cardiovascular

Dermal

Developmental

130

170

Endocrine

125

177

Gastrointestinal

Hematopoietic

Hepatobiliary

357

immune System

105

131

Metabolic

197

Musculoskeletal

Nervous System

214

174

Ocular

Reproductive

227

218

Respiratory

Urinary System

104

Grand Total

953

637

Number of Studies

357

Figure 4. Overview of Human and Other Mammalian Studies Across
Organs / Systems

Summary of the database of studies evaluating exposures to PCB mixtures and health endpoints organized by
system. Lists of studies included in each count can be accessed via the online interactive version of this figure

(https://hawc.epa.gov/summarv/visual/assessment/100500282/QverviewAIIStudies/). Shading intensity
corresponds with the number of studies in each category, from 1 to 357, which is the maximum number of
studies in any category.

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For the human studies, the database is organized by organ/system and study population in
Figure 5, by organ/system and study design in Figure 6, and by organ/system and PCB exposure
metric in Figure 7. When describing exposure metrics, the term "blood" was used to broadly
capture measurements made in whole blood or any fraction (serum or plasma). Multiple blood
metrics are identified to indicate the lifestage represented by the measurement (i.e., blood
(collected from adults outside the context of pregnancy or lactation], child blood, maternal blood,
cord blood}.

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Figure 5. Overview of Human Studies by Organ/System and Population

Summary of the database of human studies evaluating exposures to PCB mixtures and health endpoints organized
by system and population. Lists of studies included in each count can be accessed via the online interactive
version of this figure (https://hawc.epa.gov/summarv/visual/assessment/100500282/OverviewHumanStudies ).
The online figure can be expanded to include information by endpoint category and can be filtered by
organ/system (options: cardiovascular, dermal, developmental, endocrine, gastrointestinal, hematopoietic,
hepatobiliary, immune system, metabolic, musculoskeletal, nervous system, ocular, reproductive, respiratory,
urinary system), study design (options: case-control, cohort, cross-sectional, other), population (options:
accidental, contaminated schools and other buildings, fish/marine mammal (diet), general population,
occupational, residents in contaminated area, Yusho/Yu-Cheng), sex (relevant only for reproductive endpoints;
options: couple, female, male), and exposure metric (options: adipose tissue, blood, breast milk, child blood, cord
blood, dietary estimates, fish consumption, maternal blood, occupational/JEM, other metric [includes dust and
modeled estimates], other tissue). Shading intensity corresponds with the number of studies in each category,
from 1 to 167, which is the maximum number of studies in any category.

3-10

-------
Study Design

Organ/System

Cohort

Cross-sectional

Case-control

Other

Cardiovascular

40

37

4



Dermal

13

20



1

Developmental

110

12

8



Endocrine

32

82

5

11

Gastrointestinal

9

12

2

1

Hematopoietic

19

27



Hepatobiliary

26

57

1

2

Immune System

47

53

6

1

Metabolic

58

109

23

9

Musculoskeletal

11

14

3

2

Nervous System

155

44

16

1

Ocular

7

10



1

Reproductive

88

94

43

2

Respiratory

18

11



1

Urinary System

7

21

1



Number of Studies

155

Figure 6. Overview of Human Studies by Organ/System and Study Design

Summary of the database of human studies evaluating exposures to PCB mixtures and health endpoints organized
by system and study design. Lists of studies included in each count can be accessed via the online interactive
version of this figure (https://hawc,epa.gov/summary/visual/assessment/100500282/QverviewHumanStudies,).
The online figure can be expanded to include information by endpoint category and can be filtered by
organ/system (options: cardiovascular, dermal, developmental, endocrine, gastrointestinal, hematopoietic,
hepatobiliary, immune system, metabolic, musculoskeletal, nervous system, ocular, reproductive, respiratory,
urinary system), study design (options: case-control, cohort, cross-sectional, other), population (options:
accidental, contaminated schools and other buildings, fish/marine mammal (diet), general population,
occupational, residents in contaminated area, Yusho/Yu-Cheng), sex (relevant only for reproductive endpoints;
options: couple, female, male), and exposure metric (options: adipose tissue, blood, breast milk, child blood, cord
blood, dietary estimates, fish consumption, maternal blood, occupational/JEM, other metric [includes dust and
modeled estimates], other tissue). Shading intensity corresponds with the number of studies in each category,
from 1 to 155, which is the maximum number of studies in any category. JEM = job exposure matrix.

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Figure 8. Overview of Nonhuman Mammalian Studies by Organ/System and Species

Summary of the database of studies in nonhuman mammals evaluating exposures to PCB mixtures and health endpoints organized by system and species. Lists
of studies included in each count can be accessed via the online interactive version of this figure

(https://hawc.epa.gov/summarv/visual/assessment/100500282/QverviewNonhumanMammalStudies/). The online figure can be expanded to include
information by endpoint category and can be filtered by organ/system (options: cardiovascular, dermal, developmental, endocrine, gastrointestinal,
hematopoietic, hepatobiliary, immune system, metabolic, musculoskeletal, nervous system, ocular, reproductive, respiratory, urinary system), exposure
duration/life stage (options: acute [single dose], chronic, developmental, NR, short-term, subchronic), species (options: cat, cow, dog, ferret, gerbil, goat,
guinea pig, hamster, mink, mouse, nonhuman primate, rabbit, rat, sheep, swine, vole), sex (relevant only for reproductive endpoints; options: female, male,
pair), and exposure route (options: dermal, inhalation, injection, oral). Shading intensity corresponds with the number of studies in each category, from 1 to
239, which is the maximum number of studies in any category. NR=not reported.

3-13

-------
Exposure Route

Organ/System

Oral

Injection

Inhalation

Dermal

Cardiovascular

Dermal

Developmental

135

Endocrine

131

Gastrointestinal

Hematopoietic

Hepatobiliary

293

Immune System

108

Metabolic

Musculoskeletal

Nervous System

146

Ocular

Reproductive

149

Respiratory

Urinary System

Number of Studies

293

Figure 9. Overview of Nonhuman Mammalian Studies by Organ/System and
Exposure Route

Summary of the database of studies in nonhuman mammals evaluating exposures to PCB mixtures and health
endpoints organized by system and exposure route. "Oral" included gavage, diet, drinking water, and intragastric
exposures, "injection" included intravenous, subcutaneous, and intraperitoneal exposures, "inhalation" included
whole-body or nose-only inhalation exposures, and "dermal" included occlusive, semiocclusive, and nonocclusive
dermal exposures. Lists of studies included in each count can be accessed via the online interactive version of this
figure (https://hawc.epa.gov/summarv/visual/assessment/100500282/OverviewNonhumanMammalStudies ),
The online figure can be expanded to include information by endpoint category and can be filtered by
organ/system (options: cardiovascular, dermal, developmental, endocrine, gastrointestinal, hematopoietic,
hepatobiliary, immune system, metabolic, musculoskeletal, nervous system, ocular, reproductive, respiratory,
urinary system), exposure duration/life stage (options: acute [single dose], chronic, developmental, NR, short-
term, subchronic), species (options: cat, cow, dog, ferret, gerbil, goat, guinea pig, hamster, mink, mouse,
nonhuman primate, rabbit, rat, sheep, swine, vole), sex (relevant only for reproductive endpoints; options:
female, male, pair), and exposure route (options: dermal, inhalation, injection, oral). Shading intensity
corresponds with the number of studies in each category, from 1 to 293, which is the maximum number of
studies in any category. NR=not reported.

3-14

-------
Exposure Duration/Lifestage

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Endocrine

Gastrointestinal

Hematopoietic

Hepatobiliary

116

159

Immune System

Metabolic

Musculoskeletal

Nervous System

112

Ocular

Reproductive

Respiratory

Urinary System

Number of Studies

170

Figure 10. Overview of Nonhuman Mammalian Studies by Organ/System and
Exposure Duration/Lifestage

Summary of the database of studies in nonhuman mammals evaluating exposures to PCB mixtures and health
endpoints organized by system and exposure duration/lifestage. Lists of studies included in each count can be
accessed via the online interactive version of this figure

(https://hawc.epa,gov/summarv/visual/assessment/100500282/Overviewl\lonhumanMammalStudies/). The
online figure can be expanded to include information by endpoint category and can be filtered by organ/system
(options: cardiovascular, dermal, developmental, endocrine, gastrointestinal, hematopoietic, hepatobiliary,
immune system, metabolic, musculoskeletal, nervous system, ocular, reproductive, respiratory, urinary system),
exposure duration/life stage (options: acute [single dose], chronic, developmental, NR, short-term, subchronic),
species (options: cat, cow, dog, ferret, gerbil, goat, guinea pig, hamster, mink, mouse, nonhuman primate, rabbit,
rat, sheep, swine, vole), sex (relevant only for reproductive endpoints; options: female, male, pair), and exposure
route (options: dermal, inhalation, injection, oral). NR = not reported. Shading intensity corresponds with the
number of studies in each category, from 1 to 170, which is the maximum number of studies in any category.
NR=not reported.

3-15

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3.3.1. Cardiovascular

The cardiovascular system is complex, consisting of the heart and a closed system of blood
vessels: arteries, capillaries, and veins. The heart pumps oxygenated blood from the lungs to the
aorta, from which the blood is further carried to peripheral arteries and then the capillaries in the
organs and tissues of the body. Deoxygenated blood from organs and tissues is carried from the
capillaries to the peripheral veins and further to the heart

Eighty-one human studies evaluated cardiovascular endpoints and PCB exposure (see
Figure 4). Studied endpoints included ischemic heart disease (IHD; also referred to as coronary
artery disease or coronary heart disease); myocardial infarction (MI; heart attack); hypertension
(high blood pressure); cerebrovascular disease; atherosclerosis (plaque buildup inside arteries and
hardening and narrowing of their walls); and heart failure (HF; inability to pump sufficient blood to
organs and tissues). These health endpoints are interrelated—IHD is caused by decreased blood
flow through coronary arteries due to atherosclerosis resulting in myocardial ischemia. The two
most severe, immediately life-threatening cardiovascular endpoints are MI and stroke, which are
the most severe forms of IHD and cerebrovascular disease, respectively. Hypertension is a major
risk factor for MI and stroke and for kidney failure, which is discussed in detail in Section 3.3.15.
Dyslipidemias, considered important risk factors for cardiovascular disease, are discussed in detail
in Section 3.3.7.

Among the cardiovascular endpoints evaluated in the literature, those comprising well-
defined specific disorders of the cardiovascular system objectively confirmed by study investigators
(hypertension confirmed by blood pressure measurement; atherosclerosis confirmed by intima-
media thickness assessed by the ultrasound imaging) or by physicians (diagnoses of IHD, MI,
hypertension, stroke in medical records) are expected to be the most sensitive and specific. As
noted above, cardiovascular endpoints are pathogenetically interrelated; thus, if PCB exposure does
affect the cardiovascular system, one might anticipate finding associations with multiple related
endpoints. However, endpoints that are overly broadly defined (cardiovascular system diseases not
otherwise specified [NOS] or heart disease NOS), self-reported endpoints, and subjective
cardiovascular complaints are more likely to capture a range of disease severities and etiologies.
For example, cardiovascular system diseases NOS comprise a very broad group of disorders ranging
from IHD to infectious inflammation caused by various infectious pathogens (such as endocarditis
and myocarditis) to valvular heart disease (e.g., as a result of rheumatic fever), and even to
peripartum cardiomyopathy. Cardiovascular disorders caused by infectious pathogens or
pregnancy differ fundamentally from atherosclerotic cardiovascular disease by their etiology and
pathogenesis; thus, studies of cardiovascular system diseases NOS and other broadly defined
endpoints are less useful for identifying potential cardiovascular effects due to PCB exposure.

Among the 81 human studies (see Figure 4), many investigated more than one relevant
endpoint Overall, 19 studies evaluated mortality due to cardiovascular disease, and 7 of these also
evaluated mortality due to cerebrovascular disease (see Figure 11); other studies evaluated IHD

3-16

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[n = 5, including 4 evaluating MI fBergkvistetal.. 2016: Raymond etal.. 2016: Bergkvist et al.. 2015:
Van Larebeke etal.. 20151]. hypertension [n = 39, including 4 evaluating blood pressure in
prenatally exposed children fGuil-Oumrait et al. 2021: Warembourgetal.. 2019: Lee et al.. 2016:
Vafeiadi etal.. 20151]. cerebrovascular disease [n = 8, including 6 evaluating stroke fLi etal. 2020:
Lim et al. 2018: Kippler etal.. 2016: Raymond etal.. 2016: Bergkvist etal.. 2014: Lee etal.. 20121],
development of atherosclerosis (n = 3), heart failure (n = 1), subjective cardiovascular complaints
(n = 5), heart rate variability fLiberda etal.. 20211. fetal heart rate following maternal exposure
fDiPietro etal.. 20141. "diseases of the heart" or cardiovascular system diseases not otherwise
specified [NOS; n = 8, including 1 evaluating heart disease NOS fHa etal.. 20071], and
pharmaceutical consumption of cardiovascular disease medications (n = 1).

Evidence Stream

Endpoint Category

Human

Other
Mammal

Blood Pressure/Hypertension

Heart Size/Weight
Cardiovascular Histopathology

37
20

Cardiovascular Disease Mortality

"Diseases of the Heart"/Cardiovascular Disease (NOS)

Cerebrovascular Disease

Cerebrovascular Disease Mortality

IHD

Subjective Complaints
Atherosclerosis

8
8
7
5
5
3

Heart Rate

Cardiac Arrhythmia

Heart Failure

Pharmaceutical Consumption of Cardiovascular Disease Medications

1
1

Number of Studies

272

Figure ll:Overview of Human and Other Mammalian Cardiovascular Studies

Summary of the database of studies evaluating exposures to PCB mixtures and cardiovascular endpoints organized
by endpoint category. Lists of studies included in each count can be accessed via the online interactive version of
this figure (https://hawc.epa.gov/summarv/visual/assessment/100500282/QverviewAIIStudies/). Shading
intensity corresponds with the number of studies in each category, from 1 to 272, which is the maximum number
of nonhuman mammalian studies in any health endpoint category. The intent is to highlight not only differences
in the distribution of studies across cardiovascular endpoint categories but also to emphasize the number of
cardiovascular studies relative to the number of studies for other organs/systems. IHD = ischemic heart disease;
NOS = not otherwise specified.

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Forty-seven papers were identified in which experimental mammals were exposed to PCB
mixtures and cardiovascular endpoints were evaluated (see Figure 4). Exposures to PCB mixtures
have been studied in a variety of nonhuman mammalian models, including rats, mice, rhesus
monkeys, mink, rabbits, guinea pigs, and swine (see Figure 8). These animals have been exposed to
PCBs by oral, injection, inhalation, and dermal routes (see Figure 9). One important challenge in
experimental studies of cardiovascular endpoints is the resistance of wild-type rodents
(specifically, mice and rats) to the development of vascular toxicity (Zhao et al, 2020b: Oppi et al,
20191. Piglets and monkeys are much better models of cardiovascular toxicity fDaugherty etal.
20171: however, these species have been underutilized in toxicology studies. In contrast to humans,
rodents do not develop spontaneous IHD, MI, HF, or stroke. Because of these differences, drawing
inferences about human cardiovascular health risk based on the results of rodent studies can be
especially challenging. The most common cardiovascular endpoint categories evaluated in studies
of PCB-exposed mammals other than humans included heart size/weight, cardiovascular
histopathology, and blood pressure (see Figure 11).

Of the 19 human studies that investigated the most extreme endpoint—death (mortality)—
almost half evaluated reasonably specific and clinically meaningful endpoints of mortality from IHD
along with death due to at least one other cardiovascular endpoint: cerebrovascular disease
(Kimbrough etal.. 2015: Ruder etal. 2014: Prince etal. 2006b: Prince etal. 2006a: Mallin et al.
2004: Kimbrough etal. 2003: Gustavsson and Hogste T), hypertension (Kimbrough etal.

2015: Ruder etal. 2014: Prince et al. 2006b: Prince et al. 2006a: Mallin et al. 2004: Kimbrough et
al. 20031. or cardiovascular disease NOS (Ruder etal. 2006: Gustavsson et al. 19861. Ten mortality
studies evaluated death only from cardiovascular diseases/heart disease NOS, an overly broadly
defined cause fDonat-Vargas et al. 2020a: Kim et al. 2015b: van Wiingaarden etal. 2001: Sinks et
al. 1992a: Sinks et al. 1992b: Sinks etal. 1990: Fitzgerald etal. 1989: Bertazzi et al. 1987: Brown.
1987: Brown and lones. 19811. As stated above, such studies lack specificity, which makes them less
useful for identifying potential associations between PCB exposure and atherosclerotic
cardiovascular disease. Two nonoccupational studies examined mortality from cardiovascular
diseases NOS: one within the Swedish Infrastructure for Medical Population-based Life-course and
Environmental Research cohort that included the Swedish Mammography Cohort and the Cohort of
Swedish Men fDonat-Vargas et al. 2020al and one in older adult participants within the National
Health and Nutrition Examination Survey (NHANES) (Kim et al. 2015b). The remaining mortality
studies were conducted in occupational cohorts (see Figure 5), and of these, most were conducted
in (sometimes overlapping) groups of capacitor manufacturing workers.

Hypertension was the most commonly studied endpoint in humans (n = 39) (see Figure 11).
This is in addition to six studies of mortality due to hypertension (Kimbrough et al. 2015: Ruder et
al. 2014: Prince etal. 2006b: Prince et al. 2006a: Mallin et al. 2004: Kimbrough et al. 20031. The
39 nonmortality hypertension studies investigated the development or prevalence of hypertension
using cohort, nested case-control, and cross-sectional study designs (see Figure 6). Among these

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studies, only one was conducted in a capacitor manufacturing workers cohort; the remaining
studies were conducted in samples of the general population (such as NHANES and a cohort of the
graduates of the University of Navarra, Spain), in samples of populations exposed by fish or marine
mammal consumption, in samples of populations residing in proximity to PCB manufacturing
facilities, and Yusho and Yu-Cheng populations (see Figure 5). Of these nonoccupational studies,
those conducted in samples of the general population might be most informative for evaluating
potential effects of relatively lower levels of PCB exposure. Most of the nonoccupational
nonmortality hypertension studies used objective measures of hypertension—either blood
pressure (BP) measured by the investigators or diagnosis of hypertension from subjects' medical
records; only seven used self-reported hypertension as the endpoint (Aminov and Carpenter. 2020:
Zani etal, 2019: Raymond etal, 2016: Donat-Vargas etal, 2015: Van Larebeke etal, 2015:
Goncharov et al, 2008: Stehr-Green etal. 1986). Many studies used multiple measurements of BP
to mitigate information (measurement) bias known as "white coat hypertension" or "office
hypertension." For example, a study of serum concentrations of persistent organic pollutants and
prevalence of hypertension conducted by Ha etal. (2009) used the results from NHANES 1999-
2002, in which BP of the participants was measured at least three times, and the average values of
systolic and diastolic BP were used for analysis. The Ewha Birth and Growth cohort study
evaluating persistent organic pollutant exposure and health endpoints in Korean children averaged
two measurements of BP taken 5 minutes apart (Lee et al.. 2016). PCB exposures and BP were
examined in three nonhuman mammalian studies (see Figure 11), including a study of orally
exposed mice (WahlangetaL 2017). a study of rat offspring exposed during gestation and lactation
fDziennis et al. 2008). and an acute duration study using i.v. administration in cats fRighter etal.
1976).

Five studies evaluated nonfatal IHD (see Figure 11), all in nonoccupational settings. Two
evaluated only Ml (Bergkvistetal. 2016: Bergkvistetal. 2015). and three evaluated multiple
endpoints: Ml, hypertension and cerebrovascular disease (Van Larebeke etal. 2015): IHD and
cerebrovascular disease fPines et al. 1986): and IHD, Ml, hypertension, and stroke fRavmond etal.
2016). Studies conducted by Bergkvist et al. (20151 using the Swedish Mammography Cohort and
by Bergkvist et £ , using the Cohort of Swedish Men presented findings for Ml ascertained

from validated national registry data. In contrast, studies conducted by Van Larebeke etal. (2015)
using the Flemish Environment and Health Survey and a study of male anglers in Wisconsin by
Raymond et al. (2016) only provided information on self-reported endpoints of Ml (Raymond et al.
2016: Van Larebeke et al. 2015) and IHD (Raymond etal. 2016). Self-report might be a less reliable
measure, although this is less of a concern for significant, severe events such as MI, which are likely
to be recalled with greater accuracy.

Cerebrovascular disease was investigated in 15 studies, including 7 mortality studies (all in
occupational settings) (see Figure 11), 2 nonfatal cerebrovascular disease studies in a general
population setting (Van Larebeke etal. 2015: Pines et al. 1986). and 6 nonfatal stroke studies in

3-19

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nonoccupational settings fii etal. 2020: Lim etal. 2018: Kippler etal. 2016: Raymond etal. 2016:
Bergkvistetal. 2014: Lee et at. 20121. Stroke is a better-defined endpoint than a broader
diagnostic category for cerebrovascular disease that includes not only stroke, but some other
disorders, for example, a rare congenital cerebral aneurism, not likely to be causally associated with
PCB exposure. Among the six studies of nonfatal stroke, five included objectively verified diagnosis
of stroke: three studies used only hospital-treated strokes (Li etal.. 2020: Lim et al, 2018: Lee et al,
20121. and two used validated Swedish Patient Register and the Swedish Cause of Death Register
(Kippler etal.. 2016: Bergkvist et al.. 20141. One study conducted among male anglers in Wisconsin
used a less reliable measure of stroke self-report fRavmond et al. 20161. although recall bias is not
of significant concern given the severity of stroke as a life event

Atherosclerosis has been evaluated in only three studies of PCB exposure (see Figure 11).
However, these studies did include an evaluation of sensitive and specific markers of
atherosclerosis, such as carotid plaques and intima-media thickness fLiberda et al.. 2019: Lind et
al.. 20121 and coronary artery calcium score (Donat-Vargas et al. 2020b). No studies of
atherosclerosis in laboratory mammals exposed to PCB mixtures were identified; however,
atherosclerosis and associated mechanistic endpoints (e.g., aortic expression of vascular cell
adhesion molecule-1) have been evaluated following intraperitoneal exposure to individual PCB
congeners in genetically altered mice that model human cardiovascular disease (Petriello etal.
2018: Murphy etal. ; nig etal. 20021.

Other cardiovascular endpoints investigated infrequently in human studies included left
ventricular systolic and diastolic dysfunction (i.e., heart failure) (Sioberg Lind et al. 20131. heart
rate variability fLiberda et al. 20211. and fetal heart rate following maternal PCB exposure
fDiPietro et al. 20141. Two nonhuman mammalian studies of endpoints related to cardiac function
are available to supplement the information gathered in human studies (Willettetal. 1987: Righter
etal. 19761.

Finally, five human studies evaluated subjective complaints of chest pain (Eroding et al.
2008: Exxmiett et al. 1988bl. general cardiovascular complaints fPeper etal. 20051. subjective
complaints and broad clinical measures (heart rate, blood pressure, and heart sounds) (Kanagawa
et al. 20081. and the Subjective Complaint List for Children and Adolescents fLiebl etal. 20041 as
cardiovascular endpoints. However, such complaints are less useful for evaluating potential health
effects of PCB exposure due to their nonspecific and self-reported nature.

In addition to the endpoints described above, studies of nonhuman mammals exposed to
PCB mixtures also evaluated endpoints such as cardiovascular histopathology and heart
size/weight in diverse species, including rhesus monkeys, rats, guinea pigs, rabbits, mink, and
swine (see Figure 8). As mentioned above, rodent models are relatively insensitive to the
development of vascular toxicity fZhao et al. 2 02 Obi, so it is notable that this database does include
some studies of PCB-exposed pigs and monkeys (see Figure 8). Some studies of nonhuman
mammals exposed to PCB mixtures included evaluations following exposure during prenatal and

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postnatal developmental periods (see Figure 10). Heart weight was the cardiovascular endpoint
studied most often in mammals other than humans (see Figure 11). Evaluations of heart weight and
PCB exposure can be further supported by the inclusion of other types of data (e.g., heart
histopathology or endpoints related to cardiac function). Of the 37 nonhuman mammalian studies
that evaluated heart size/weight and PCB exposure, 12 also included assessments of other
cardiovascular endpoints, most often histopathological evaluations (Chu et al. 2008: Blake et al,
2000: Hornshawetal, 1986: Price et al, 1979: Allen etal, 1976: Hansen etal, 1975: Itokawa et al,
1975: Under etal. 1974: Bruckner et; ; alter and Zinkl. 1973: Vos and de Roil 1972: Vos

and Beems. 19711.

In summary, the human database, supplemented with data from nonhuman mammalian
studies conducted using sensitive and informative models and methods, is likely to provide enough
information to evaluate the potential for PCB-associated effects on the cardiovascular system.
However, further study of PCB exposures and atherosclerosis and other cardiovascular endpoints
in humans and in genetically altered mouse models of human vascular diseases is warranted to
fully address the potential for PCB cardiovascular toxicity.

3.3.2. Dermal

Dermal endpoints relate to the outer layer of the body, including skin and subcutaneous
tissue, some mucous membranes (e.g., gingivae), and fingernails and toenails. The main function of
these tissues is to act as a protective barrier, and they are among the first tissues to contact
exogenous agents. Responses of the skin and nails to chemical exposures can include dermal
irritation and scar formation; and, specifically in the case of exposures to halogenated aromatic
hydrocarbons, especially dioxin-like chemicals, acne and chloracne flu et al, 2009). Other
endpoints evaluated with PCB exposure include abnormal pigmentation, deformities in fingernails
or toenails, hyperkeratosis, and gingival swelling or recession. Studies in mammals other than
humans also evaluated alopecia, dermal/subcutaneous histopathology, and wound healing.
Although some of these endpoints could be perceived as less severe than those evaluated for other
organs/systems, effects on dermal endpoints can negatively impact quality of life, potentially
resulting in physical discomfort and anxiety and depression fBarankin and Dekoven. 20021.

In the database of PCB exposure studies, 34 human studies and 52 studies in other
mammals evaluated dermal endpoints (see Figure 4). Of the human studies, most were reports of
occupational exposures, Yu-Cheng or Yusho poisoning, or other accidental exposures (see Figure 5).
In many of these studies, the dermal endpoints were symptoms reported or clinical observations
after the exposure. Many dermal endpoints reported were part of the initial diagnosis and were not
necessarily the focus of the publications. Other human studies included two conducted among
general population samples fSmitetal. 2015: Lee et al. 20081. one cross-sectional study in a
population living in a highly polluted area (Arisi et al, 2021). and one cross-sectional study of
people living near waste sites (Stehr-Green et al, 1986). This study only evaluated self-reported,
physician-diagnosed skin problems without further description.

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The most studied endpoint category was acne/chloracne in both humans and other
mammals (see Figure 12}. Eight studies in humans evaluated subjects from the Yusho and Yu-Cheng
cohorts, and 12 were conducted among populations with other accidental or occupational
exposures (see Figure 5). The remaining studies were conducted in populations with exposure via
diet (Dewaillv et al.. 2000) or living in a highly polluted area (Arisi etal.. 20211. Although these
studies, especially those conducted in the Yusho and Yu-Cheng cohorts, might have additional
exposures to dioxin-like chemicals other than PCBs that could contribute to acne/chloracne, several
studies in other mammals might help determine whether PCB exposure alone is sufficient to cause
this dermal effect Other dermal endpoints evaluated in other mammals and in human populations
with relatively high exposure levels, such as occupational and the Yusho and Yu-Cheng cohorts,
include abnormal pigmentation (18 human and 8 studies in other mammals], dermal irritation (18
human and 6 studies in other mammals), hyperkeratosis (6 human and 12 studies in other
mammals), and fingernail and toenail deformities (8 human and 13 studies in other mammals) (see
Figure 12). Although many studies in nonhuman mammals evaluated alopecia or subcutaneous
edema, these endpoints were not described in human studies. In addition, 19 studies in other
mammals evaluated dermal histopathology. Nonhuman mammalian studies of dermal
histopathology could complement the data from human studies. Less commonly studied endpoints
included gingival swelling or recession (one human and four studies in other mammals), scar
formation (one human study), and wound healing (one study in mice).

Evidence Stream

Endpoint Category Human Other Mammal

Acne/Chloracne

Alopecia

Abnormal Pigmentation

Dermal Irritation

Finger/Toenail Deformity

Dermal Histopathology

Hyperkeratosis

Subcutaneous Edema

Gingival Swelling/Recession

Wound Healing/Scar Formation

"Skin Problems"

Number of Studies

1 272

Figure 12:Overview of Human and Other Mammalian Dermal Studies

Summary of the database of studies evaluating exposures to PCB mixtures and dermal endpoints organized by
endpoint category. Lists of studies included in each count can be accessed via the online interactive version of this
figure (https://hawc.epa.gov/summarv/visual/assessment/100500282/QverviewAIIStudies/). Shading intensity
corresponds with the number of studies in each category, from 1 to 272, which is the maximum number of
nonhuman mammalian studies in any health endpoint category. The intent is to highlight not only differences in
the distribution of studies across dermal endpoint categories but also to emphasize the number of dermal studies
relative to the number of studies for other organs/systems.

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Although most human studies available for dermal endpoints were focused on populations
with potential for relatively high exposure, two studies were conducted among general population
samples, including one prospective birth cohort (Smit et al. 2015) and a population-based cross-
sectional survey (NHANES) focused on periodontal disease (Lee etal, 20081. The study conducted
in a birth cohort was focused on immune endpoints but included evaluations of eczema, a form of
dermal irritation often associated with atopic immune reactions. As such, studies of eczema are also
considered in Section 3.3.8.

Most of the 52 nonhuman mammalian studies (see Figure 4) were conducted in nonhuman
primates, followed by rats, mice, and other species, with 2 studies using more than one species
(Kunita etal. 1984: Thomas and Hinsdill. 1978) (see Figure 8). Of the mammalian species
evaluated, nonhuman primates are most similar to humans and could provide the strongest animal
evidence linking PCBs to dermal endpoints in humans. All but five nonhuman mammalian studies
evaluated endpoints following only oral PCB administration (see Figure 9). The remaining studies
included a subchronic inhalation study in rats (Casey etal. 1999). a 10-day injection study in m ice
fWatanabe and Sugahara. 19811. an acute injection study in m ice fPillai etal.. 20201. and two
subchronic dermal exposure studies in rabbits fYos and Notenboom-Ram. 1972: Vos and Beems.
19711.

Overall, the bulk of the human database is limited to events of high PCB exposure including
accidental and occupational exposures that generally provide qualitative information on dermal
symptoms and are likely to include exposures to other compounds that could cause the same types
of effects. Few studies of dermal endpoints in humans exposed at PCB levels experienced in the
general population are available. Dermal endpoints in these studies are limited to periodontal
disease and eczema. However, the combined human and animal database is likely to provide
enough information to draw conclusions about the potential for PCB exposure to cause dermal
effects, especially at relatively high exposure levels.

3.3.3. Developmental

Fetal development and early childhood can be particularly sensitive stages for adverse
effects from exposure to environmental agents, as they are periods of rapid growth and
development that can be affected by a range of toxicants through diverse biological mechanisms.
Although exposures during development can impact any biological system, for the purpose of this
review, developmental endpoints included in this domain are as follows: offspring mortality; body
weight and size in early life, which includes fetal growth, anthropometric measures at birth, and
childhood height or weight status and rates of growth; birth defects; placental
weight/histopathology; and, in mammals, timing of postnatal developmental milestones, such as
eye opening and pinna detachment Exposures that occur at critical developmental stages for
specific target organ systems (e.g., nervous, reproductive, and endocrine systems) could also result
in negative health impacts in neonatal or adult life. These other potential effects of developmental

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exposures, including those that could occur from parental exposure and influence reproductive
capacity, are described in the sections devoted to those organs/systems.

Developmental effects resulting from exposure are critical to consider due to their
substantial health and economic costs, which persist across the lifespan. For example, low birth
weight and fetal growth restriction are associated with increased risk of infant mortality and
morbidity and increased risk for disorders later in life such as metabolic disorders, type II diabetes,
obesity, elevated blood pressure, and cardiovascular disease fNobili et al, 2008: Barker, 2006:
Gluckman and Hanson. 20061. The small decrements in size at birth for gestational age (even if size
is classified in the normal range) caused by an inadequate fetal environment, could have health
consequences later in life (Gluckman and Hanson. 2006). Other measures of fetal growth
(e.g., ultrasound scans) and specific anthropometric parameters (e.g., head circumference) have
also been significantly associated with infant growth and neuredevelopment (Henrichs etal. 2010:
van Batenburg-Eddes et al. 20101. Outcomes at the low end of the distributions (i.e., low birth
weight, intrauterine growth restriction, small for gestational age) have been well characterized
with regard to associated costs at the time they occur and throughout life. Extremes at the high end
of these distributions (e.g., large for gestational age) might also be harmful and indicative of
abnormal fetal development but are less studied in relation to chemical exposures.

Of the 130 human and 170 other mammalian studies identified on PCB exposure and
developmental endpoints (see Figure 4), most focused on measures of birth weight or other aspects
of fetal growth (see Figure 13). Most human studies of PCB exposure and birth weight used
biomarkers of exposure, measuring various PCB congeners in maternal or cord blood (see Figure
7). Twenty-five studies used measures of PCB congeners in breast milk to estimate gestational
exposures. Given the long half-life of certain PCB congeners in blood and the proximity of available
biomarker measurements to the exposure window of interest, the data available to assess
relationships between PCB exposure and birth weight are quite robust For example, one report by
Govarts etal. (20121 presented a meta-analysis of PCBs and birth weight among 12 European birth
cohorts involving 7,990 participants who had PCB 153 concentrations measured in maternal blood,
cord blood, or breast milk samples. Several cohort studies that explored PCB exposure and birth
size continued follow-up of children, which enabled them to also investigate in utero exposure to
PCBs and height/weight status and rates of growth at different ages or developmental stages in
childhood [e.g., (Karlsen et al. 2017: Hertz-Picciotto etal. 20051], Less commonly, studies
investigated PCB exposure and growth among children newly recruited at various ages [e.g., (Burns
et al. 20201], However, differences are notable in the timing and nature of the growth
measurements and in the exposure period assessed (e.g., PCBs measured in samples collected in
pregnancy/at delivery versus samples collected in childhood). Placental weight or placental
histology was measured in several human and nonhuman mammalian studies (see Figure 13).
Although placental weight is positively associated with fetal growth and birth weight, the human
health relevance of this measure in isolation remains uncertain; however, placental dysfunction can

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be detrimental to fetal viability. PCB exposure and body weight and size in early life were also
evaluated in 148 studies of a wide variety of nonhuman mammalian species (see Figure 13 ),
including nonhuman primates and various strains of mice and rats (see Figure 8); these studies
could be useful to support the findings in human studies.

Endpoint Category

Evidence Stream
Human Other Mammal

Weight and Size (Following Early Life Exposure)

117

148

Offspring Mortality

128

Birth Defects

Developmental Milestones

Placental Weight

Placental Histopathology

Number of Studies

272

Figure 13; Overview of Human and Other Mammalian Developmental Studies

Summary of the database of studies evaluating exposures to PCB mixtures and developmental endpoints organized
by endpoint category. Lists of studies included in each count can be accessed via the online interactive version of
this figure (https://hawc.epa.gov/summarv/visual/assessment/100500282/QverviewAIIStudies/). Shading
intensity corresponds with the number of studies in each category, from 1 to 272, which is the maximum number
of nonhuman mammalian studies in any health endpoint category. The intent is to highlight not only differences
in the distribution of studies across developmental endpoint categories but also to emphasize the number of
developmental studies relative to the number of studies for other organs/systems.

Seventeen human studies investigated PCB exposure and miscarriage, stillbirth, or infant
mortality (see Figure 13). These studies varied in design and sample size; results for stillbirth
typically involved few cases, and differences in study design (e.g., timing of recruitment, method of
outcome ascertainment, and ability to adequately detect early pregnancy losses) can limit the
ability to synthesize results for miscarriage across studies. However, these data can be
supplemented by information from 128 studies in other mammals that assessed offspring viability
in the context of PCB exposure, many including direct measures such as observation of stillborn
pups and others relying on indirect measures such as litter size.

Birth defects (e.g., neural tube defects) and PCB exposure were investigated in nine human
studies (see Figure 13). Birth defects and other endpoints associated with testicular dysgenesis
syndrome fSkakkebaek et al., 20011. including cryptorchidism and hypospadias, are included in
Section 3.3.13. In general, the human studies of birth defects are few and tend to have few cases,
which limits the robustness of the overall findings. Twenty-four studies of PCB exposure and birth

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defects in other mammals, including skeletal malformation and cleft palate, can provide additional
information on potential causal relationships. Twenty-one studies in nonhuman mammals
investigated PCB exposure and the timing of postnatal developmental milestones, such as eye
opening and pinna detachment Changes in the timing of these milestones could be informative
together with other measures of growth and development, but the human health relevance of these
endpoints observed in isolation is uncertain.

Overall, the strength of the database for assessing human evidence of relationships between
PCB exposure and developmental endpoints is high for birth weight, including both continuous
measures of birth weight and, from many studies, dichotomized outcomes based on size at birth
(low birth weight, small for gestational age) and other measures that can be collected at birth, such
as birth length and head circumference. The strength of the human evidence for other
developmental endpoints is limited by few studies, small sample sizes or numbers of cases, and
important variations in study designs across cohorts. However, nonhuman mammalian studies of
similar endpoints are often available and represent exposures in multiple species at a wide range of
doses, routes, durations, and developmental timings; these could provide additional information
useful for evaluating potential hazards of PCB exposure.

3.3.4. Endocrine

Endocrine organs synthesize and secrete hormones, chemical messengers that travel
through the blood stream to bind to specific receptors and initiate biological responses at target
tissues. Major endocrine organs include the hypothalamus, pituitary, testes, ovaries, pancreas,
thyroid, and the adrenals. The focus here is on thyroid and adrenal endpoints because of the
potential for the PCB literature to support exposure-response evaluations for these endpoints,
which regulate physiological processes related to metabolism, growth and development, stress
response, and immunity. Studies of PCBs and sex-steroid hormones are discussed in Section 3.3.13,
and studies of insulin are discussed in Section 3.3.9. Thyroid and adrenal activity are regulated by
hypothalamic and pituitary hormones through negative feedback pathways, comprising the
hypothalamus-pituitary-thyroid (HPT) and hypothalamus-pituitary-adrenal (HPA) axes. Peripheral
tissue deiodinases catalyze conversion of thyroxine (T4), a thyroid prohormone, to biologically
active triiodothyronine (T3). A system of hepatic serum carrier proteins governs hormone
bioavailability. Endocrine responses to chemical exposures could include thyroid disease,
differences in circulating thyroid hormone concentrations, such as thyroid stimulating hormone
(TSH), T4, and T3, and histopathological thyroid changes. Endocrine responses can also include
differences in circulating adrenal hormone concentrations (e.g., adrenocorticotropic hormone
[ACTH]), the glucocorticoids Cortisol, cortisone, and their metabolites, and histopathological
adrenal changes. Adrenal hormones also include sex-steroid and mineralocorticoid hormones.

Studies evaluating thyroid endpoints included 116 human studies and 113 studies in other
mammals (see Figure 14); 15 human studies and 84 studies in other mammals evaluated adrenal
endpoints. Few human or nonhuman mammalian studies evaluated other endocrine endpoints,

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such as parathyroid endpoints, or levels of vitamin D, insulin-like growth factor, growth hormone,
or melatonin. The lack of information for these other hormones precludes the ability to draw
hazard conclusions.

Evidence Stream

Endocrine Endpoint Category Human Other Mammal

Thyroid Endpoints

116

113

Adrenal Endpoints

Pituitary Endpoints

Parathyroid Endpoints

Insulin-Like Growth Factor

Vitamin D

"Endocrine Disease"

Growth Hormone

Melatonin

Thyroid Endpoints

HPT Hormones

109

Thyroid Histopathology

Thyroid Size/Weight

Thyroid Disease

Thyroid Nodules

Adrenal Endpoints

Adrenal Weight

HPA Hormones

Adrenal Histopathology

Pituitary Endpoints

Pituitary Weight

Pituitary Histopathology

Parathyroid Endpoints

Parathyroid Histopathology

Parathyroid Hormone

Parathyroid disease

Insulin-Like Growth Factor

Vitamin D

"Endocrine Disease"

Growth Hormone

Melatonin

Number of Studies

1272

Figure 14, Overview of Human and Other Mammalian Endocrine Studies

Summary of the database of studies evaluating exposures to PCB mixtures and endocrine endpoints organized by
endpoint category. Lists of studies included in each count can be accessed via the online interactive versions of
this figure: (https://hawc.epa.gov/summarv/visuai/assessment/100500282/EndocrineEndpointsHumans/ for
human studies; and

(https://hawc.epa.gov/summarv/visual/assessment/100500282/EndocrineEndpointsNonhumanMammals/) for
studies of nonhuman mammals. These interactive summaries can be adjusted to group endocrine endpoint
categories into three levels of organization. The interactive summary of the human database can be filtered by
study design (options: case-control, cohort, cross-sectional, other), population (options: fish/marine mammal
[diet], general population, occupational, residents in contaminated area, Yusho/Yu-Cheng), and exposure metric
(options: adipose tissue, blood, breast milk, child blood, cord blood, maternal blood, occupational/JEM, other
tissue). The interactive summary of the nonhuman mammalian database can be filtered by species (options: cat,
dog, guinea pig, hamster, mink, mouse, nonhuman primate, rabbit, rat, sheep, swine), exposure duration/life
stage (options: acute [single dose], chronic, developmental, short-term, subchronic), and exposure route (options:
dermal, inhalation, injection, oral). Shading intensity corresponds with the number of studies in each category,
from 1 to 272, which is the maximum number of nonhuman mammalian studies in any health endpoint category.
The intent is to highlight not only differences in the distribution of studies across endocrine endpoint categories
but also to emphasize the number of endocrine studies relative to the number of studies for other
organs/systems. HPT = hypothalamus-pituitary-thyroid; HPA= hypothalamus-pituitary-adrenal.

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The most informative endpoints for assessing the potential for PCBs to cause thyroid effects
are clinical disease diagnoses, based on deviations in the amount of circulating TSH and unbound,
or "free," T4 (FT4) concentrations compared to population-specific laboratory reference intervals
(Chaker et al. 2017: De Leo et al. 20161. Fifteen human studies evaluated thyroid disease (see
Figure 14); yet only six were based on a clinically confirmed diagnosis (Pufour etal, 2020: Han et
a! ; four et al., 2018: Petrosino et al. 2018: Raffetti et al.. 2018: Nagavaina etal. 2007a).
raising the potential for outcome misclassification (Section 3.2.1). Except for a few case-control or
cohort designs, the studies of thyroid disease were mostly cross-sectional (see Figure 14), which
means that temporality of exposure preceding outcome is not ensured (Section 3.2.1). Even in the
absence of a clinical thyroid disease diagnosis, altered thyroid hormone levels are also informative
endpoints that can provide insight into subclinical changes in thyroid function, although
distinguishing changes that are adaptive from those that are pathological is difficult at the
individual level. Still, small shifts in hormones at the individual level might result in significant
numbers of clinical disease cases at the population level. Numerous studies collected thyroid
hormone measures in the absence of known clinical thyroid disease, including TSH on its own [e.g.,
fde Cock et al. 2017: Han etal. ; 3z-Espinosa etal. 2010: Alvarez-Pedrerol et al. 2008a:
Chevrier et al. 2007: Langer etal. 2006: Langer et al. 2003: Ribas-Fito etal. 2C ; 'hard et al.
1998: DewaillvetaL 1993)] and in combination with FT4 [e.g..(Abdelouahab etal. 2013: Dallaire et
al. 2009a: Alvarez-Pedrerol et al. 2008b: Langer et al. 2007a: Maervoet et al. 2007: Takser etal.
2(105; Sala et al. 2001: Longnecker et al. 2 00 01] .The addition of total (i.e., including protein bound)
and other iodothyronines (e.g., reverse T4) offers greater insight into the state of the HPT axis, and
these hormones frequently accompanied TSH measures [e.g., fBenson etal. 2018: Roze et al.
2009)].Characteristics of well-conducted studies for evaluating changes in TSH and FT4 include
measurement of these hormones repeatedly in a population with known iodine status, respectively
using a highly sensitive third-generation assay and direct separation techniques coupled to mass
spectrometry (e.g., equilibrium dialysis), which avoids potential biases from binding protein
differences fChaker etal. 2017: De Leo etal. 2016: Demers and Spencer. 20031. Although no
studies in the database had all these design characteristics, two studies employed a direct FT4
separation technique fChevrier et al. 2008: Steuerwald etal. 20001. one of which was a prospective
investigation of PCB exposure in Faroese mothers and thyroid function among their newborns
(Steuerwald et al. 2000). and another study measured children's thyroid hormones at both 6 and
12 months of age (Kronke et al. 2022). Most studies used appropriate tissue samples, although
newborn cord blood hormones are impacted by parturition (Gupta et al. 2014) and reflect
maternal hormone in part, possibly leading to misclassification in 11 studies fKim et al. 2015a:
Brueker-Davis et al. 2011: Dallaire et al. 2009b: Roze etal. 2009: Dallaire et al. 2008: Herbstroan
et al. 2008: Maervoet et al. 2007: Takser et al. 2005: Wang etal. 20 ; ignecker etal. 2000:
Koopman-Esseboom etal. 1994). and similarly for thyroid hormones measured in newborn blood
spots collected within 48 hours of delivery by 3 studies (Berlin et al. 2021: Kim et al. 2015a:

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Herbstman etal. 20081. One study quantified thyroid hormones in breast milk collected 2-9 days
postpartum fMatovu et al. 20211. although the relation to infant thyroid hormones was likely
modest (Mallva and Ogilvv-Stuart. 20181. Plasma and serum levels of HPT hormones, including T3,
FT3, T4, FT4, and TSH, were measured in 88 nonhuman mammalian studies (see Figure 14).

Subclinical structural thyroid gland changes evaluated in 11 human studies (Gaum et al.
2016: Trnovec et al. 2013: Langer etal. 2009: Trnovec etal. 2008: Langer et al. 2007a: Langer et
al. 2007b: Langer etal. 2006: Langer etal. 2005: Langer etal. 2003: Langer et al. 2001: Murai et
al. 19871. including differences in volume, echogenicity, and presence of nodules, could also inform
thyroid effects, although they are less informative given potential intra- and interobserver
variabilities. Many more studies investigated thyroid weight or histopathology in mammals other
than humans (see Figure 14). Evaluations of thyroid structure in animals might provide supporting
information for endpoints measured in humans, especially thyroid hormone levels. The 113
nonhuman mammalian studies investigating thyroid-related endpoints included analyses of rats,
nonhuman primates (cynomolgus or rhesus monkeys), mice, mink, and other species (see Figure 8).
Importantly, many studies measured thyroid weight or histopathology in conjunction with
measurements of thyroid hormones [e.g., fBowers et al. 2004: Kato et al. 2003: Hallgren and
Darnerud, 2002: Hood etal. 1999: Liu etal. 1995: Seo and Meserve, 1995: Murk et al. 1991: Bvrne
et al. 1987: Collins and Capen. 1980b. a)].

Cortisol (a glucocorticoid adrenal hormone) is a preferred stress response biomarker for
human studies fLee et al. 20151 and the most informative endpointto assess the potential for PCBs
to cause adrenal effects. Multiple blood, urine, or saliva collections over time are recommended to
accommodate diurnal variability and acute responses. Hair Cortisol has also been used, as an
integrated measure over time. However, of 15 human studies that measured adrenal hormones (see
Figure 14), only 6 measured Cortisol or its metabolites (Gaum etal. 2020: Mivashita et al. 2018: Xu
et al. 2014: Perskv et al. 2012: Perskvetal, 2011: Romeo et al. 20091. all using a single
biospecimen, and 1 study additionally measured adrenocorticotropic pituitary hormone (ACTH)
fXu etal. 20141. Seven studies measured dehydroepiandrosterone sulfate (DHEAS), another
adrenal-specific biomarker (Gaum et al. 2020: Emeville et al. 2013: Perskvetal. 2012: Rennert et
al. 2012: Perskv et al. 2011: Perskvetal. 2001: Gerhard et al. 19981: as an androgenic biomarker,
DHEAS is also discussed in Section 3.3.13. Other studies measured nonspecific hormone
metabolites that are not as useful in assessing the potential for adrenal effects; for example,
pregnanes [e.g., (D'Errico et al. 2016)] are metabolites common to both adrenal glucocorticoids and
to adrenal and ovarian progestogens. Many studies were cross-sectional, but one was a longitudinal
investigation fGaum et al. 20201. Three others were prospective studies of gestational PCB
exposure and offspring's HPA hormones (Mivashita et al. 2018: Su et al. 2015: Rennert et al.
20121. One measured Cortisol fMivashita et al. 20181. but one measured DHEAS only (Rennert et
al. 20121. and one measured aldosterone only, an osmoregulatory hormone (Su et al. 20151. Of 84
nonhuman mammalian studies of HPA endpoints (see Figure 14), 45 were conducted in rats,

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although studies were also identified examining rhesus monkeys, mice, mink, and other species
(see Figure 8). Mostnonhuman mammalian studies evaluated exposure to PCBs and adrenal
weights or histopathology (see Figure 14). An additional 13 studies examined pituitary weight or
histopathology (see Figure 14), and 1 nonhuman mammalian study measured corticotropin
releasing hormone (CRH) and ACTH levels (Meserve et al. 19921. Serum or urinary glucocorticoid
measurements were well represented in the nonhuman mammalian literature (see Figure 14).
Critically, many studies measured adrenal hormones in conjunction with measurements of adrenal
weight or histopathology [e.g., fKrishnan et al. 2019: Reillvetal. 2015: Meserve etal. 1992:
Nagaoka et al. 1986: Dunn etal. 1983: Sanders etal. 1977: Sanders and Kirkpatrick. 1977: Zepp
and Kirkpatrick. 1976: Sanders and Kirkpatrick. 1975: Bruckner etal. 1974)]. Whereas the
literature database in humans is modest, observations in other mammals might provide important
supporting information for evaluating glucocorticoid levels in humans exposed to PCBs.

In summary, a strong database of human studies for thyroid function is available,
comprising multiple moderate to large prospective studies assessing occupational and
nonoccupational PCB exposures, using valid endocrine biomarkers. The human database also
includes a number of cross-sectional studies evaluating thyroid disease and function, although
there is some uncertainty due to inability to establish temporality from cross-sectional evaluations
(see Section 3.2.1). There is also an extensive database of nonhuman mammalian studies to inform
the potential for PCBs to affect thyroid endpoints. The strength of the human database for adrenal
effects is limited by the few modest-sized (mostly cross-sectional) studies. In contrast, the
nonhuman mammalian database is more robust and can provide information on potential links
between PCB exposures and changes in levels of circulating glucocorticoids and structural
alterations of the adrenal cortex.

3.3.5. Gastrointestinal

The gastrointestinal (GI) tract is a joined series of hollow organs from the mouth to the
anus, including the esophagus, stomach, small intestines, and large intestines. The GI tract, along
with the liver, pancreas, and gallbladder, constitutes the digestive system. In addition to digestion,
the primary functions of the GI tract include excretion, absorption, and protection from gastric acid
and foreign microbes. Twenty-four studies in humans and 57 in other mammals examined GI
endpoints and PCB exposure (see Figure 4); these evaluated GI histopathology or gut permeability
(in nonhuman mammals), abdominal ultrasonography (in humans), and digestive system
symptoms and diseases (in humans or other mammals), including specific clinical conditions
(e.g., gastric ulcer and colorectal polyps) and more subjective symptoms such as abdominal pain,
nausea/vomiting, changes in bowel habits, bloating, indigestion, and loss of appetite (see
Figure 15). Additional endpoints reported in nonhuman mammals included intestinal bleeding,
bloody stools, edema, intestinal blockage, and diverticula of the large bowel. Two human studies
assessed mortality due to digestive system diseases; however, this endpoint is nonspecific and
often includes liver disease (see Section 3.3.7). The most informative studies for assessing the

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potential for PCB exposure to cause GI effects are those that examined GI histopathology,
abdominal ultrasonography, and specific clinical conditions; remaining endpoints are often
subjective or ill-defined or capture a broad range of conditions with potentially unrelated
etiologies, reducing the prospect of successful integration in a systematic review.

Evidence Stream

Endpoint Category

Human

Other Mammal

Digestive System Symptoms/Diseases

Gastrointestinal Histopathology

Abdominal Ultrasonography

Digestive System Disease Mortality

Gut Permeability

Number of Studies

272

Figure 15. Overview of Human and Other Mammalian Gastrointestinal Studies

Summary of the database of studies evaluating exposures to PCB mixtures and gastrointestinal endpoints
organized by endpoint category. Lists of studies included in each count can be accessed via the online interactive
version of this figure (https://hawc.epa.gov/summarv/visual/assessment/100500282/QverviewAIIStudies/).
Shading intensity corresponds with the number of studies in each category, from 1 to 272, which is the maximum
number of nonhuman mammalian studies in any health endpoint category. The intent is to highlight not only
differences in the distribution of studies across gastrointestinal endpoint categories but also to emphasize the
number of gastrointestinal studies relative to the number of studies for other organs/systems.

Abdominal ultrasounds can detect abnormalities in the abdominal anatomical structure and
are generally used as a diagnostic tool in patients reporting abdominal pain. T wo human studies
investigated PCB exposure and abdominal ultrasonography in cross-sectional studies of Yusho
patients fTokunaga and Kataoka. 2001: Hirota etal.. 19951. Ultrasounds were conducted as part of
an annual physical examination in Yusho patients. Both studies evaluated blood levels of PCBs and
nonspecific clinical abdominal ultrasound findings. The broad categorization of the ultrasound
results does not identify a specific GI endpoint and would therefore not contribute to a review of
potential PCB-related GI effects. Two human studies that examined more specific clinical endpoints
in general populations might be more informative. These include a case-control study that
measured serum PCB levels in patients with colorectal polyps fLee et al.. 20181 and a cross-
sectional study that related blood levels of PCBs to self-reported history of physician-diagnosed
gastric ulcer fNakamoto et al.. 20131. These human studies ultimately provide a limited database
for integration. GI symptoms and diseases evaluated in nonhuman mammals also included gastric
ulcers, which were described in six studies of PCB-exposed mink and rhesus monkeys (Hornshaw et

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at. 1986: Aulerich etal. 1985: Aulerich and Ringer. 1977: Allen et at. 1974a: Allen et al b;

Aulerich etat. 19731.

Because of limitations of the GI endpoint data in humans, hazard identification for PCBs
would likely depend on nonhuman mammalian studies of GI histopathology to help understand
changes in GI structure and function that could result from PCB exposure. Fourteen studies in
nonhuman primates investigated PCB exposure and gastric and intestinal histopathology (see
Figure 8). These studies included evaluations of chronic, subchronic and acute exposure in adults
and exposures in developing offspring (see Figure 10). GI histopathology has also been evaluated in
PCB-exposed rodents and other species (see Figure 8). Furthermore, tight junction permeability of
the intestinal mucosa was evaluated in one study of developmental PCB exposure in mice (Rude et
at. 20191. Although studies in rodents and other species have been more limited in scope, these
could provide information on variations in GI sensitivity across species. Most studies that evaluated
GI histopathology exposed mammals to PCBs via the oral route (see Figure 9), but the database also
includes one study of dermal exposure in rabbits (Vos and Beems. 19711 and one study of
inhalation exposure in rats fCasev et at. 19991.

In summary, the existing database has limited potential to support hazard evaluation for
PCB-associated GI effects. There are few epidemiological studies that have examined PCB exposure
and GI endpoints. Further, most human studies meeting PECO evaluated digestive system
symptoms that do not provide a strong foundation for evidence integration. However, the larger
body of nonhuman mammalian studies can provide insight into more specific GI endpoints that
could be further explored in human studies of PCB exposure.

3.3.6. Hematopoietic

Hematopoiesis describes the process by which mature blood cells are derived from stem
cells along three primary lineages: erythropoiesis gives rise to red blood cells (RBCs), which carry
oxygen throughout the body; lymphopoiesis produces lymphocytes, which are the cornerstone of
adaptive immunity (e.g., T cells, B cells, and natural killer (NK) cells); and myelopoiesis generates
cells of myeloid lineage, which are involved in innate immunity and clotting processes
(e.g., granulocytes, monocytes, megakaryocytes, and platelets) fLandreth. 2 , 021. Leukocytes,
or "white blood cells" (WBCs), include lymphocytes, granulocytes, and monocytes. Hematopoietic
endpoints evaluated following PCB exposure include RBC and WBC counts (overall and by type),
platelet counts, hemoglobin levels, mean corpuscular volume (MCV), mean corpuscular hemoglobin
(MCH), hematocrit levels, bone marrow histopathology, and clotting function. Many of these
measures are used in clinical practice but can also be useful to detect sub- or preclinical health
effects in epidemiological studies. Changes in the number or distribution of WBC types might
suggest the potential for immunotoxicity. Therefore, WBC counts also are discussed in Section 3.3.8.
Hematopoietic endpoints also include mortality associated with disorders/disease of the blood,
although the specific codes used in these mortality studies can be ill-defined, capturing a broad
range of conditions with potentially unrelated etiologies.

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Changes in RBC counts, or hemoglobin can indicate the presence of anemia, which
represents a decrease in the blood's oxygen transport capacity and is a significant health impact
(Papanikolaou and Pantopoulos. 2017). No studies were identified that evaluated anemia per se;
and, of the 14 human studies evaluating RBCs or hemoglobin (see Figure 16), all were cross-
sectional, and only two were conducted in general population samples (see Figure 5). All the
remaining studies were on persons occupationally exposed or with other known potential for PCB
exposure. One general population study evaluated participants aged 12 years and older in the
2003-2004 cycle of the cross-sectional NHANES fSerdar etal.. 20141. This study examined
individual and grouped (dioxin-like and nondioxin-like) PCB congeners and RBC and WBC counts,
platelet count, hemoglobin, and hematocrit. The second general population study evaluated current
levels of grouped dioxin-like PCBs (TEQ [toxic equivalency] approach) and a similar set of
hematopoietic parameters (thrombocytes, hemoglobin, thrombopoietin, and WBC counts) in a
sample of 30 children enrolled in a birth cohort in the Netherlands fLelis et al.. 20091. Although the
use of general population samples allows examination of health endpoints at relatively lower levels
of exposure, the cross-sectional nature means that temporality cannot be determined; however, in
the case of longer-lived PCBs measurements made at the time of the study likely represent
exposure prior to outcome ascertainment Furthermore, RBC and hemoglobin measurements were
among the most common hematopoietic endpoints evaluated in nonhuman mammals following
exposure to PCB mixtures, and the results of these investigations might provide additional evidence
to inform an assessment of potential effects of PCB exposures on these endpoints (see Figure 16).

Evidence Stream

Endpoint Category

Human

Other Mammal

White Blood Cell Counts

Red Blood Cells/Hemoglobin

Platelets

Bone Marrow Histopathology

Blood Disease Mortality

Clotting Function

Number of Studies

272

Figure 16, Overview of Human and Other Mammalian Hematopoietic Studies

Summary of the database of studies evaluating exposures to PCB mixtures and hematopoietic endpoints organized
by endpoint category. Lists of studies included in each count can be accessed via the online interactive version of
this figure (https://hawc.epa.gov/summarv/visual/assessment/100500282/OverviewAIIStudies/). Shading
intensity corresponds with the number of studies in each category, from 1 to 272, which is the maximum number
of nonhuman mammalian studies in any health endpoint category. The intent is to highlight not only differences
in the distribution of studies across hematopoietic endpoint categories but also to emphasize the number of
hematopoietic studies relative to the number of studies for other organs/systems.

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Hemostasis is the process through which vascular integrity is restored following injury;
clotting, or coagulation is a critical component of this process, vital for prevention of blood loss
(Trip 30). Impaired clotting function can lead to excessive bleeding; however, enhanced

clotting function is also detrimental as it can lead to thrombosis and potentially life-threatening
consequences (e.g., heart attack, stroke, pulmonary embolism). Platelets (or thrombocytes) are one
of the primary elements of the hemostatic system. Platelet counts were measured in 5 human
studies and 16 studies in other mammals (see Figure 16). However, hemostasis relies not only on
the number of platelets but also on vascular endothelial cell function and the presence and function
of an array of coagulation proteins. Clotting function was not assessed in any of the identified
human studies of PCBs and was infrequently studied in other mammals, with only two studies
evaluating this endpoint: one in rhesus monkeys (Arnold et al. 1997) and another in pigs
(Platonow et al, 1976).

Of the 37 human studies of WBC counts (see Figure 16), most were cross-sectional, but
there were more than ten cohort studies (see Figure 6). Eleven studies were conducted in general
population samples; the remaining studies were conducted among persons either occupationally
exposed or with other known potential for PCB exposure (see Figure 5). The general population
samples included participants in the cross-sectional NHANES (Serdar etal. 2014: Lee et al. 2008)
and birth cohorts in Sweden (Glvnn et al. 2008). Norway (Stalevik et al. 2013). and Japan
(Nagavama et al. 2007b). WBC counts were among the most common hematopoietic endpoints
evaluated in nonhuman mammals following exposure to PCB mixtures (see Figure 16). Taken
together, the human and animal data could be useful to inform an assessment of potential impacts
of PCB exposure on WBC numbers, which could reflect effects on hematopoietic processes or could
lead to effects on immune function (see Section 3.3.8). Information on hematopoietic processes can
also be gleaned from histopathological evaluations of the bone marrow, which were conducted in
11 nonhuman mammalian studies of PCBs (see Figure 16), in both rodents and nonhuman primates
(see Figure 8).

Of the six human studies evaluating mortality due to blood disease (see Figure 16), all were
conducted among exposed workers and relied mainly on duration of employment as a proxy for
magnitude of PCB exposure. The study populations for these analyses were sometimes overlapping
but covered different time periods. Causes of death were very broad and comprise a range of
conditions with potentially different etiologies: diseases of the blood and blood forming organs,
other and unspecified anemia, coagulation and hemorrhagic conditions, and other disease of the
circulatory system. This group of studies is considered less informative because of this broad and
non-specific outcome grouping as well as use of employment duration rather than PCB exposure
measured during a relevant time window.

In summary, there were numerous studies evaluating hematopoietic endpoints, including
RBC, WBC, and platelet counts, as well as bone marrow histopathology (in nonhuman mammals),
likely providing a sufficient foundation for evaluating hazard for these endpoints. However, there

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are very few studies for endpoints related to hemostasis (e.g., clotting function), which represents
an area of uncertainty that would benefit from further research.

3.3.7. Hepatobiliary

Hepatobiliary endpoints inform changes to the structure or function of the liver, gall
bladder, bile ducts, or bile. The liver has broad and diverse biological functions, which support
digestion, protein synthesis, nutrient homeostasis including glucose homeostasis, endogenous
chemical and xenobiotic metabolism, and formation of bile and biliary excretion. Specifically, the
liver regulates the following: protein, heme, hormone and lipid synthesis and breakdown; glycogen
synthesis and availability; micronutrient storage and release; synthesis/metabolism of fats,
proteins, and carbohydrates for energy; and the metabolism of other endogenous chemicals and
xenobiotics. The gallbladder is a small pouch that stores bile (fluid containing cholesterol and bile
acids), which is used for lipid digestion via emulsification in the small intestine. Bile is also a route
of excretion for bilirubin (a byproduct of RBC recycling) and a broad range of other excretion
products, including the metabolic progeny of xenobiotics and lipophilic substances themselves,
including PCBs (Bover. 2013). Responses of the hepatobiliary system to chemical exposures can
range from adaptive induction of metabolic enzymes to structural or functional damage, such as
cholestasis (decreased bile flow), steatosis (fatty liver), hepatitis (inflammation), necrosis (cell
death), fibrosis (scarring), and cirrhosis (late-stage necrosis and fibrosis; frank liver disease). We
identified 86 human and 357 other mammalian studies of PCB exposure and hepatobiliary
endpoints (see Figure 4). Nonhuman mammalian models used in these studies included laboratory
rodents, nonhuman primates, rabbits, mink, and other species (see Figure 8) and included exposure
durations from acute to chronic, as well as developmental exposures (see Figure 10).

Of the 86 human studies of PCBs and hepatobiliary endpoints identified, only 11 included
direct evaluations of liver injury, including 7 studies of deaths from cirrhosis (Kimbrough et al,
2015: Prince et al, 2006b: Prince etal, 2006a: Ruder etal, 2006: Mallin etal, 2004: Kimbrough et
al, 2003: Brown and lones, 1981) and individual studies of self-reported nonspecific liver disease
fStehr-Green etal. 19861. self-reported hepatitis (Fitzgerald et al. 19891. steatosis diagnosed from
liver biopsies in bariatric surgery patients fRantakokko etal. 20151. and ultrasonography of liver
structure abnormalities in an occupational cohort of former recycling factoly workers (Kaifie et al,
2019). Studies examining mortality (i.e., deaths from cirrhosis) were occupational cohort studies
(Kimbrough etal, 2015: Prince et al, 2006b: Prince et al, 2006a: Ruder etal, 2006: Mallin et al,
2004: Kimbrough etal, 2003: Brown and lones, 1981). As is common in occupational cohorts of
PCB exposure, all but two of the studies used duration of employment as an exposure surrogate. In
contrast, Ruder et al. (20061 and Prince et al. f2006bl used semiquantitative job exposure matrices
to assign cumulative exposure categories. Despite implementing different exposure estimates, each
study assessed potential relationships between PCB exposure and deaths from cirrhosis using
standardized mortality ratios (SMRs). The small database of human studies with direct evaluations
of liver injury can be supplemented with information from studies of other hepatobiliary endpoints

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(see below] and studies of nonhuman mammals exposed to PCBs, especially those that employed
histological evaluations of liver damage (see Figure 17). Nonhuman mammalian studies of PCBs
also commonly evaluate the presence of lipid-containing vacuoles within hepatocytes, a sign of fatty
liver [e.g., (Shi etal.. 2019: Wahlang et al.. 2017: Madra et al.. 1995: Bergman etal.. 1992: Baumann
et 1983: Lipskv etal.. 1978: Bruckner et al. 1974: Burse etal, 1974: Hansell and Ecobichon.
1974: Aulerich et al.. 19731],

Evidence Stream

Endpoint Category

Human

Other Mammal

Liver Weight/Hepatomegaly

272

Cholesterol

Liver Enzyme Induction

137

Liver Histopathology

127

Blood Triglycerides

Serum Biomarkers of Liver Health & Function

Liver Lipids/Steatosis

Micronutrients

Porphyrins

Liver Disease/Cirrhosis

Bile Acid Content/Excretion

Gall Bladder Histopathology

Ultrasonography (Liver)

Micronutrients Vitamin C

Vitamin A

Vitamin E

Metals

Riboflavin

Number of Studies

272

Figure 17. Overview of Human and Nonhuman Mammalian Hepatobiliary
Studies

Summary of the database of studies evaluating exposures to PCB mixtures and hepatobiliary endpoints organized
by endpoint category. Lists of studies included in each count can be accessed via the online interactive versions of
this figure: (https://hawc.epa.gov/summarv/visual/assessment/100500282/QverviewAIIStudies/) for an overview
across human and nonhuman mammalian studies; and

(https://hawc.epa.gov/summarv/visual/assessment/100500282/HepatobiliarvEndpointsNonhumanMammals/)
for studies of nonhuman mammals only. The interactive summary of the nonhuman mammalian studies can be
adjusted to group hepatobiliary endpoint categories into two levels of organization. Shading intensity
corresponds with the number of studies in each category, from 1 to 272, which is the maximum number of
nonhuman mammalian studies in any health endpoint category. The intent is to highlight not only differences in
the distribution of studies across hepatobiliary endpoint categories but also to emphasize the number of
hepatobiliary studies relative to the number of studies for other organs/systems.

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Hepatomegaly (enlarged liver) can provide indirect evidence of liver damage but might also
result from dysfunction in other organ systems (e.g., cardiovascular conditions). Because of this
lack of specificity, studies evaluating hepatomegaly might provide stronger evidence for potential
hepatobiliary effects of exposure when they also collect data on other endpoints from this system.
Hepatomegaly was evaluated in four studies of Yusho patients (Kanagawa et al. 2008: Tokunaga
and Kataoka, 2001: Hirota et al, 1995) or occupationally exposed workers (Maroni et al. 1980).
Additionally, one other study of an occupational cohort used sonographic examination to measure
liver size in PCB-exposed workers fKaifie et al. 20191. These studies were a mix of cross-sectional
and cohort studies, all of which had PCB measurements from serum or blood. Two of the five
studies also evaluated serum biomarkers of liver function and health (Kaifie et al. 2019: Maroni et
al. 1980). The types of serum biomarkers examined and their significance are discussed in more
detail below. Like human studies of hepatomegaly, nonhuman mammalian studies of liver weight
and PCB exposure can be bolstered by the inclusion of other types of data (e.g., liver histopathology
or levels of serum biomarkers). Of the 272 nonhuman mammalian studies that evaluated liver
weight and PCB exposure (see Figure 17), most also included evaluations of other hepatobiliary
endpoints [e.g., fWahlangetal. 2014: Oda and Yoshida. 1994: Sager. 1983: Oishi et al. 1978:
Schmoldtetal, 1977: Allen etal, 1975: Bastomskvetal, 1975: Kirivama etal, 1974: Allen etal,
1973: Vos and Notenboom-Ram. 1972)].

Many nonhuman mammalian studies evaluated endpoints that can be used to detect the
induction of the xenobiotic metabolizing enzyme apparatus (see Figure 17), which is an important
contributor to increased liver mass in experimental models. A robust database evaluated PCB
exposures and both liver weight and markers of xenobiotic metabolism [e.g., f Arena etal. 2003:
Segre etal. 2002: Aulerich etal. 1985: Saito et al. 1983a: Saito et al. 1983b: Narbonne. 1979:
Bruckner et al. 1977: Grant and Phillips. 1974: lohnstone etal. 1974: Litterstetal, 1972)]. A few
human studies also examined PCB exposure and drug metabolism. A small cohort study of Native
American adults analyzed serum PCB levels and cytochrome P-450 1A2 (CYP1A2) (Fitzgerald et al.
20051. Activity of CYP1A2, an enzyme instrumental in drug metabolism, was estimated using a
caffeine breath test to measure caffeine metabolism. Additionally, a few small occupational studies
examined PCB exposure and antipyrine half-life fEmmettetaL 1988a: Krampl and Kontsekova.
1978: Alvares etal. 19771.

Serum biomarkers can also be used as evidence of liver damage. For example, elevated
levels of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) can indicate
hepatocellular injury or necrosis (Lala etal. 2022: Gibonev. 20051. elevated levels of bilirubin,
alkaline phosphatase (ALP), or gamma-glutamyl transferase (GGT) can be associated with
cholestasis (Lala et al. 2022). and cytokeratin 18 (CK18) is a validated biomarker for
steatohepatitis fFeldstein et al. 20091. However, like hepatomegaly, changes in serum biomarker
levels might also be related to the function of other biological systems. For example, elevated GGT
can also occur with chronic heart failure, and elevated ALP can be used to detect bone disorders.

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Therefore, compared to studies evaluating a single biomarker, studies evaluating these biomarkers
in combination are more likely to yield hazard information specific for this organ/system. PCB
exposure and levels of serum biomarkers of liver health and function, including ALT, AST, bilirubin,
ALP, GGT, and CK18 were evaluated in 37 human studies (see Figure 17), many of which evaluated
more than one biomarker [e.g., (Sala etal. 2001: Brown et al. 1991: Brandt-Ranf and Niman. 1988:
Steinberg etal, 1986: Emmett. 1985: Fischbein. 1985: Hara, 1985: iawton etal, 1985: Smith et al,
1982: Ouw et al, 19761], Most of the identified studies were cross-sectional (see Figure 6) and
included PCB measurements from serum, plasma, whole blood, or adipose tissue (see Figure 7);
other exposure metrics included placental PCBs fWang et al. 20051 and generalized exposure
categories based on air PCB concentrations at a capacitor manufacturing plant (Fischbein etal,
19791. Cross-sectional studies generally focused on occupational exposures or subjects in industrial
areas or communities otherwise at risk for high exposure (see Figure 5). However, there were a few
general population studies identified, including those using survey data from the NHANES [e.g.,
(Wahlang et al, 2020: Serdar et al, 2014: Christensen etal, 20131], In addition to cross-sectional
studies, a smaller number of cohort studies examined PCBs and serum biomarker levels. These
studies included mostly occupational cohorts or Yusho patients, although one was a general
population study of mother-newborn pairs (Wang etal. 2005) and another was of bariatric surgery
patients (Rantakokko etal, 2015). PCB exposure and biomarkers of liver health and function also
were examined in 62 nonhuman mammalian studies, which can provide additional information
useful for evaluating potential causal relationships between exposure and effect (see Figure 17).
However, the types of histopathological changes observed with chemical exposures do not always
include necrosis; therefore, it is not clear that release of liver enzymes into the blood would be
among the most sensitive indicators of liver damage. Many studies in the nonhuman mammalian
database evaluated serum biomarkers of liver health and function in combination with
histopathological evaluations [e.g., (Wahlang et al. 2019: Wahlang etal. 2016: Wang et al. 2011:
Pereira and Rao, 2006: Maves et al, 1998: Baumann etal, 1983: Zinkl 1977: Barsotti et al, 1976:
Abrahamson and Allen. 1973: Allen et al. 19731],

Inhibition of uroporphyrinogen decarboxylase, a key enzyme in the heme biosynthetic
pathway, leads to a buildup of various uroporphyrins and increases the concentration of these
products in urine. The accumulation of porphyrins is known as porphyria, and the type of porphyria
caused by environmental chemicals is known as porphyria cutanea tarda. Human studies generally
evaluate excretion of porphyrins in urine in individuals exposed to environmental chemicals and
the relative concentrations of individual porphyrins, especially the ratio of uro- to coproporphyrins.
Three human studies examined urinary porphyrins: one in individuals exposed transiently to
smoke from a PCB-containingtransformer fire (Osterloh etal, 1986) and two in individuals
exposed occupationally during capacitor manufacture fColombi etal. 1982: Smith etal. 19821. To
supplement the data from human studies, 23 nonhuman mammalian studies measured porphyrin
accumulation in liver and excretion in urine (see Figure 17).

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Many fatty acids, lipids, and cholesterol are synthesized and eliminated in the liver; the
relationships among them and their relevance to human health are complex (see Sections 3.3.1 and
3.3.9). Increases or decreases in serum or liver cholesterol levels can be associated with liver
damage, although determining whether the changes are a consequence of that damage or a
contributing factor in disease progression can be challenging (Arguello et al. 2015: Chrosteketal,
20141. Additionally, in the case of evaluating lipid-related endpoints in observational studies,
reverse causality whereby lipophilic PCBs accumulate more in individuals with higher lipid levels is
a possibility. PCB exposure and cholesterol levels were evaluated in 43 human studies (see
Figure 17). Most of these studies used a cross-sectional design (see Figure 6), and most included
PCB measurements from serum, plasma, whole blood, or adipose tissue (see Figure 7). Of the cross-
sectional studies, many also investigated PCB exposures and blood triglycerides [e.g., (D'Errico et
al, 2012: IJemura etal, 2009: Lee etal, 2007b: Karmaus et al, 2005: Bloom et al, 2003: Stehr-
Green etal. 1986: Takamatsu etal. 1984: Chase etal. 1982: Smith etal. 1982: Baker etal. 19801],
Similar to studies on serum biomarkers, cross-sectional studies of PCB exposure and cholesterol
levels were generally conducted in occupationally exposed populations or included subjects from
communities that were at high risk for exposure (see Figure 5). A few general population studies
included those conducted using national survey data, such as NHANES (Patel et al. 2012: Lee et al.
2007b). Additionally, four of the cross-sectional studies were focused on children of various ages
(including studies of infants, school children, and teenagers) (Nakamoto etal, 2013: Karmaus etal,
2005: Schell etal. 2004: Kreiss et al. 19811. Notably, six prospective studies examined PCB
exposure and cholesterol and triglyceride levels in children (Guil-Oumrait et al, 2021: Su et al,
20121. young adults fSuarez-Lopez et al. 2019: Lee etal. 20111. or older adults fStubleski etal.
2018: Penell etal. 20141. In addition to providing evaluations of general populations at lower PCB
levels, the longitudinal nature of these studies might address the potential for reverse causality, as
discussed previously. Finally, a subset of studies of occupational cohorts or Yusho patients also
examined PCBs and cholesterol or triglyceride levels using a longitudinal design (Gaum et al, 2019:
Kaifie etal. 2019: Kimakova etal. 2018: Tokunaga and Kataoka. 2003: Hirota et al. 1993b: Hirota
et al, 1993a: Brown etal, 1991: Murai et al, 1987: Fitzgerald et al, 1986: Hara, 19851. PCB
exposures and cholesterol or triglyceride levels also were examined in 99 and 60 nonhuman
mammalian studies, respectively; data collected following controlled exposures in animals can
provide additional information useful for evaluating potential causal relationships between
exposure and effect (see Figure 17). As discussed in Section 3.3.land Section 3.3.9, elevated blood
levels of cholesterol or triglycerides are considered important risk factors for cardiovascular
disease and type 2 diabetes mellitus (T2D).

The liver also plays an important role in nutrient homeostasis, regulating micronutrient
storage and release. Fifty-two nonhuman mammalian studies explored PCB exposure and liver
levels of micronutrients, including vitamin A (retinoids), vitamin C (ascorbic acid), vitamin E
(alpha-tocopherol), vitamin B2 (riboflavin), zinc, calcium, copper, iron, magnesium, potassium,

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manganese, and selenium (see Figure 17). Vitamin A is stored in the liver, primarily in specialized
fat storing cells, in the form of retinyl palmitate, and an equilibrium exists with blood by which
vitamin A as retinol is delivered to tissues. Twenty-two nonhuman mammalian studies explored
PCB exposures and the dynamics of vitamin A storage, distribution, metabolism, and excretion (see
Figure 17). Twenty-three studies of PCBs in mammals other than humans assessed water-soluble
vitamin C, while seven evaluated lipid-soluble vitamin E. These studies were well designed to
ascertain possible adverse effects. The liver is also a principal storage site for several metals,
including zinc, calcium, copper, iron, magnesium, potassium, manganese, and selenium. Five studies
described PCB exposures and distribution of these metals within the liver and the activity of
enzymes that contain them, especially important antioxidant enzymes, like Cu/Zn superoxide
dismutase, Mn superoxide dismutase, Se-dependent glutathione peroxidases and others.
Investigations of metals in the liver also can have important implications for other organ systems;
for example, calcium metabolism can influence bone and tooth health and development (see Section
3.3.10).

Four studies have investigated gallbladder and biliary duct histopathology in nonhuman
primates (see Figure 17). However, experimental studies of PCB exposure often use rats (see Figure
8), which have no gallbladder, and this could have contributed to a general lack of attention to this
organ. In addition to potential changes in bile duct morphology, bile content and flow rate can also
reflect liver status and health. Bile acid content and excretion of bile have been evaluated in nine
studies of rats exposed to PCB mixtures (see Figure 17).

In summary, the human database of PCB exposure and hepatobiliary endpoints contains
only a few studies that directly evaluate liver injury, and those consist mostly of prospective studies
on cirrhosis mortality in occupational cohorts. Most available human studies were cross-sectional
analyses, particularly those evaluating serum biomarkers of liver function or cholesterol or
triglyceride levels. Particularly in the case of lipid measurements, where the potential for reverse
causality is significant, cross-sectional studies are limited in that they do not establish temporality
between the exposure and outcome (see Section 3.2.1). However, there is a robust database of
nonhuman mammalian studies to inform temporality between PCB exposures and these endpoints
at a wide range of exposure levels. Animal studies also have evaluated PCB exposures and a broad
range of structural and functional parameters of the liver. Therefore, the overall database likely
provides sufficient information to draw hazard conclusions for hepatobiliary endpoints and PCB
exposure. Additional prospective human studies, including more studies in nonoccupational
cohorts, might strengthen the database, while PCB exposure and gallbladder and biliary endpoints
represent an area of uncertainty that would benefit from further research.

3.3.8. Immune

The immune system is highly dispersed, comprising multiple organs, tissues, and cell types,
the main function of which is to ensure homeoregulatory maintenance by preventing or limiting
infection and malignancy (IPCS. 2012). Adverse effects can result from suppression of the immune

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system, which can lead to reduced antibody production, greater infectious morbidity, and poorer
surveillance of tumor producing cells. Inappropriate stimulation, as is the case with allergy and
atopic disease, or inappropriate recognition of self-antigen, in the case of autoimmunity, can also
result from immune dysregulation. Immune endpoints can be grouped based on proposed
mechanistic pathways of immunosuppression, hypersensitivity, and autoimmunity. For this review,
endpoints included in this domain are as follows: susceptibility to infection/malignancy, atopy
(i.e., allergy and asthma), autoimmune disease, antigen-specific antibody responses (e.g., to
vaccination), WBC function, delayed-type hypersensitivity (DTH) responses, antibody levels,
immune organ size and weight, immune organ histopathology, and endotoxin sensitivity. WBC
counts are considered briefly here, but these can also reflect effects on hematopoietic processes and
are discussed primarily in Section 3.3.6. With respect to identifying hazards from chemical
exposures, the most informative immune endpoints are those that measure a change in immune
function in response to challenge, such as susceptibility to infection, atopy, autoimmune disease,
antigen-specific antibody responses, WBC function (e.g., lymphocyte proliferation assays, NK cell
activity assays), and DTH. These endpoints have been routinely measured in epidemiological
studies and in clinical settings. Other immune endpoints might be less sensitive or less reliable
indicators of significant and persistent effects on immune function (e.g., WBC counts,
immunoglobulin [Ig]) levels, immune organ size/weight, immune organ histopathology, and
endotoxin sensitivity) (IPCS. 20121. Because of the potential lack of sensitivity and specificity of
these endpoints, studies evaluating these in combination, especially alongside more informative
measures of immune function, might provide greater evidence for meaningful health implications
compared with studies that evaluate only one of these endpoints in isolation.

One hundred and five human and 131 other mammalian studies evaluated PCB exposure
and immune endpoints; many of these included multiple assays (see Figure 4). Most human studies
of immune endpoints used biomarkers to characterize PCB exposure, with varying numbers of PCB
congeners measured in blood or breast milk (see Figure 7). Less commonly, PCBs were measured in
sputum fNakanishi et al. 1985: Shigematsu etal. 19781. adipose tissue fChase et al. 19821.
umbilical cord tissue (Ochiai etal.. 20141. or placental tissue (Reichrtova et al.. 19991. or
characterized using dietaiy assessment fStelevik etal.. 2013: Stalevik et al.. 2011: Svensson et al.
19941. In some cases, occupational exposure was inferred based on work history rather than
biospecimens or biomonitoring (Kimakovaetal. 2018: Parker-Lalomio etal.. 2018: Kimbrough et
al.. 2015: Mallin et al. 2004: Langer et al. 2002: Osterloh et al. 19861. Nonhuman mammalian
studies of PCBs and immune endpoints have been conducted most frequently in laboratory rodents,
rabbits, and nonhuman primates, but some studies have also used mink or livestock (see Figure 8).
Study designs include exposure durations from acute to chronic and multigenerational studies
evaluating endpoints following exposures during critical developmental periods (see Figure 10); for
the immune system, these include prenatal and postnatal periods through adolescence (Dietert et
al. 20001.

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One endpoint with clear relevance for immune function is the occurrence of infectious
disease, as evaluated in 31 human studies (see Figure 18), mainly prospective cohorts (see
Figure 6). Many studies relied on questionnaires of the participant (or parent) to ascertain
outcomes, which could lead to outcome misclassification. However, some studies in the database
used other methods such as medical chart review [e.g., (Dallaire etal. 2006: Dallaire et al. 2004)].
which would alleviate misclassification to some degree. The bulk of the studies focused on the
following: respiratory disease (upper or lower respiratory tract infection (Gascon etal. 2014b:
Stflleviketal. 2013: Gascon et al. 2012: Stelevik et al ; iver etal. 2010: Glvnn et al. 2008:
Dallaire etal. 2006: Dallaire et al. 2004: Weisglas-Kuperus et al. 2004: Rogan etal. 1987:
Shigematsu etal. 1978): rhinitis, bronchitis, or tonsillitis (Gascon et al. 2014a: Sunver et al. 2010:
Mallin etal. 2004: Yu etal. 1998: Weisglas-Kuperus et al. 1995): pneumonia (Kimbrough et al.
2015: Sunver et al. 2010: Mallin etal. 2004: Weisglas-Kuperus et al. 2004: Weisglas-Kuperus et al.
20001: influenza fYu et al. 19981: cold symptoms fLiebl et al. 2004: Hara. 19851: or otitis media
(Parker-Lalomio et al. 2018: lensen et al. 2013: Stalevik etal. 2013: Stalevik et al. 2011: Dallaire
et al. 2006: Dallaire et al. 2004: Weisglas-Kuperus et al. 2004: Dewaillv et al. 2000: Weisglas-
Kuperus etal. 2000: Yu etal. 1998: Chao et al. 1997: Weisglas-Kuperus etal. 1995: Rogan et al.
1987)1. Fewer studies evaluated a range of other infectious diseases (gastrointestinal infection
(Henrfauez-Hernandez et al. 2015: Stalevik et al. 2013: Stalevik etal. 2011: Dallaire etal. 2004:
Yu et al. 1998: Rogan et al. 1987). chicken pox (Stalevik etal. 2013: Stalevik et al. 2011: Weisglas-
Kuperus etal. 2004: Weisglas-Kuperus etal. 20001. and other diseases fArisi et al. 2021: Karmaus
et al. 2005: Weisglas-Kuperus etal. 2004: Van Den Heuvel et al. 2002: Weisglas-Kuperus et al.
200011. The human database is supplemented by studies that used rodent models of host resistance
to tumor challenge fLubetetal. 1986: Loose etal. 1981: Kerkvliet and Kimeldorf. 19771 and to
infectious agents such as Plasmodium berghei (malaria) (Loose etal. 1979: Loose et al. 1978a:
Loose et al. 1978b). Salmonella typhimurium (Thomas and Hinsdill, 1978). Listeria monocytogenes
(Lubetetal, 1986). Staphylococcus aureus (imanishi etal. 1984). herpes simplex virus (imanishi et
al. 19801. ectromelia virus fimanishi etal. 19801. and influenza virus fimanishi etal. 19841. Six
studies evaluated PCB exposure and bacterial endotoxin sensitivity in mice and rats (see Figure 18).
Endotoxin is a lipopolysaccharide found in the cell wall of gram-negative bacteria that can trigger a
strong inflammatory response, leading, in some cases, to sepsis and septic shock fOpal. 20101.
Endotoxin sensitivity can have significant implications for susceptibility to and ability to recover
from gram-negative bacterial infections. Of the six studies that measured endotoxin sensitivity, four
also evaluated susceptibility to infection (Loose et al. 1979: Loose et al. 1978a: Loose et al. 1978b:
Thomas and Hinsdill. 19781. although only one fThomas and Hinsdill. 19781 included infection with
gram-negative bacteria (S. typhimurium).

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Evidence Stream

Endpoint Category

Human

Other Mammal

Immune Organ Size/Weight

Immune Organ Histopathology

Susceptibility to Infection

Atopy (Allergy/Asthma)

Antibody Responses

Ex Vivo WBC Function

Immunoglobulin Levels - Nonspecific

Autoantibody Levels

Delayed-Type Hypersensitivity

Endotoxin Sensitivity

Autoimmune Disease

Number of Studies

272

Figure 18. Overview of Human and Other Mammalian Immune Studies

Summary of the database of studies evaluating exposures to PCB mixtures and immune endpoints organized by
endpoint category. Lists of studies included in each count can be accessed via the online interactive version of this
figure (https://hawc,epa.gov/summarv/visual/assessment/100500282/QverviewAIIStudies/). Shading intensity
corresponds with the number of studies in each category, from 1 to 272, which is the maximum number of
nonhuman mammalian studies in any health endpoint category. The intent is to highlight not only differences in
the distribution of studies across immune endpoint categories but also to emphasize the number of immune
studies relative to the number of studies for other organs/systems. WBC = white blood cell.

The production of antigen-specific antibodies in response to an immune challenge is a
sensitive and specific measure of immune function that is relatively easy to quantify in both
humans and other mammals, making it highly informative for the identification of immune hazards,
especially those resulting in immune suppression flPCS. 20121 Seven human studies conducted in
prospective birth cohorts evaluated vaccine-specific antibody levels among children born in the
Netherlands (Weisglas-Kuperus etal.. 2000 j. Norway fStalevik etal.. 20131. the Faroe Islands
(Heilmann etal.. 2010: Heilmann etal.. 20061 Greenland (TimmermannetaL 20211. and eastern
Slovakia flusko etal.. 2016: lusko etal. 20101. Five of these reported antibody responses to tetanus
or diphtheria vaccines (Timmermann et al.. 2021: Stalevik etal.. 2013: Heilmann et al, 2010: lusko
et al.. 2010: Heilmann etal.. 20061. Two studies evaluated response to measles and rubella
vaccination f Stfllevik et al.. 2 013: Weisglas-Kuperus etal.. 20001. Other vaccine responses evaluated
included anti-Haemophilus influenzae type b fStdlevik etal.. 2013: lusko etal.. 20101. anti-
Mycohacterium bov/sbacille Calmette-Guerin (BCG, the vaccine for tuberculosis) flusko etal..
20161. and mumps (Weisglas-Kuperus etal. 20001. In most cohorts, PCB exposure was
characterized using biosamples taken from the mother or offspring (see Figure 7), while one
fStalevik etal., 20131 used reported maternal dietary intake to estimate exposure. Antigen-specific

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antibody responses have also been evaluated in 28 nonhuman mammalian studies (see Figure 18),
including studies in rhesus monkeys that evaluated antibody responses to sheep red blood cells
after several years of oral exposure to PCBs in adult females (Trvphonas et al. 1991: Trvphonas et
al, 19891 and perinatal exposure in their offspring (Arnold et al, 19951.

Although the integrity of the immune system is maintained within its major organs
(e.g., bone marrow, spleen, thymus, lymph nodes), its effector functions occur primarily through the
actions of individual cells. For this reason, many assays of immune function are based on
measurements of WBC function (e.g., NK cell activity, mixed leukocyte reaction (MLR), lymphocyte
proliferation assays, phagocytosis assays). These assays have been found predictive for immune
suppression, especially when used in combination, and have concordant results (Luster etal,
19921. Fourteen human studies, many of which were cross-sectional, evaluated WBC function (see
Figure 18, Figure 6). A few cohort studies were conducted among populations of postmenopausal
women fSpector et al. 20141. occupationally exposed workers fHaase et al. 20161. and one
prospective birth cohort (Belles-Isles et al. 20021. All three of these included measures of NK cell
activity and T cell responses to mitogenic stimulation, with Haase et al. (20161 also measuring the
ability of WBCs to phagocytize and kill bacteria via oxidative burst Twenty-one studies conducted
in PCB-exposed mice, rats, rabbits, and nonhuman primates evaluated WBC functions including NK
cell activity, MLR, cytotoxic T lymphocyte activity, phagocytic activity, macrophage superoxide
production, lymphocyte proliferation in response to mitogenic stimulation, and cytokine
production (see Figure 18, Figure 8). Of these 21 studies, all but 5 fSmith etal. 2003: Nakanishi et
al. 1995: Talcott et al. 1985: Carter and Clancy. 1980: Bonnvns and Bastom ) evaluated

multiple assays of WBC function or a single assay of WBC function in combination with some other
measure of immune function (e.g., host resistance, antigen-specific antibody responses, DTH).

Like assays of WBC function, the DTH response has been found to be useful for predicting
immune suppression, especially when evaluated in combination with other assays of immune
function (Luster et al. 1992). Three studies evaluated DTH among Yu-Cheng patients (Wu etal.
1984a: Wu et al. 1984b: Chang etal. 19811. comparing exposed patients to unexposed individuals
matched for age and sex. However, findings from these studies are limited by the potential for
selection bias and the inability to separate potential effects of the PCBs themselves from effects of
their degradation products, especially PCDFs (see Section 3.2.1). Four studies in laboratory
mammals exposed to PCBs evaluated DTH responses to agents including oxazolone [one study in
mice (Talcott and Koller. 1983)]. dinitrofluorobenzene [one study in rabbits (Thomas and Hinsdill.
1980)]. and tuberculin [one study in rabbits (Street and Sharma. 1975) and one in guinea pigs (Vos
and Van Driel-Grootenhuis. 19721], All four of these studies evaluated DTH in combination with
other measures of immune function.

Forty-three human studies evaluated PCB exposure and endpoints related to allergy or
asthma (see Figure 18). The most informative studies in this database evaluated clinical diagnoses
of asthma. One investigation, reported across two publications (Meng et al. 2016a: Mengetal.

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2016b), ascertained asthma via doctor's examination, while another fHarisen et al. 20141 inferred
asthma on the basis of asthma medication use from a medical registry. Other studies focused on
infants or children and evaluated dermal (e.g., eczema) or respiratory (e.g., wheeze, cough,
congestion, or shortness of breath) symptoms and self-/parent-reported occurrence of allergy or
asthma. Overall, the numerous studies conducted with a variety of study populations should allow
identification of potential hazard. Furthermore, studies of allergy and asthma cases are
supplemented by studies that measured allergen specific IgE antibodies, including studies of
prospective birth cohorts in Demark fHansen et al. 20151 and the Faroe Islands fGrandiean et al.
20101. a cross-sectional study of Flemish adolescents fVan Den Heuvel et al. 20021. and a study of
asthmatic and nonasthmatic children in Japan (Tsuii etal, 20121. These studies measured levels of
IgE specific for a wide variety of allergens, including dust mites, animal danders, grasses, molds,
trees, pollen, egg, milk, and wheat

Among the human studies of autoimmune dysfunction, occurrence of autoimmune
disease—as evaluated in three human studies—could be more informative compared with
autoantibody levels (n = 23) (see Figure 18). One study examined arthritis in a cross-sectional
sample of the general US population (NHANES) flee et al. 2007cl: the analyses specific to
rheumatoid arthritis among women are relevant to evaluating potential immune hazard, while
analyses of osteoarthritis are discussed elsewhere (see Section 3.3.10). A second study was a case-
control analysis of type 1 diabetes (Rignell-Hydbom et al. 2010). which was constructed from a
biobank of maternal serum samples and thus had prenatal measures of PCB 153. The last study,
conducted among occupationally exposed workers, evaluated both autoimmune disease and
autoantibody titers fSchoenroth et al. 20041. In total, 23 studies, including Schoenroth et al. f20041.
evaluated autoantibody titers (see Figure 18). Many evaluated thyroid antibody levels (e.g., anti-
thyroid peroxidase)[e.g., (Benson etal. 2018: Gaum etal. 2016: Brucker-Davis etal. 2011: Langer
et al. 2009: Schell etal. 2009: Langer et al. 2007a: Langer etal. 2005: Langer et al. 2003: Langer et
al. 2002: Murai etal. 19871]. which have also been measured in one study of PCB-exposed rats (Gil
et al. 20091: thyroid hormone levels are discussed in Section 3.3.4. Most of the human studies of
autoantibody titers were cross-sectional (see Figure 6), limiting inference; however, one study
fQsuna et al. 20141 was based on a prospective cohort, evaluating IgM and IgG autoantibody levels
in children born in the Faroe Islands, while two other studies evaluated thyroid autoantibodies, one
in Yusho patients (Murai et al. 1987) and one in a medical surveillance study with repeated
evaluations (Gaum etal. 20161. Thus, there are few data available to inform potential associations
of PCB exposure with autoimmune disease, but more data are available for the less specific
endpoint of autoantibody levels.

Although considered less informative endpoints due to their nonspecific nature, several
studies evaluated WBC counts (see Section 3.3.6) or nonspecific antibody levels (15 human and 16
other mammalian studies) (see Figure 18). In addition, three human studies measured immune
organ size—two evaluated thymus volume in the same cohort of children born to mothers living in

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eastern Slovakia flusko etal. 2012: Park etal. 20081. and one evaluated splenomegaly in Yusho
patients fHirota etal. 19951. Immune organ weight and histopathology have been evaluated
extensively in PCB-exposed mammals other than humans (88 and 52 studies, respectively) (see
Figure 18). Although not as sensitive and specific as measures of immune function, these endpoints
can be useful for supporting hazard conclusions.

Overall, information available to draw hazard conclusions for immune endpoints and PCB
exposure is sufficient, especially with regard to immune suppression, which can be supported by
studies of highly informative endpoints, such as susceptibility to infection/malignancy, antigen-
specific antibody responses, WBC function, and DTH responses. The database also has some
potential to support conclusions about PCB exposure and allergies/asthma. However, scant data
are available on PCBs and autoimmunity, representing an area of uncertainty that would benefit
from further research.

3.3.9. Metabolic

For this review, metabolic endpoints include measures related to glucose metabolism and
overweight/obesity (OW/OB). Measures related to glucose metabolism evaluated in combination
with PCB exposure in humans include the following (see Figure 19): insulin resistance (IR);
impaired glucose tolerance (IGT)/prediabetes; T2D; gestational diabetes; diabetes mellitus not
otherwise specified (DM NOS); and metabolic syndrome (MetS). Diabetic nephropathy is a renal
complication of DM discussed in Section 3.3.15. The most common metabolic endpoints evaluated
in humans were OW/OB and DM NOS. Sixty-nine published articles (see Figure 4) reporting the
results of studies in laboratory mammals exposed to PCB mixtures have evaluated metabolic
endpoints such as increases in body weight/adiposity, markers of glucose homeostasis, and basal
metabolic rate (see Figure 19). Most of these studies were conducted in rats, followed by mice,
rhesus or cynomolgus monkeys, and other species (see Figure 8).

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Evidence Stream

Endpoint Category Human Other Mammal

Overweight/Obesity

Blood/Urinary Glucose

Diabetes Mellitus (NOS)

Type 2 Diabetes Mellitus

Insulin Resistance

Impaired Glucose Tolerance

Metabolic Syndrome

Pancreatic Histopathology

Body Temperature/Metabolic Rate

Insulin Levels

Gestational Diabetes Mellitus

Adipose Tissue Histopathology

Pancreas Weight

Number of Studies

i 272

Figure 19. Overview of Human and Other Mammalian Metabolic Studies

Summary of the database of studies evaluating exposures to PCB mixtures and metabolic endpoints organized by
endpoint category. Lists of studies included in each count can be accessed via the online interactive version of this
figure (https://hawc.epa.gov/summarv/visual/assessment/100500282/QverviewAIIStudies/). Shading intensity
corresponds with the number of studies in each category, from 1 to 272, which is the maximum number of
nonhuman mammalian studies in any health endpoint category. The intent is to highlight not only differences in
the distribution of studies across metabolic endpoint categories but also to emphasize the number of metabolic
studies relative to the number of studies for other organs/systems. NOS = not otherwise specified.

All the endpoints mentioned above are closely related on a pathophysiological basis,
primarily via visceral obesity and IR. OW/OB facilitates the development of IR. The progression of
IR results in glucose homeostasis dysregulation further advancing to clinically significant and
detectable glucose intolerance andT2D. Development of IR during pregnancy can progress to
gestational DM (DM diagnosed during pregnancy in women without prior DM, which resolves after
delivery). IR also plays a key role in the pathogenesis of MetS. MetS is a complex pathophysiological
state composed of causally interrelated conditions that increase the risk of T2D and cardiovascular
disease: OW/OB; IR; hypertension; high triglyceride levels; and low high-density lipoprotein (HDL)
cholesterol levels. As discussed below, the combi nations of these conditions used as diagnostic
criteria vary slightly per various definitions of MetS. Studies of PCB exposure and cardiovascular
disease and hypertension are discussed in Section 3.3.1; triglyceride and cholesterol levels are
included in Section 3.3.7.

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The most informative metabolic endpoints for supporting hazard identification include
markers of glucose homeostasis and gestational diabetes. IR, IGT, and T2D are particularly
informative because glucose homeostasis/IR is a pathophysiological continuum, all stages of which
can be verified using standard clinical laboratory tests. However, the accuracy of specific methods
used for evaluating metabolic endpoints in humans varies. For IR, the better measures are the ones
calculated on the basis of insulin and glucose blood levels, such as homeostasis model assessment-
IR (HOMA-IR) and insulin sensitivity index (ISI-gly), both of which were investigated in cohort and
case-control studies of PCBs [e.g., fPark et al. 2016: Suarez-Lopez etal. 2015: Tang-Peronard et al.
20151] and in cross-sectional studies fArrebola etal. 2015: lensen etal. 20141. For IGT/preDM, the
preferred measure is a laboratory test of impaired fasting glucose (IFG); this method was used only
in cross-sectional studies of PCB-exposed populations [e.g., (lorgensen et al. 2008: Langer et al.
2007a)]. For T2D, the better measures include lab tests based on plasma glucose concentration, a
diagnosis of T2D by a physician, or treatment with antidiabetic medications other than insulin.
Several studies investigating PCBs and T2D using preferred endpoint measures were conducted as
cohort and case-control studies [e.g., fRvlander etal. 2015: Lee et al. 2010: Rignell-Hvdbom et al.
2009a: Turvk et al. 20091]: others used a cross-sectional design [e.g., fFaerch et al. 2012: Tanaka et
al. 20111], Gestational diabetes has been evaluated in relatively few studies of PCBs but is likely
diagnosed more completely than other metabolic endpoints due to use of routine screening during
prenatal care. Four cohort studies (Rahman etal. 2019: Vafeiadi et al. 2017: Valvi et al. 2017:
Shapiro etal. 20161 and five case-control studies fAlvarez-Silvares et al. 2021: Liu et al. 2021: Liu
et al. 2019: Zhang etal. 2018: Eslami etal. 20161 used preferred measures (laboratory tests,
diagnosis at a hospital) to define gestational diabetes, while one cohort study flaacks et al. 20161
and one cross-sectional study f N eblett et al. 20201 used self-re porting to define gestational
diabetes.

In addition to the rich database of human studies of PCB exposure and glucose homeostasis,
a substantial database of nonhuman mammalian studies evaluating related endpoints is available,
including blood and urinary glucose levels, blood insulin levels, IR, and IGT (see Figure 19). The
most informative studies are likely those that evaluated IR or IGT; all were conducted in mice (see
Figure 8). Of the 8 studies evaluating blood insulin levels, 7 were conducted in mice and 1 in rats
(see Figure 8). Blood and urinary glucose levels were evaluated in a wide variety of species,
including mice, rats, nonhuman primates, mink, and dogs (see Figure 8); two of these studies
assessed glucose levels following gestational and lactational PCB exposure in rats (Dziennis etal.
2008: Chu etal. 20051. and one evaluated cynomolgus monkey infants exposed directly from birth
to 20 weeks of age f Arnold et al. 19991. This database can be used to supplement the data from
human studies. Furthermore, pancreas weight and histopathology have also been evaluated in PCB-
exposed mice, rats, nonhuman primates, mink, rabbits, and guinea pigs (see Figure 8). Studies in
nonhuman mammalian models might also provide insights into sex dependency of potential
responses to PCB exposure. Some studies of laboratory mammals exposed to PCBs have compared

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endpoints including IR and pancreatic histopathology in males and females [e.g., fWafalang et al.

201911.

Metabolic endpoints that are less informative for hazard identification include MetS, DM
NOS (diabetes mellitus, not otherwise specified), and OW/OB. Several different sets of MetS
diagnostic criteria have been used in the past two decades (since 1998), impeding the comparison
of results across different studies, and a designated ICD-9 code was not approved for MetS until
2001. However, the same set of five components - OW/OB, IR/IGT, hypertension, elevated
triglycerides, and decreased HDL cholesterol - is used by all MetS definitions, and because all five
MetS components are pathophysiological^ interrelated and strongly associated, use of different
criteria across studies does not dismiss the existence of MetS when it is reported in those studies,
but rather emphasizes different aspects of its clinical manifestations. Fifteen human studies
evaluated MetS and PCB exposure (see Figure 19), including 5 cohort studies in adults of varying
age ranges fLind etal. 2017: Mustieles etal. 2017: Dirinck etal. 2016: Lee etal. 20111 or
preadolescents (Lee et al. 20161. as well as a nested case-control study of adults free of MetS at
baseline fLee et al. 20141.

DM NOS is the broadest diagnostic category for diabetes (a "top" ICD code that has no
"parent" code: ICD-9 three-digit code 250) encompassing all types ofDM, including type 1 DM
(T1D), which is caused by autoimmune destruction of beta-cells in the pancreas (the immunological
mechanism) rather than by IR (the metabolic mechanism of T2D and gestational DM). Studies
explicitly evaluating T1D are addressed in Section 3.3.8 However, because about 90% of individuals
with DM have T2D, DM NOS, although much less accurate, is still usable, and cohort and case-
control studies of PCB exposure and DM NOS have been conducted (see Figure 6). Overall, 40
studies of PCB exposure and DM NOS are available, including DM NOS mortality (see Figure 19).
The better measures of DM NOS are lab tests, a record of antidiabetic medications in an
administrative database, a diagnosis of DM in a hospital discharge record, or a death record (for DM
NOS mortality), as used in several studies of PCB exposure [e.g., (Nakamoto et al. 2013: Ukropec et
al. 2010: Mallin et al. 20041],

OW/OB is multifactorial and highly prevalent in the general population, which can make
detecting associations with chemical exposures challenging. However, this is the most commonly
evaluated metabolic endpoint in the database of human PCB studies, and preferred measures of
0W/OB (i.e., body mass index [BMI] and waist circumference) have been used in cohort and case-
control studies of PCB exposure [e.g., (Agay-Sfaay et al. 2015: Vafeiadi et al. 20151], Also,
23 nonhuman mammalian studies have focused on PCB exposures and increases in body weight
and adiposity (see Figure 19). These studies were conducted in mice, rats, mink, and nonhuman
primates (see Figure 8). Adiposity has been estimated using measures of body weight and BMI and
direct measures of the size of specific adipose tissue depots. Notably, at least one study in mice (Xj.
et al. 20191 evaluated adiposity using visceral fat somatic index (visceral fat weight/body weight),
which is a particularly relevant measure because of the association in humans between visceral

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adipose tissue mass and the development of insulin resistance and T2D fBjflrndal etal. 20111.
There are also eight studies of adipose tissue histopathology in mice, rats, and Yorkshire piglets
(see Figure 19, Figure 8), and four studies of OW/OB in rats and mice measured blood leptin levels
(Tin et al. 2020: Wahlang et al. 2019: Wahlangetal. 2016: Provost et al. 2007). Leptin is an
adipokine, which is primarily secreted by adipocytes, and acts by suppressing hunger and food
intake and increasing energy expenditure (Stern etal. 2016).

Basal metabolic rate has been evaluated in 12 studies in species including mice, rats, cats,
and Holstein cattle (see Figure 19, Figure 8). Measures of basal metabolic rate used in these studies
include oxygen consumption, carbon dioxide production, respiratory exchange rate, total energy
expenditure, and body temperature. These observations could be used to supplement the
information reported by studies of other metabolic endpoints in humans and other mammals.

In summary, the human and other mammalian databases are likely to provide enough
information to evaluate the potential for PCB-associated metabolic effects, including effects on
glucose metabolism and overweight/obesity.

3.3.10. Musculoskeletal

The musculoskeletal system consists of the bones, teeth, muscles, joints, cartilage, and other
connective tissues that support the body, allow for movement, and protect vital organs.
Musculoskeletal endpoints, including measures of bone strength and density, bone histopathology,
bone development, dentition, skeletal muscle histopathology, muscle mass and tone, and arthritis
have been evaluated in the context of PCB exposure. Of the 30 human studies identified (see
Figure 4), 10 examined musculoskeletal complaints and diseases (see Figure 20), including only
subjective endpoints such as muscle and joint pain and muscle weakness. Because these studies
captured a broad range of nonspecific conditions with potentially unrelated etiologies, they are of
limited use for supporting conclusions about potential causal relationships between PCB exposure
and specific musculoskeletal endpoints. Most of the remaining human studies evaluated bone
strength and density and dental abnormalities, which are critical to overall health and quality of life
(see Figure 20). An adverse effect on bone strength and density can increase the risk of fractures,
which is an important public health concern due to its related morbidity, mortality, and diminished
quality of life (HHS. 2000). Similarly, poor dental health can lead to periodontal disease and tooth
decay, which have been associated with systemic health conditions such as cardiovascular disease
(Mayo Clinic. 2021: Evans. 20091. A few studies evaluated PCB exposure and bone age and arthritis,
including rheumatoid arthritis, which is an autoimmune condition also considered in Section 3.3.8
(see Figure 20). Through controlled experiments, 23 studies in nonhuman mammalian models (see
Figure 4), including mice, rats, rabbits, mink, swine, and nonhuman primates (see Figure 8),
assessed PCB exposure and bone density, development, and histopathology, as well as dental
abnormalities and skeletal muscle histopathology (see Figure 20).

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Evidence Stream

Endpoint Category

Human

Other Mammal

Bone Density/Strength & Osteoporosis

Dental Abnormalities

Musculoskeletal Complaints/Diseases

Bone Histopathology

Bone Development/Bone Age

Skeletal Muscle Histopathology

Arthritis

Muscle Mass/Tone

Number of Studies

272

Figure 20. Overview of Human and Other Mammalian Musculoskeletal Studies

Summary of the database of studies evaluating exposures to PCB mixtures and musculoskeletal endpoints
organized by endpoint category. Lists of studies included in each count can be accessed via the online interactive
version of this figure (https://hawc.epa.gov/summarv/visual/assessment/100500282/OverviewAIIStudies/).
Shading intensity corresponds with the number of studies in each category, from 1 to 272, which is the maximum
number of nonhuman mammalian studies in any health endpoint category. The intent is to highlight not only
differences in the distribution of studies across musculoskeletal endpoint categories but also to emphasize the
number of musculoskeletal studies relative to the number of studies for other organs/systems.

Most human studies of bone density and strength were conducted among populations in
which the major source of exposure to PCBs was through regular consumption of fish or marine
mammals (see Figure 5). Five studies were from Sweden, where fatty fish from the Baltic Sea is a
major source of PCB exposure (Rignell-Hvdbom etal.. 2009b: Hodgson etal.. 2008: Weiss et al,
2006: Wallin et al. 2005: Glynn etal.. 20001. In addition, studies have been conducted in aboriginal
populations from Canada (Paunescu et al. 2013b: Paunescu etal.. 2013a) and Greenland (Cote et
al. 20061 where fish and marine mammals are major sources of PCB exposure in traditional diets.
Because regular fish and marine mammal consumption can contribute both harmful and beneficial
coexposures, generalizing these results to populations with other dietary patterns can be difficult
(see Section 3.2.1). Of the studies referenced above, only two fPaunescu etal.. 2013b: Paunescu et
al.. 2013a) included adjustments for possible harmful (e.g., mercury) and beneficial (e.g., omega 3
polyunsaturated fatty acids) coexposures from fish and marine mammals.

Several quantitative measures of bone health have been used in human and mammalian
studies of PCB exposure. The stiffness index (SI) was used in two human studies of Canadian
aboriginal populations (Paunescu et al.. 2013b: Paunescu etal, 2013a). while most human studies
evaluated bone mineral density fFukushi etal.. 2016: Cho et al.. 2011: Rignell-Hvdbom etal.. 2009b:
Hodgson etal.. 2008: Weiss etal.. 2006: Wallin etal.. 2005: Glvnn etal.. 20001. One study measured
both SI and density using quantitative ultrasound parameters (Cote etal.. 2006). Bone mineral

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density was also quantified in studies of rats perinatally exposed to PCBs fElabbas et al.. 2011:
Cocchi et at. 20091. Other measurements evaluated in these rat studies included bone geometry
(e.g., cortical thickness, bone length, total area), epiphyseal cartilage width, bone mineral content,
and a range of biomechanical properties (e.g., bone strength as indicated by parameters of force,
energy absorption, and stiffness). In studies of rats exposed to PCBs as adults, endpoints evaluated
included tibia weight and femur morphometry (Andrews. 1989: Carter and Koo. 19841.

Dental abnormalities, including enamel defects, dental caries, and the occurrence of natal
and neonatal teeth, have been examined in human studies of infants and children, with most studies
using PCB levels in breast milk, blood, or serum to characterize exposure flan and Reinert. 2008:
lan et al.. 2007: Wang et al. 2003: Alaluusuaetal, 2002: Yakushiii etal. 19841. Early childhood
caries can begin soon after tooth eruption and can have a lasting detrimental impact on dentition
(e.g., higher risk of new carious lesions in both the primary and permanent teeth, enamel defects)
and an increased risk of hospitalizations and emergency room visits, lost school days (leading to
diminished ability to learn), and other markers of oral health-related quality of life (AA ).

Five studies in the database examined enamel defects and dental caries together with PCB exposure
flan and Reinert. 2008: Laisi etal. 2008: lan et al. 2007: Wang etal. 2003: Yakushiii etal. 19841.
Four of these were conducted among populations with potential for higher PCB exposure via
marine mammals and fish in the diet (lan and Reinert. 2008). regional contamination from a
manufacturing facility flan et al. 20071. maternal occupation (Yakushiii et al. 19841. and exposure
via contaminated rice oil (Yu-Cheng population) fWangetal. 20031: one was conducted among a
general population sample in Finland (Laisi etal. 20081. Finally, three studies evaluated PCB
exposure and the occurrence of natal and neonatal teeth flan et al. 2007: Wang et al. 2003:
Alaluusua et al. 20021. Dental abnormalities have also been evaluated in rats, mice, and monkeys
(see Figure 20); the primary endpoint assessed was tooth eruption, which is analogous to the
occurrence of natal and neonatal teeth in humans (Sugawara et al. 2008: Sugawara etal. 2006:
Branchi etal. 2002: Gerstenberger and Tripoli. 2001: Arnold etal. 1999: Arnold etal. 19951.

PCB exposure and arthritis have been evaluated in three human studies (see Figure 20), but
each used a different definition of arthritis. One study considered all arthritis and arthritis
subtypes, including rheumatoid arthritis, osteoarthritis, and unspecified arthritis, using data from
the NHANES fLee et al. 2007cl. In a mortality study of PCB-exposed capacitor manufacturing
workers, spondylitis arthritis was included as a noncancer cause of death (Mallin et al. 20041. In
addition, a Japanese study measured blood levels of PCBs and gout (Nakamoto et al. 20131. Due to
the limited number of studies available and the different etiologies of different arthritis types,
further investigation would be needed to support an assessment of arthritis as a potential health
effect of PCB exposure.

Overall, a limited number of epidemiological studies examined PCB exposure and
musculoskeletal endpoints. Bone density and dental abnormalities were the most studied
endpoints in humans, and together with available data from nonhuman mammalian studies, the

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available information might be sufficient to support an evaluation of potential musculoskeletal
hazards of PCB exposure, especially at higher exposure levels relative to the general population.

3.3.11. Nervous System

The nervous system is composed of the central nervous system (CNS), which includes the
brain and spinal cord and the peripheral nervous system (PNS), which includes the ganglia and
nerves outside the CNS. The CNS is the command center for a complex network of neurological
functions. In humans, higher-order brain functions involved in cognitive processes are managed in
the cerebral cortex, the gray matter on the outermost layer of the cerebrum. Specific regions in the
left and right hemispheres of the cerebral cortex, which are further divided into the frontal, parietal,
temporal, and occipital lobes, control a diverse set of functions, including language, movement,
memory, vision, and executive functions (Mai and Paxinos. 2012). The PNS primarily serves as a
conduit to connect the CNS to the periphery and other organs. The somatic (i.e., voluntary
movement), autonomic (i.e., involuntary sympathetic and parasympathetic functions), and enteric
(e.g., involuntary gastrointestinal control) nervous systems comprise the PNS. Signals from the CNS
to the periphery are relayed via motor nerves and, conversely, sensory nerves provide feedback to
the brain from the periphery.

The vulnerability of the brain to injury is well recognized and can manifest in a range of
impairments depending on the timing and location(s) of injury. The primary mode of evaluating
neurocognitive function in humans is neuropsychological assessment. Neuropsychological
assessment typically includes a battery of performance-based tests across a variety of domains
(e.g., cognition or intelligence, memory, and learning), which can be administered by a trained
psychometrician or computer administered, in a controlled setting. Assessment can also include
behavioral rating scales, which are used to assess behavior problems quantitatively such as
externalizing behaviors (e.g., aggression, hyperactivity), internalizing behaviors (e.g., anxiety,
depression), and social behavior (e.g., social skills, peer problems). These behavioral scales can be
completed in a variety of settings by a clinician, parent, caregiver, or teacher or via self-assessment.
When impairment measured across a set of specified criteria rises to a certain threshold, an
individual might be diagnosed by a clinician with a brain-related disorder, such as a
neurodevelopmental disorder (e.g., attention deficit hyperactivity disorder [ADHD] or autism
spectrum disorder [ASD]), or a neurodegenerative disorder (e.g., Alzheimer's or Parkinson's
disease). These disorders are characterized in the Diagnostic and Statistical Manual of Mental
Disorders, 5th edition (DSM-V) (APA. 2013). However, it should be noted that decrements in
neuropsychological function can result in considerable functional consequences even in the
absence of a clinically diagnosed disorder fSagiv et al. 2015: Rose. 19851.

An ever-growing literature evaluates exposures to neurotoxic chemicals in relation to
poorer cognitive and behavioral function in humans across the lifespan. Many chemicals readily
cross the placenta and can be transferred to infants via breast milk; thus, potential for exposure
starts in early gestation, when the neural tube is first forming, and continues throughout pregnancy

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as brain cells proliferate, differentiate, and migrate fGoasdoue etal. ; Barone et al. 2000: Rice
and Barone. 20001. This heightened vulnerability to neurotoxic chemical exposure continues during
synaptogenesis and myelination, processes that persist in some brain regions through early
adulthood. Among older adults, exposure to neurotoxicants can accelerate declines in cognitive
function at the subclinical level (Weiss. 20101. placing elderly individuals at potentially greater risk
of developing clinically relevant neurodegenerative disorders (e.g., Alzheimer's disease, Parkinson's
disease) (Siblerud etal.. 2019: Monnet-Tschudi etal.. 20061.

Of the epidemiological studies that met inclusion criteria, 214 evaluated PCB exposures and
neuropsychological endpoints in human adults and children (see Figure 4). Below we summarize
those studies evaluating PCB exposures with the following seven domains: (1) cognitive function;
(2) attention, impulse control, externalizing behaviors, and internalizing behaviors (including
activity level); (3) executive function; (4) social cognition and social behavior, including traits
related to ASDs; (5) motor function/development; (6) brain aging disorders; and (7) auditory
function (see Figure 21). That endpoints described in each domain are not mutually exclusive
should be noted, as they arise in an interconnected brain. For example, executive function bears
greatly on cognitive processes involved in planning and working memory and is often impaired
among individuals with ADHD and ASD. Additional endpoint categories identified in eligible studies
outside these domains include olfactory function, visual function, neurological condition, peripheral
sensation or pain, headache, dizziness, fatigue/level of consciousness, sleep problems, neurological
disease mortality, neurophysiology or neuroimaging, and play behavior (see Figure 21). However,
these endpoint categories are less informative for hazard identification because they are broadly
defined (e.g., neurological condition), provide a limited database (e.g., olfactory function, sleep
problems, play behavior), or are inherently subjective (e.g., headache, fatigue). In addition,
endpoints within the neurophysiology/neuroimaging category (e.g., sensory and motor nerve
conduction, nerve conduction velocity, event-related potentials, neuroimaging) might be most
useful to inform possible mechanisms/modes of action once specific apical nervous system effects
have been implicated. As such, this review of the human data for neurological endpoints has
focused on the aforementioned seven domains.

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Evidence Stream

Endpoint Category

Human

Other
Mammal

Attention, Impulse Control, & Externalizing/Internalizing Behaviors

Cognitive Function

Motor Function/Development

Brain Weight & Histopathology

Executive Function

Social Cognition & Social Behavior

Auditory Function

Neurophysiology/Neuroimaging

Neurotransmitter Levels

Neurological Condition

Peripheral Sensation/Pain

Level of Consciousness/Fatigue

Brain Aging Disorders

Visual Function

Neurological Disease Mortality

Headache

Dizziness

Olfactory Function

Play Behavior

Sleep Problems

Number of Studies

J 272

Figure 21. Overview of Human and Other Mammalian Nervous System Studies

Summary of the database of studies evaluating exposures to PCB mixtures and nervous system endpoints
organized by endpoint category. Lists of studies included in each count can be accessed via the online interactive
version of this figure (https://hawc.epa.gov/summarv/visual/assessment/100500282/QverviewAIIStudies/).
Shading intensity corresponds with the number of studies in each category, from 1 to 272, which is the maximum
number of nonhuman mammalian studies in any health endpoint category. The intent is to highlight not only
differences in the distribution of studies across nervous system endpoint categories but also to emphasize the
number of nervous system studies relative to the number of studies for other organs/systems.

Additionally, a database of studies is summarized that examined PCB exposures and
nonhuman mammalian behaviors that have face validity to the behavioral domains examined in the
human literature. We identified 174 published studies in mammals other than humans that
evaluated nervous system endpoints applicable to human neurobehavioral domains (see Figure 4),
including studies that examined endpoints such as neuropathology and neurochemistry (see
Figure 21). Most nervous system studies in nonhuman mammals were conducted using rat models
(see Figure 8), Endpoints have also been studied in mice, nonhuman primates, and other species. In

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most studies, PCBs were administered orally (e.g., in the diet or via oral gavage) (see Figure 9).
Fewer studies administered PCBs via alternative routes of exposure, including inhalation and
injection (e.g., intraperitoneal or subcutaneous]. As described above, the nervous system is
especially sensitive to effects of chemical exposure from the gestational period through early
adulthood, and such exposure could result in permanent disruption (Barone etal.. 20001. Thus, for
assessing potential hazard to the nervous system, it is important for a database to include studies of
exposures during this window. In the PCB database, gestational and lactational exposures were
investigated most often, with about half of these studies including evaluations of endpoints in the
adult offspring (see Figure 22). Fewer studies examined developmental PCB exposures
administered directly to juvenile animals or nervous system endpoints following adult exposures to
PCBs.

Lifestage at Endpoint Evaluation
Lifestage of Exposure Juvenile Adult

Gestational/Lactational

Juvenile

Adult

Number of Studies

Figure 22. Overview of Nonhuman Mammalian Studies of Nervous System
Endpoints by Lifestage of Exposure and Lifestage at Endpoint Evaluation

Summary of the database of studies in nonhumari mammals evaluating exposures to PCB mixtures and nervous
system endpoints organized by life stage of exposure and life stage at endpoint evaluation. Lists of studies
included in each count can be accessed via the online interactive version of this figure

(https://hawc.epa.gov/summarv/visual/assessment/100500282/NervousSvstemEndpointsNonhumanMammals/),
which can be filtered by endpoint category (options: activity levels, affective behavior, attention, auditory
function, brain weight & histopathology, cognitive function, executive function, inhibitory control, level of
consciousness, motor function/development, neurophysiology/neuroimaging, neurotransmitter levels, olfactory
function, peripheral sensation/pain, social behavior/development, visual function), exposure route (options:
inhalation, injection, oral), and species (options: guinea pig, mink, mouse, nonhuman primate, rabbit, rat, sheep,
swine). Shading intensity corresponds with the number of studies in each category, from 1 to 65, which is the
maximum number of studies in any category.

Cognition comprises the mental processes involved in a variety of functions, such as
reasoning learning, memory, and problem solving. Epidemiological studies examining PCB
exposure typically assess cognition by measuring intellectual function using Intelligence Quotient
(IQ) tests. In addition to generating a total IQ score, these tests can be grouped into verbal and
nonverbal IQ and commonly include subscales of intelligence across more specific domains, such as
working memory, processing speed, attention, and language comprehension. Some studies also

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employ domain-specific tests that assess specific aspects of cognition, such as memory, learning,
and visuospatial abilities. An advantage of domain-specific tests is that they can allow for better
localization of potential damage to the brain than an omnibus IQ score (White etal. 2009).

Sixty-nine published studies examined developmental exposure to PCBs and cognitive
function in children (some reporting results in multiple publications for the same study population)
(see Figure 23). In most of these studies, primarily prospective cohort studies (see Figure 6), PCB
exposure was measured in biological media during the prenatal period (e.g., umbilical cord
serum/plasma, maternal serum/plasma collected during pregnancy) or in the early
postnatal/childhood period (e.g., breast milk, serum/plasma collected in children) (see Figure 7).
Many of these studies evaluated infant and toddler cognition using scales such as the Bayley Scales
of Infant Development and the Fagan Testof Infant Intelligence [e.g., (Lynch et al. 2012: Park et al,
2010: Wilhelm et al, 2008b: Walkowiaketal, 2001: Darvill etal. 2000: Winneke et al. 1998:
Koopman-Esseboom et al. 1996: Rogan and Gladen. 1991: Yu et al. 1991: Gladen etal. 19881].
Using slightly different instruments, these studies all capture aspects of cognition during
infancy/toddlerhood, allowing for potential hazard identification across numerous studies.
However, results from studies of neuropsychological measures of infants and toddlers can be noisy
due to difficulty in achieving a desired state for testing in younger children; results in older children
are more reliable (Skovgaard et al. 2004). Several studies evaluated developmental PCB exposure
and general intelligence scales in older, school-age children using tests such as the Wechsler Scale
for Intelligence in Children and the McCarthy Scales of Children's Abilities [e.g., fGrandiean et al.
2012b: Zhou et al. 2011a: Zhou et al. 2011b: Stewart et al. 2008: Gray etal. 2005: lacobson and
lacobson. 2002: Vreugdenhil et al. 2002: lacobson and lacobson. 1996: Chen et al. 1992: Yu etal.
19911], In addition to full-scale IQ, these tests often report domain-specific subscales that assess
verbal and nonverbal intelligence, processing speed, and visuospatial skills. This large database of
studies on IQ provides one of the best opportunities for assessing potential associations of PCB
exposure with neurodevelopment. As mentioned above, however, a downside of these omnibus
measures is that they might not capture effects on specific intellectual domains, such as working
memory and visuospatial skills. Several of these studies and others did use domain-specific
neuropsychological tests to assess specific cognitive skills, such as memory and learning, and
academic performance fWangetal. 'JO lr>: Orenstein etal. 2014: Grandiean etal. 2012b: Roze et
al. 2009: Newman et al. 2006: Vreugdenhil et al. 2004a: lacobson and lacobson. 2003: Patandin et
al. 1999: lacobson etal. 1992: lacobson etal. 1990). Only a few studies reported on developmental
exposure to PCBs and academic achievement (Strain etal. 2014: Gladen and Rogan. 1991). learning
disabilities flee et al. 2007al. and intellectual disability fHainra et a ; all etal. 20171. The

smaller body of literature on these individual cognitive abilities might make hazard identification
more difficult for these domain-specific functions.

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Exposure Lifestage

Nervous System Endpoint Category

Developmental

Adult

Cognitive Function

Motor Function/Development

Attention, Impulse Control, S Externalizing/Internalizing Behaviors

Executive Function

Neurological Condition

Social Cognition & Social Behavior

Peripheral Sensation/Pain

Neurophysiology/Neuroimagirtg

Brain Aging Disorders

Auditory Function

Visual Function

Neurological Disease Mortality

Headache

Fatigue

Dizziness

Play Behavior

Sleep Problems

Olfactory Function

Number of Studies

Figure 23. Overview of Human Studies of Nervous System Endpoints by
Endpoint Category and Exposure Lifestage

Summary of the database of human studies evaluating exposures to PCB mixtures and nervous system endpoints
organized by endpoint category and life stage of exposure assessment. Lists of studies included in each count can
be accessed via the online interactive version of this figure

(https://hawc.epa.gov/summarv/visual/assessment/100500282/NervousSvstemEndpointsHumans ), which can
be filtered by study design (options: case-control, cohort, cross-sectional, other), population (options: accidental,
contaminated schools and other buildings, fish/marine mammal [diet], general population, occupational,
residents in contaminated area, Yusho/Yu-Cheng), exposure metric (options: blood, breast milk, child blood, cord
blood, dietary estimates, maternal blood, occupational/JEM, other metric [includes dust and modeled estimates],
other tissue), and lifestage of endpoint evaluation (options: adolescent, adult, child, early childhood, infant, NR).
Shading intensity corresponds with the number of studies in each category, from 1 to 69, which is the maximum
number of studies in any category.

Fifteen published studies (some reporting results in multiple publications for the same
cohort) assessed PCB exposure and cognitive function among adults (see Figure 23). Among these,
most were cross-sectional, and the remaining study designs were retrospective cohort fLin etal..

2010: Lin etal.. 20081. prospective cohort (Tanner etal.. 20201. and case-control (Kilburnetal.
19891. PCB exposure was measured primarily in biological media

(e.g., serum/plasma/blood/tissue) collected concurrent with or after exposure. Several studies
assessing cognition were conducted among occupationally exposed subjects, primarily related to
production of electrical capacitors (Fimm etal.. 2017: Seegal et al.. 2013: Seegal. 2011: Kilburn et
al. 1989: Fischbein et al. 19791. and among adults primarily exposed through consumption of

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contaminated fish fScfaantz et ai. 20011 or rice oil (i.e., Yu-Cheng) flirt etal. 2010: Lin et al. 20081.
The studies most informative for hazard identification are those using reliable, validated test
instruments of cognitive function, such as the Wechsler Adult Intelligence Scale (WAIS) and the
Wechsler Memory Scale (WMS). Eight studies evaluated exposure to PCBs and cognition using the
WAIS (Tanner etal. 2020: Przybvla etal.; ; Sou chard etal. 2014: Seegal etal. 2013: Lin etal.
2010: Lin et al. 2008: Peper etal. 2005: Kilburn et al. 19891. and eight used the WMS (Tanner et
al. 2020: Seegal et al. 2013: Haase et al. 2009: Fitzgerald et al. 2008: Lin etal. 2008: Peper et al.
2005: Schantz etal. 2001: Kilburn et al. 19891. In addition to the WAIS and WMS, the California
Verbal Learning Test (CVLT), a well-known, validated test of verbal learning and memory that can
also inform PCB hazard assessment among adults, was used in five studies (Tanner etal. 2020:
Fimm et al. 2017: Seegal et al. 2013: Fitzgerald etal. 2008: Schantz et al. 20011.

Within the database are 42 nonhuman mammalian studies that evaluated cognitive function
in a variety of species, including rodents and nonhuman primates (see Figure 21, Figure 8). Of
these, most evaluated cognitive function in offspring exposed to PCBs during the gestational or
lactational period (see Figure 24). Eleven studies investigated cognitive endpoints following direct
PCB exposure in juvenile or adult mammals. Many cognitive tests measure spatial learning and
memory; the most common of these assays include the Morris water maze (MWM), radial arm maze
(RAM), spatial alternation (sometimes referred to as reversal learning), and novel object
recognition assays (NOR; sometimes referred to as object-based attention). The MWM, RAM, and
spatial alternation assays are well established in animal models fWenk. 20041. NOR assays can
additionally provide insight into attention and internalizing/externalizing behaviors (Vogel-Ciernia
and Wood. 20141. Many of the included studies evaluated spatial learning and memory using these
tests, including four studies in nonhuman primates fRice. 1998: Schantz et al. 1989: Levin etal.
1988: Bowman et al. 19781] and many others in rodents [e.g., (Nam etal. 2014: Elnar et al. 2012:
Tian etal. 2011: Yang etal. 2009: Sugawara etal. 2006: Zahalka etal. 2001: Gilbert et al. 2000:
Roegge etal. 2000: Corey et al. 1996: Lilienthal and Winneke. 19911], Other tests of cognitive
function, learning, and memory include operant paradigms (e.g., nonspatial reversal learning, fixed
interval, progressive ratio, differential reinforcement of low/high rate, attention set-shifting,
Wisconsin card sorting task, passive/active avoidance). Operant paradigms are considered robust
for testing learning and memory in animals and have face validity to cognitive responses in humans.
The database contains many studies that used operant-based tests in mammals, including seven
studies in nonhuman primates (Rice and Hay ward. 1999: Rice. 1998.1997: Rice and Havward.
1997: Schantz etal. 1989: Mele etal. 1986: Bowman etal. 19781 and others in rats [e.g., (Monaikul
et al. : viever et al. 2015: Sable etal. 2006: Widholm etal. 2004: Bushnell et al. 2002: Berger
et al. 2001: Geller etal, 2001: Widholm etal. 2001: Nishida et al. 1997: Lilienthal et al. 19901],

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Endpoint Category

Evidence Stream
Other Mammal

Attention, Impulse Control, 8 Activity Levels
Externalizing/Internalizing Affective Behavior

Behaviors ... ..

Attention

Inhibitory Control

Brain Weight 8 Histopathology

4
23

Cognitive Function

Motor Function/Development

Executive Function

Neurotransmitter Levels

Auditory Function

Social Cognition 8 Social Behavior

Neurophysiology/Neuroimaging

Level of Consciousness/Fatigue

Peripheral Sensation/Pain

"Behavioral Function"

Olfactory Function

Visual Function

Gestational/Lactational

Lifestage of Exposure
Juvenile

Adult

Number of Studies

Figure 24. Overview of Nonhuman Mammalian Studies of Nervous System Endpoints by Endpoint Category and
Lifestage of Exposure

Summary of the database of studies in nonhuman mammals evaluating exposures to PCB mixtures and nervous system endpoints organized by endpoint
category and lifestage of exposure. Lists of studies included in each count can be accessed via the online interactive version of this figure

(https://hawc.epa.gov/summarv/visual/assessment/100500282/NervousSvstemEndpointsNonhumanMammals;). which can be filtered by exposure route
(options: inhalation, injection, oral), species (options: guinea pig, mink, mouse, nonhuman primate, rabbit, rat, sheep, swine), lifestage at endpoint evaluation
(options: adult, juvenile), and lifestage of exposure (options: adult, gestational/lactational, juvenile). Shading intensity corresponds with the number of studies
in each category, from 1 to 69, which is the maximum number of studies in any category.

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Another category of endpoints captures behaviors related to ADHD, including attention and
externalizing behaviors such as impulsivity/hyperactivity; other externalizing behaviors, such as
aggression and disruptive behaviors that, at the extreme, are characteristic to disorders such as
conduct disorder and internalizing behaviors such as anxiety and depression. Evaluating many of
these behaviors in children involves using behavioral rating scales completed by the parent or the
teacher. Behaviors rated include inattention, impulsivity/hyperactivity and other externalizing
behaviors, and internalizing behaviors like anxiety. A limitation of these behavioral rating scales is
that they are subjective and introduce risk for informant bias fEmser et al. 2018: Edwards etal.
20071. However, they are valuable for assessing child behavior problems across different
environments and can provide information for assessing PCB exposures and problem behaviors
such as inattention, hyperactivity/impulsivity, and internalizing behaviors. Performance-based
tests, used to measure sustained attention and response inhibition, are conducted with reaction
time tests or continuous performance tests. For these assessments, which are typically computer
based, the individual must attend to a continuous activity or stimulus, respond to target stimuli, and
inhibit response to nontarget stimuli. These tests have the advantage of being a more objective
measure of behavior than behavioral rating scales but offer only a snapshot of behavior at a single
time point in a single environment and therefore do not reflect behavior across different settings
(e.g., home, school).

PCB exposures during the prenatal/early postnatal periods and endpoints associated with
attention, impulse control, and externalizing/internalizing behaviors were evaluated in 43 studies
(see Figure 23). Many of these studies assessed attention and response inhibition with
performance-based tests [e.g., fNeugebauer etal.. 2015: Boucher etal.. 2012a: Forns et al. 2012:
Grandiean etal. 2012b: Roze et al. 2009: Stewart et al. 2006: Stewart et al. 2005: Vermeir et al.
2005: lacobson and lacobson. 2003: lacobson et al. 1992)]. Although the type of test varied, most
produce measures of reaction time, reaction time variability, errors of omission, and errors of
commission, which are markers of attention and response inhibition. Thus, this large number of
studies provides an opportunity to evaluate potential PCB exposure hazard for these functions.
Many studies also investigated developmental PCB exposure and behavioral rating scales [e.g.,
fForns et al. 2016: Kvriklaki et al. 2016: Zhang et al. 2016: Wang etal. 2015: Newman et al. 2014:
Boucher et al. 2012b: Tatsuta etal. 2012: Sagiv etal. 2010: Roze et al. 2009: Chen et al. 19941],
Only three studies investigated developmental exposure to PCBs and parent reports of ADHD
diagnosis or stimulant medication use (Lenters et al. 2019: Strain et al. 2014: Lee etal. 2007al.
Thus, few data are available for assessing potential associations of developmental PCB exposure
with clinically diagnosed ADHD, but a greater database enables the evaluation of potential effects
on quantitative traits related to ADHD.

Twenty studies evaluated PCB exposure and attention and externalizing/internalizing
behaviors among adults (see Figure 23). Among this group of studies, most were cross-sectional,
seven were cohort in design, and one was a case-control study. PCB exposure was based on

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measurements in biological media in all studies (e.g., serum, plasma, blood, tissue). Seven studies in
adults evaluated exposure to PCBs and the WAIS digit symbol substitution/coding test, a reliable
measure of attention that is informative for assessing potential PCB hazard (Tanner etal. 2020:
Przvbvla et al, 2 ; tuchard etal. 2014: Fitzgerald et al, 2008: Lin etal. 2008: Peper etal.
2005: Schantz et al. 20011. Several studies assessing internalizing behaviors were conducted
among occupationally exposed subjects (see Figure 23), primarily related to production of electrical
capacitors (Gaum et al. 2019: Fimm et al. 2017: Gaum etal. 2017: Esser et al. i ; sser etal.
2014: Gaum et al. 2014: See gal etal. 2013: Kilburn etal. 1989: Fischbein et al. 19791 or among
adults exposed to PCBs through the air fPeper et al. 20051 or diet fSchantz et al. 20011. Most
studies examining PCB exposure and internalizing behaviors (e.g., depression, anger, and anxiety)
used validated self-report symptom questionnaires, such as the Beck Depression Inventory (BDI)
(Tanner et al. 2020: Gaum et al. 2017: Seegal etal. 2013: Fitzgerald et al. 20081. State-Trait
Anxiety Inventory (STAI) fTanner et al. 2020: Seegal et a ; zgerald et al. 20081. Geriatric

Depression Scale (GDS) (Lin etal. 20081. EQ-5D-3L (Esser et al. 2015: Esser et al. 20141. Symptom
Checklist-90-Revised (SCL-90-R) fSantiago-Rivera et al. 20071. Center for Epidemiologic Studies
Depression Scale (CES-D) fSantiago-Rivera et al. 20071. and Patient Health Questionnaire (PHQ-D)
(Gaum et al. 2019: Gaum etal. 20141.

In animals, information about attention can be derived from cognitive function tasks,
including object-based attention tasks such as NOR. In these tests, a reduction in time interacting
with an object can be interpreted as a deficit in attention. These assays also overlap with other
aspects of cognitive function, such as short-term visual memory. Four nonhuman mammalian
studies in the database specifically evaluated PCB exposures and NOR or object-based attention
(see Figure 24).

As in humans, impulsivity and inhibitory control can be measured in animals using several
operant behavioral paradigms, such as differential reinforcement of low-rate, fixed-interval,
progressive-ratio, fixed-ratio, and reversal tasks (Mitchell. 2014: Barrett and Vanover. 2004: Arnold
et al. 20031. These assays — considered "gold standard" tests of impulsivity and attention — can
detect subtle shifts in inhibitory control in the form of perseverative errors, and other output
metrics can additionally be used to evaluate learning, working memory, and cognitive flexibility
over time. Twenty-three studies in the database measured inhibitory control using operant or
object-based attention assays in nonhuman primate or rodent models (see Figure 24). Sixteen
studies evaluated these endpoints in nonhuman mammals exposed through gestation or lactation,
while seven studies evaluated direct PCB exposures to juvenile mammals, including four studies in
nonhuman primates that evaluated direct exposure during the pre weaning period fRice and
Havward. 1999: Rice. 1998.1997: Rice and Havward. 19971.

Hyperactivity is considered a type of externalizing behavior and can be measured directly
by measuring the distance traveled by rodents in spontaneous locomotor and open field assays,
which are common "gold standard" behavioral paradigms (Pierce and Kalivas. 2007). Indirect

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measures of hyperactivity include measurement of movement in tests designed to assess other
behavioral domains (e.g., MWM), although such activity measurements relate more to general
motor function and have minimal validity for evaluating externalizing behavior. Thirty-eight
studies provided data on general activity levels with PCB exposure, including spontaneous
locomotor activity, open field, and activity levels in other assays using nonhuman primates, rats,
and mice (see Figure 24). Most studies evaluated developmental PCB exposure via the dam while
the remaining studies assessed direct juvenile or adult exposure. Although a relatively large
number of studies measured PCB exposure and activity levels, further scrutiny of study methods
and endpoint reporting would be needed to identify those most valid for evaluating
externalizing/internalizing behaviors.

Open field and spontaneous locomotor behavior assays are well-established methods that
can provide insight into emotional state and affect in rodents as they tend to avoid open spaces.
Thus, assessing where in the arena animals travel (along the edges vs. in the center) can provide
insight into shifts in an animal's behavior toward risk-taking or risk-aversive (i.e., anxiety-like)
emotional states. The elevated plus maze (EPM) and elevated zero maze (EZM) are also used to
determine emotional reactivity and risk-taking behavior in rodents fBraun et al. 2011: File etal.
2004). Thirty-nine studies tested affective behavior with PCB exposure (see Figure 24). Many
rodent studies used "gold standard" assays, including the open field test, usually following
developmental PCB exposure via the dam [e.g., (Nam etal. 2014: Elnar etal.. 2012: Tian et al. 2011:
Sugawara et al. 2006: Meerts etal. 2004b: Branchi et al. 2002: Lilienthal et al. 1990: Pantaleoni et
al. 1988: Storm etal. 1981)]. but also in one study of male rats exposed during adolescence (Casey
et al. 19991 and in four studies evaluating adult exposure fBavithra et al. 2017: Sumathi etal.
2016: Selvakumar et al. 2013: Freeman et al. 20001. Other studies tested performance in a
spontaneous locomotor behavior assay in rodents or nonhuman primates, with six studies
evaluating developmental exposure via the dam (Colciago etal. 2009: Steinberg et al. 2007: Goldev
aj 1998: Bowman and Heironimus. 1981: Bowman etal. 1981: Bowman et al. 1978) and

one study evaluating adult exposure fFreeman et al. 20001. Eight studies evaluated rodents in the
EPM or EZM, seven evaluating developmental exposure via the dam (Gillette etal.; ; ell etal.
201.6; Nam et al. 2014: Elnar etal. 2012: Curran etal. 2011a: Tian et a ; ilciago etal.

20091. and one study evaluating adult exposure fBavithra etal. 20171.

Executive function is a multidimensional construct involved in higher-order cognitive and
behavioral processes; it is critical for planning, problem solving, sustaining attention, and inhibitory
control. These functions underlie goal-oriented behavior and emotional regulation, and can have
important implications for academic achievement, social behavior, risk-taking behavior, and
socioeconomic attainment. Features of executive function that have been covered in other endpoint
categories are not included below. For example, sustained attention and response inhibition
(measured with continuous performance tests), both of which are core features of executive
function, were included under the attention, externalizing behaviors, and internalizing behaviors

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category and are not described here. In addition, some tests of working memory, another seminal
feature of executive function, were included under cognitive function (e.g., Working Memory
subtest of the Wechsler Scale for Intelligence in Children).

Eight human studies evaluated PCB exposures during the prenatal/early postnatal periods
and measures of executive function (not included in other endpoint categories) (see Figure 23).
These include skills around planning and organization [e.g., (Rocha-Amador et al. 2009:
Vreugdenhil et al, 2004a)]. cognitive flexibility [e.g., (lacobson and lacobson, 2003)]. and working
memory [e.g., flacobson and lacobson. 2003: lacobson etal. 19921], Twelve studies evaluated PCB
levels measured in biological (e.g., serum, plasma, blood, tissue) or environmental media during
adulthood and measures of executive function (not included in other endpoint categories) (see
Figure 23). Among these 12 studies, most were cross-sectional, 2 were retrospective cohort (Lin et
al.. 2010: Lin etal. 2008). 1 was prospective cohort (Tanner etal. 2020). and 1 was case-control
fKilburn et al. 19891. Several studies in adults evaluated exposure to PCBs and tests of executive
function that are informative for assessing potential PCB hazard, including the Wisconsin Card
Sorting Test fTanner etal. 2020: Seegal etal. 2013: Haase etal. 2009: Fitzgerald etal. 2008:
Schantz et al. 20011. the Trail Making Test fTanner et al. 2020: Fimm etal. ; ?al etal.
2013: Haase etal. 2009: Fitzgerald et al. 2008: Peper etal. 2005: Schantz et al. 2001: Kilburn et
al. 1989). the Stroop Color and Word Test fTanner et al. 2020: Seegal et al. 2013: Haase etal.
2009: Fitzgerald et al. 2008: Schantz et al. 2001). and the Short Category Test (Schantz etal.
20011. Overall, several well-designed studies administered reliable tests of executive function in
developmental and adult populations that should provide sufficient evidence for potential hazard
identification of PCBs and executive function.

Nonhuman mammalian studies that examined PCBs and executive function used delayed
spatial alternation (DSA), reversal learning/alternation (e.g., operant-based tasks, Y-maze, T-maze),
and attention set-shifting (e.g., Wisconsin card sorting test in nonhuman primates, cued operant
tests in rodents). Such assays can detect subtle shifts in executive function domains commonly
perturbed in human neurodevelopmental disorders, such as ASD and ADHD. Twenty-one studies
reported evaluations of executive function (see Figure 21), including 9 that investigated DSA,
reversal learning, or attention set-shifting in nonhuman primates fRice. 1998: Rice and Havward.
.1997; Schantz etal. 1989: Levin et al. 1988: Bowman etal. 19781 and rats fMever etal. 2015:
Widholm et al. 2004: Widholm et al. 2001: Zahalka et al. 2001) and 14 that evaluated executive
function through operant-based tasks in nonhuman primates (Rice and Havward. 1999: Rice. 1997:
Mele et al. 1986) and rats (Miller et al. 2017b: Monaikul et al. 2017: Lombardo etal. 2015: Mever
et al. 2015: Sable et al. 2006: Widholm et al. 2004: Bushnell et al. 2002: Tavlor et al. 2002: Berger
et al. 2001: Geller etal, 2001: Lilienthal et al, 1990). Of these executive function studies (see
Figure 24), 14 were conducted using developmental exposures via the dam, and 7 evaluated direct
exposure to young animals, including 4 that administered PCBs directly to neonatal nonhuman
primates (Rice and Havward. 1999: Rice. 1998.1997: Rice and Havward. 1997) and 3 that

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evaluated exposure to adolescent rats fMonaikul etai. 2017: Lombardo et a I,. 'J 01 r>: Merger et ai.
20011. The administered tests are considered "gold standard" and have suitable face validity to the
abovementioned tests that assess human executive function.

ASD is characterized by restricted interests and behaviors, including stereotyped patterns
of behavior, sensory sensitivities, and circumscribed interests. Social cognition, which is often
impaired among individuals with ASD, involves the ability to interpret and respond to social cues,
communication, and interaction. These traits (or behaviors) can be measured on a continuum in the
general population using tests such as the Social Responsiveness Scale (SRS); scores exhibit a fairly
normal distribution with those at the extreme impaired end indicating higher risk for ASD
(Constantino. 2011). Deficits in social cognition have been associated with lifelong educational,
vocational, adaptive functioning, and mental health challenges among individuals with and without
a clinically diagnosed disorder. Social behavior and traits related to ASD can be measured using
behavioral rating scales, observation, and performance-based tests, such as tests of theory of mind.

Fourteen human studies evaluated PCB exposure during the prenatal/early postnatal
periods and social behavior and other traits related to ASD (see Figure 23). These include seven
studies of clinically diagnosed ASD fBach et ai. 2020: Granillo etal. 2019: Hamra etal. 2019:

Brown etal, 2018: Lvall et ai, 2017: Cheslack-Postava etal. 2013: Otake etal. 2006) and seven
studies of quantitative traits related to ASD, assessed using behavior rating scales (Alampi et ai.

; rnardo et ai. 2019: Kim et ai. 2018: Nowack et ai. 2015: Braun et ai. 2014: Doi et ai.
2013: Plusauellec et ai. 20101. Two studies assessed PCB exposure and social behavior and other
traits related to ASD among adults. One was an occupational study evaluating two measures of
social behavior, the Freiburg Personality (FPI-R) and aggregated secondary factors (introversion,
low sociability) fPeper et ai. 20051. The other included individuals stated to have ASD in a
postmortem brain study (Mitchell etal. 2012): however, no information was reported for how ASD
was determined. The few studies on PCBs and social behavior and the diversity in assessment
methods could make hazard identification challenging.

Nonhuman mammalian studies could supplement the small human database but modeling
social cognition and social behavior in animals presents unique challenges in that many aspects of
human social interaction are not recapitulated in other species, especially rodent species fYang et
ai. 20111. However, researchers can take advantage of species-specific social interactions to assess
animal social behaviors that have face validity to aspects of human social behaviors, such as social
approach/social novelty assays (Mathiasen and Dicamillo. 2010: Winslow. 2003). social-
conditioned place preference (SCPP) (Pearson etal. 2012). and maternal behavior (Lucion and
Bortolini. 20141. In addition, some aspects of reproductive behaviors rely on social cognition and
can be assessed in rodents by measuring ultrasonic vocalizations (USVs) between opposite-sex
conspecifics fBarfield et ai. 19791 or through paced mating tests fZipse etal. 20001.

Fifteen studies in the database evaluated PCB exposures and social behavior in rodents (see
Figure 21). Of these, five studies evaluated social approach/social novelty (Reillv et ai. 2018:

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Karkabaetal. 2017: Belletat. 2016: Reillvetal. i'jitini etal. 19901. five measuredUSVs in
social or sociosexual contexts fKrisfanan et al. 2019: Topper etal. 2019: Krishnan etal. 201 8: Bell
et al. 2016: Steinberg et al. 20071. four evaluated paced mating behavior (Krishnan et al. 2018:
Steinberg etal. 2007: Chung etal. 2001: Chung and Clemens. 19991. three investigated maternal
behavior (Krishnan et al. 2019: Elnar etal. 2012: Brezner et al. 19841. and two studies assessed
mate preference (Hernandez Scudder etal. 2021: Hernandez Scudder etal. 20201. With the
exception of four studies conducted following adult exposure and one study assessing juvenile
exposure, most studies of social behavior evaluated offspring following developmental exposure via
the dam (through prenatal or lactational exposure) (see Figure 24). Although relatively few
nonhuman mammalian studies examined PCB exposures and specific aspects of social behavior, the
existing studies were well conducted and can supplement human study observations, especially in
assessments of the potential effect(s) of developmental PCB exposure on social behavior.

Forty-seven studies in humans evaluated PCB exposures during the prenatal/early
postnatal periods and motor function (see Figure 23). Of these, most assessed motor function of
infants or toddlers, primarily using the Bayley Scales of Infant Development, Psychomotor
Development Index (PDI) [e.g., fKuel et al. 2019: Kim et al. 2018: Brucker-Davis et al. 2015:

Gascon etal. 2013: Park et al. 2009: Wilhelm et al. 2008a: Daniels et al. 2003: Walkowiaketal,
2001: Koopman-Esseboom etal. 1996: Rogan and Gladen. 19911], Only 13 studies of PCBs
examined gross/fine motor function in older children (Boucher etal. 2016: Haver et al. 2015:
Sovcikova etal. 2015: Wang etal. 2015: Grandiean etal. 2012b: White etal. 2011: Plusauellec et
al. 2010: Roze et al. 2009: Vermeir etal. 2005: Winneke etal. 2005: Vreugdenhil et al. 2004a:
lacobson and lacobson. 2003: Vreugdenhil et al. 20021. Overall, more data are available to inform
hazard assessment for motor endpoints in infants and toddlers, although there are caveats of
measuring these functions in early childhood, as noted earlier3.3.11. The few studies and lack of
diversity in tests of these functions could make hazard identification challenging for fine/gross
motor function in older children.

Eighteen studies evaluated PCB levels in biological (e.g., serum, plasma, blood, tissue) or
environmental media during adulthood and endpoints associated with motor function (see
Figure 23). Among these, eleven were cross-sectional, six were cohort studies, and one was case-
control. Among these 18 studies, 8 used reliable instruments that would be most informative for
assessing potential hazard, such as the Grooved Pegboard Test, Finger Tapping Test, Static Motor
Steadiness Test, and Motor Performance Series (Gaum et al. 2021: Tanner etal. 2020: Fimm et al.
2017: Seegal et al. 2013: Haase etal. 2009: Fitzgerald et al. 2008: Lin etal. 2008: Kilburn et al.
19891. All but one of these studies fKilburn etal. 19891 were conducted in samples with more than
100 participants.

Tests for motor activity and coordination are one of the most common types of assays
performed in animal models of developmental neurotoxicity. Tests that measure motor function
directly in juvenile or adult animals include spontaneous locomotor activity, open field, rotarod,

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beam walking, and gait analysis fPierce and Kalivas. 2007: Carter etal. 20011. Aspects of motor
activity can also be derived from other assays that track the animal's motion automatically
(e.g., tests that use mazes or multichambered arenas). Spontaneous locomotor activity and open
field assays are considered "gold standard" tests of motor activity and also can measure aspects of
emotional reactivity or habituation on the basis of if, where, and how the animal moves in the arena
over time.

The database includes 42 studies that measure motor function and coordination in
mammals other than humans (see Figure 21) through assays of behaviors such as locomotor
activity [e.g., fWafalangetal. 2016: Steinberget al. 2007: Sugawaraetal. 2006: Roegge etal. 2004:
Nishida et al, 1997: Goldev et al. 1 ; remiann et al. 1987: Bowman and Heironimus. 1981:
Bowman etal. 1981: Bowman et al. 1978)]. open field [e.g., (Sumathi et al. 2016: Elnar etal. 2012:
Curran etal. 2011a: Sugawara etal. 2008: Meerts et al. 2004b: Branchi et al. 2002: Freeman et al.
2000; Pantaleoni etal. 1988: Storm etal. 19811], rota rod fBavithra et ; umathi etal.

2016: Nguon et al. 2005a: Nguon et al. 2005b: Fanini et al. 1990: Rosin and Martin. 1981). walking
behaviors f Sugawara etal. 2008: Sugawara et al. 20061. and gait analysis fBushnell et al. 2002:
Bruckner et al. 19731. Like humans, rodents exhibit certain motor reflexes in response to stimuli,
and alterations in these reflexes can indicate possible disruption of motor neural pathways. Assays
that evaluate motor reflexes include surface righting [e.g., (Wei et al. 2015: Tewari etal. 2009:
Sugawara et al. 2008: Nguon et al. 2005a: Bowers etal. 2004: Branchi etal. 2002: Bushnell etal.
2002: Gerstenberger and Tripoli. 2001: Pantaleoni etal. 1988: Overmann etal. 19871], negative
geotaxis (Wei et al. 2015: Elnar et al. 2012: Sugawara et al. 2008: Sugawara etal. 2006: Nguon et
al. 2005a: Bowers et al. 2004: Branchi et al. 2002: Gerstenberger and Tripoli. 2001: Pantaleoni et
al. 1988: Overmann et al. 19871. cliff avoidance fWei etal. 2015: Sugawara et al. 2008: Sugawara
et al. 2006: Pantaleoni et al. 1988). and grasping reflex (Sugawara etal. 2008: Sugawara etal.
2006: Branchi etal. 2002). Motor and coordination tests can be performed in both juvenile and
adult animals and are useful in characterizing both developmental and adult exposures (see
Figure 24). Overall, the database of studies evaluating PCB exposure and motor activity and
coordination in nonhuman mammalian models is quite robust.

Thirteen human studies evaluated PCB levels in biological media (i.e., serum, plasma, blood,
cerebrospinal fluid, tissue) during adulthood and endpoints associated with brain aging disorders
(see Figure 23). Among these 13 studies, 6 were case-control, 4 were cross-sectional, and 3 were
prospective cohort studies. Eight of these studies assessed PCB exposure and Parkinson's disease
with varying disease assessment methodology (Raffetti etal. 2020: Hatcher-Martin et al. 2012:
Weisskopf et al. 2012: Seegal. 2011: Petersen etal. 2008: Koldkiaer etal. 21 ; an et al.
2000: Corrigan etal. 1998). Seven studies assessed PCB exposures and dementia (e.g., Alzheimer's
Disease) fRaffetti et al. 2020: Medehouenou etal. 2019: Medehouenou etal. 2014: Hatcher-Martin
et al. 2012) or amyotrophic lateral sclerosis (ALS) (Goutroan etal. 2019: Vinceti et al. 2017: Su et
al. 2016). Overall, the relative paucity of human studies examining PCB exposures and brain aging

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disorders, heterogeneity of endpoints assessed, including methodology for endpoint evaluation,
and a small number of cases in several studies, indicate the database is unlikely sufficient for
hazard identification. No studies meeting PECO in nonhuman mammalian models of brain aging
disorders were identified.

Twelve studies evaluated auditory function and PCB exposures in humans (see Figure 21).
Half of these were either cross-sectional (Trnovec etal. 2010: Trnovec etal. 20081 or prospective
(Kostiakova et al, 2016: Palkovicova Murinova et al, 2016: Sisto et al, 2015: lusko et al, 20141
performed in (sometimes overlapping) groups of children in eastern Slovakia. These studies used
otoacoustic emission testing along with other indicators of auditory function including pure tone
audiometry. The remaining references report on prospective studies in birth cohorts from the
Netherlands (Vreugdenhil etal, 2004b). the Faroe Islands (Grandiean etal. 2001) and the United
States (two related studies performed in the same cohort (in et al. 2017: Longnecker et al. 2004)1.
One study was performed in children from the Yu-Cheng population fii et al. 20151. and only one
study was conducted among adults, in the cross-sectional NHANES survey (Min et al. 2014).
Endpoints evaluated in these studies included hearing thresholds and impairment evaluated using
audiometry and otoacoustic emissions.

Auditory function was assessed in 15 studies in rats (see Figure 21). Many studies
measured auditory thresholds using methods such as reflex modification audiometry, distortion
product otoacoustic emissions, and auditory evoked brainstem responses [e.g., (Powers etal. 2009:
Powers etal. 2006: Meerts et al. 2004b: Laskvetal. 2002: Herr et al. 2001: Crofton etal. 2000a:
Crofton et al. 2000b: Goldev and Crofton. 1998: Herr etal. 1996: Goldev et al. 19951], Three
studies evaluated the acoustic startle response (ASR), which can provide a relatively crude measure
of hearing sensitivity fNgiion et al. 2005a: Bushnell et al. 2002: Overmann et al. 19871: however,
an altered ASR might also reflect changes in motor function or emotional state. All 15 studies
evaluated developmental PCB exposure via the dam (see Figure 24), including 1 study with a cross-
fostering design (Crofton et al. 2000b). which enables evaluation of gestational, lactational, and
perinatal exposures independently. Although relatively few studies examined auditory function in
PCB-exposed mammals, the existing studies were well conducted, and most used specific and
quantitative endpoint evaluation methods. These studies can be used to supplement the human
studies of auditory function, especially when evaluating potential effects of developmental PCB
exposures.

Changes in brain structure and neurotransmitter levels are thought to contribute to deficits
in behavior, including deficits in the behavioral domains discussed above. Fourteen human studies
and nine studies in rats or mice evaluated PCB exposure and neurophysiology (e.g., sensory and
motor conduction, nerve conduction velocity, event-related potentials) or neuroimaging (see
Figure 21, Figure 8). Sixty-nine studies assessed PCB exposures and brain structure at varying
levels of biological organization in rats, mice, nonhuman primates, and other nonhuman
mammalian species, and 21 studies measured neurotransmitter levels in the brains of PCB-exposed

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rats, mice, nonhuman primates, and mink (see Figure 21, Figure 8). These endpoint categories
contain more studies evaluating PCB exposures in adult mammals compared with the behavioral
domain endpoints (4 human studies of neurophysiology/neuroimaging [see Figure 23], 1 study of
neurophysiology in nonhuman mammals [Figure 24], 36 studies of brain structure in nonhuman
mammals [see Figure 24], and 14 studies of neurotransmitter levels in nonhuman mammals [see
Figure 24]). Eleven studies of neurophysiology or neuroimaging were conducted in human children
or adolescents (see Figure 23), and studies evaluating developmental exposure via the dam also
comprise a large proportion of the nonhuman mammalian studies in this category (8 studies of
neurophysiology, 35 studies of brain structure, and 5 studies of neurotransmitter levels), although
a subset of studies assessed brain morphology and neurotransmitter levels following direct juvenile
exposure (see Figure 24). Overall, the database contains many studies characterizing PCB exposure
and neurophysiology, neuropathology, and neurotransmitters and can be considered robust for
hazard identification. However, many endpoints in these categories are more mechanistic and
might be most useful for informing subsequent analyses of possible mechanisms/modes of action.
Variation in the specific neurotransmitters and histopathological or neurophysiological endpoints
evaluated is also considerable; therefore, the comparison of results between studies might be
limited. Further, as neuropathology and neurotransmitters are not usually evaluated in humans,
and the extent of species differences is not yet fully understood, these data might have unclear
human relevance. Another limitation is that not all studies that characterized neurophysiology,
brain structure/histology, or neurotransmitter levels also conducted behavioral assays. Therefore,
the behavioral correlate(s) of observed molecular changes might yet be unknown.

In summary, the human and nonhuman mammalian databases provide sufficient
information to evaluate the potential for PCB-associated nervous system effects in several
behavioral domains. Specifically, numerous studies were identified that use well-accepted and
validated measures of cognitive function, attention, impulse control, externalizing and internalizing
behaviors, motor function, and executive function across the lifespan. In addition, the existing
database is likely sufficient to make a determination regarding potential effects of developmental
PCB exposures on social cognition and social behavior and auditory function. However, the
combined human and nonhuman mammalian databases are likely insufficient to draw conclusions
regarding potential PCB-mediated effects on other nervous system endpoint categories.

3.3.12. Ocular

Ocular endpoints encompass those that are measured on or in the eye and tissues
surrounding the eye. The mammalian eye consists of many parts, including the iris, cornea, pupil,
and sclera. Behind the iris and pupil is a lens that focuses light on the back of the eye where it is
sensed by the retina. Special cells within the retina transmit electrical signals via the optic nerve to
the brain for vision. Periocular tissues include the orbit (the space surrounding the eye),
conjunctiva (the mucous membrane covering the inner surface of the eyelids and part of the sclera),
tear ducts, and oil glands in the eyelid (i.e., Meibomian glands), which help maintain eye moisture.

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Like chloracne, some ocular endpoints, such as Meibomian gland enlargement, ocular discharge,
and periorbital edema, are markers of exposure to dioxin-like chemicals fATSDR. 20001. Other
endpoints evaluated with PCB exposure include ocular irritation, abnormal pigmentation of ocular
tissues, and conjunctivitis; increased rates of infectious forms of conjunctivitis are considered an
indication of increased susceptibility to infection (see Section 3.3.8). Nonhuman mammalian studies
also evaluated periocular tissue histopathology. Although periocular endpoints could be perceived
as less severe than those evaluated in the eye itself, effects on periocular tissues such as the
Meibomian glands can range from minor discomfort to visual impairment fChhadva etal.. 20171.

In the database of studies of PCB exposures, 18 studies in humans and 27 in other mammals
evaluated ocular endpoints (see Figure 4). Of the 18 human studies, most are reports following
occupational exposures, Yu-Cheng and Yusho poisoning, or other accidental exposures (see
Figure 5). These studies generally evaluated endpoints with higher exposures than would occur in
the general population. Many of the ocular endpoints were symptoms reported or clinical
observations and were not necessarily the focus of the publications. Other human studies included
one conducted in an Inuit population fDewaillv etal.. 20001 and one cross-sectional study of people
living near waste sites fStehr-Green etal.. 19861. Exposures in these studies also could have been
higher than those in the general population, and the latter study only evaluated self-reported,
physician-diagnosed eye problems without further description.

In the database of studies of PCB exposures, the most commonly studied endpoints were
periorbital edema, ocular discharge, Meibomian gland enlargement, ocular irritation, conjunctivitis,
and abnormal pigmentation (see Figure 25). In humans, these endpoints were most often evaluated
in the Yusho or Yu-Cheng cohorts or in populations with occupational exposures (see Figure 5);
these populations could have additional exposures to chemicals other than PCBs that might affect
ocular endpoints.

Evidence Stream

Endpoint Category Human Other Mammal

Periorbital Edema

Ocular Discharge

Meibomian (Tarsal) Gland Enlargement

Ocular Irritation

Ocular Histopathology

Conjunctivitis

Abnormal Pigmentation

Number of Studies

Figure 25. Overview of Human and Other Mammalian Ocular Studies

Summary of the database of studies evaluating exposures to PCB mixtures and ocular endpoints organized by
endpoint category. Lists of studies included in each count can be accessed via the online interactive version of this
figure (https://hawc.epa.gov/summarv/visual/assessment/100500282/QverviewAIIStudies/). Shading intensity
corresponds with the number of studies in each category, from 1 to 272, which is the maximum number of
nonhuman mammalian studies in any health endpoint category. The intent is to highlight not only differences in
the distribution of studies across ocular endpoint categories but also to emphasize the number of ocular studies
relative to the number of studies for other organs/systems.

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Most studies available for ocular endpoints were conducted in populations with high PCB
exposures (see Figure 5). One was a prospective birth cohort study in Inuit infants exposed via
breast milk compared with bottle-fed infants (Dewailly et al. 2000). The focus of this study was
susceptibility to infections and immune status in Inuit infants, but nurses screened the children at
3, 7, and 12 months of age for Meibomian gland enlargement and eyelid edema, and the study
provided relative risk estimates for conjunctivitis; however, results were based on comparing
bottle-fed and breast-fed infants rather than more specific measures of PCB exposure.

Most of the 27 nonhuman mammalian studies (see Figure 4) were conducted in primates,
followed by rats, and mice (see Figure 8); 1 study used more than one species fThomas and
Hinsdill, 19781. Of the species evaluated, nonhuman primates are most similar to humans. All
studies evaluated ocular endpoints following oral PCB administration (see Figure 9). One study also
exposed the animals via inhalation (Casey et al. 1999). Nine nonhuman mammalian studies
evaluated ocular histopathology (see Figure 25).

Overall, the human database is limited to endpoints measured following high PCB
exposures, including accidental and occupational exposures, and these studies generally provide
qualitative information on ocular symptoms. Although most of the human studies evaluated
endpoints at high PCB exposure levels in situations for which other exposures were possible, taken
together with available data from nonhuman mammalian studies, the database is likely to provide
enough information to draw conclusions about the potential for PCB exposure to affect periocular
tissues, especially at higher exposure levels.

3.3.13. Reproductive

Reproductive endpoints include all those related to the ability to produce a healthy
pregnancy, sustain that pregnancy, and produce healthy offspring. Successful reproduction involves
direct and indirect interplays among the endocrine, reproductive, and other systems, such that
disruption of any of these can lead to adverse reproductive outcomes, defined primarily as failure
to conceive, delayed time to pregnancy, and inability to carry a pregnancy to term (i.e., preterm
delivery) fLuderer et al.. 20191. Several recent reviews and commentaries fArzuaga et al.. 2019:
Luderer et al ; [den etal. 2017: Sifakis etal. 20171 have proposed approaches to group
reproductive endpoints on the basis of either key mechanistic characteristics or functional
outcomes; these approaches have both similarities and differences, reflecting the difficulty inherent
in grouping such endpoints for both animal and human studies. For this review, female
reproductive endpoints are as follows (see Figure 26): sex hormone levels; pubertal development;
menstrual cycle characteristics; ovulation; reproductive organ size/weight and histopathology;
female anogenital distance; reproductive aging; endometriosis; sexual behavior; female and couple
fertility and fecundity (including number of offspring, pregnancy/conception rates, and time to
pregnancy [TTP]); gestational length (including preterm birth); pregnancy-related disorders
(e.g., preeclampsia, dystocia); and other gynecological disorders (e.g., fibroids and polycystic ovary
syndrome [PCOS]). Male reproductive endpoints are as follows: semen and sperm production and

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sperm morphology; levels of reproductive hormones; pubertal development; reproductive organ
size/weight and histopathology; fertility and fecundity; sexual behavior; male anogenital distance,
cryptorchidism, hypospadias, sex ratio of offspring; and erectile dysfunction. Other endpoints
related to reproduction, such as endocrine endpoints (see Section 3.3.4) and other developmental
endpoints that might occur in the offspring following exposure during pregnancy (including
spontaneous abortion and anthropometric measures at birth; see Section 3.3.3), are described
elsewhere.

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Evidence Stream

Sex

Human

Other Mammal

Female

126

143

Male

131

Couple/Pair

Sex

Endpoint Category

Human

Other Mammal

Female

Sex Hormone Levels

Reproductive Organ Size/Weight

Female Fertility

Gestation Duration/Preterm Birth

Reproductive Organ Histopathology

Estrous/Menstrual Cycle

Pubertal Development

Endometriosis

Ovulation

Anogenital Distance

Sexual Behavior

Gynecologic Disorders (Other Than Endometriosis)

Reproductive Aging

Preeclampsia

Pregnancy-Related Disorders

Male

Sex Hormone Levels

Reproductive Organ Size/Weight

Reproductive Organ Histopathology

Sperm/Semen Parameters

Sex Ratio

Pubertal Development

Anogenital Distance

Sexual Behavior

Male Fertility

Hypospadias/Cryptorchidism

Erectile Dysfunction

Couple/Pair

Time-to-Pregnancy & Couple/Pair Fertility

Number of Studies

272

Figure 26. Overview of Human and Other Mammalian Reproductive Studies

Summary of the database of studies evaluating exposures to PCB mixtures and reproductive endpoints organized
by sex and endpoint category. Lists of studies included in each count can be accessed via the online interactive
versions of this figure: (https://hawc.epa.gov/summarv/visual/assessment/100500282/QverviewHumanStudies/)
for human studies; and

(https://hawc.epa.gov/summarv/visual/assessment/100500282/QverviewNonhumanMammalStudies/) for
studies of nonhuman mammals. The interactive summary of the human database, with the reproductive
organ/system filter applied, can be further refined by study design (options: case-control, cohort, cross-sectional,
other), population (options: contaminated schools and other buildings, fish/marine mammal (diet), general
population, occupational, residents in contaminated area, Yusho/Yu-Cheng), sex (options: couple, female, male),
and exposure metric (options: adipose tissue, biood, breast milk, child blood, cord blood, dietary estimates, fish
consumption, maternal blood, occupational/JEM, other metric [includes dust and modeled estimates], other
tissue). The interactive summary of the nonhuman mammalian database, with the reproductive organ/system
filter applied, can be further refined by exposure duration/life stage (options: acute [single dose], chronic,
developmental, short-term, subchronic), species (options: cow, ferret, gerbil, guinea pig, mink, mouse, nonhuman
primate, rabbit, rat, swine, vole), sex (options: female, male, pair), and exposure route (options: dermal,
inhalation, injection, oral). Shading intensity corresponds with the number of studies in each category, from 1 to
272, which is the maximum number of nonhuman mammalian studies in any health endpoint category. The intent
is to highlight not only differences in the distribution of studies across reproductive endpoint categories but also
to emphasize the number of reproductive studies relative to the number of studies for other organs/systems.

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Female reproductive endpoints are related via alterations in the synthesis, production,
secretion, or metabolism of sex-steroid hormones (estradiol [E2], progesterone, and testosterone)
and gonadotropins (follicle stimulating hormone [FSH] and luteinizing hormone [LH]). Further,
many of the endpoints are dependent on each other. For example, some infertility problems can be
attributable to endometriosis, which itself can be attributable to alterations in hormone production
or immune suppression (Birnbaum and Cummings. 20021. The data available for evaluating PCB
exposures and immune function are described in Section 3.3.8. Importantly, the female
reproductive system could be affected by exposures occurring not only across the woman's
lifespan, but also by intergenerational exposures. Because a woman's primordial ovarian follicles
form during her in utero period, exposures occurring to the mother or even grandmother might be
instrumental in the development of the reproductive system, especially for factors related to
fertility (Hover. 2005). Indeed, a recent review finds that at least in animal models, effects of
exposures could last for four generations fNelson et al. 20201. For this reason, multiple-generation
studies (animals) and prospective (birth cohort) studies in humans are useful for evaluating female
reproductive endpoints. However, studies that evaluate exposure during discrete windows of
development can also be useful for identifying windows of susceptibility. For endpoints potentially
affected by exposures in either or both members of a couple (TTP, fecundity, and fertility), the most
informative study designs are based on preconceptual ascertainment of exposure and prospective
follow-up until pregnancy occurs; an excellent example is the Longitudinal Investigation of Fertility
and the Environment (LIFE) study fBloom et al. 20151. Many male reproductive endpoints can be
related via the prevailing hypothesis of the testicular dysgenesis syndrome, which states that early
life exposure to endocrine disrupting chemicals can disrupt the normal development of fetal germ
cells that eventually form the mature male reproductive organs, including sperm production
(Skakkebaek et al. 20011. However, male reproductive endpoints can also be sensitive to chemical
exposures throughout the lifespan. Regardless of when exposure occurred, endpoints such as
production of androgens (such as testosterone), FSH, and LH are clearly related to sperm
parameters. Adequate and high-quality sperm are also related to the more "functional" endpoints of
fertility/fecundity. Although fertility and fecundity are characteristics of the couple, adequate
reproductive function in both partners is necessary (although not sufficient) to produce pregnancy.

With respect to identifying hazard from PCB exposure, the most informative female
reproductive endpoints in epidemiological studies are those that are clearly measurable, including
age at menarche, menopause, presence of endometriosis, and hormone levels. Important potential
confounders for these endpoints include age, body composition, and cooccurring pollutants,
especially given the ubiquity of coexposure to other potential endocrine disrupting compounds that
could affect female reproductive endpoints (Gore et al. 20151. The most informative male
reproductive endpoints observed in humans are also those that are readily measurable for
population studies: semen parameters and hormone levels. These endpoints have been routinely
measured in epidemiological studies and in clinical settings where infertility evaluations are

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performed fDadhich etal. 20151. Sperm parameters are also among the endpoints considered most
sensitive to insult in animal studies, along with histopathology and reproductive organ weights
(Mangelsdorf et al. 2003). Other male reproductive endpoints might be less specific and more
difficult to evaluate with respect to PCB exposure; for example, erectile dysfunction shares many
risk factors with cardiovascular disease (Yiigixnaa et al. 20201 such as hypertension fde Oliveira
and Nunes. 20211 or diabetes mellitus fKouidratetal. 20171. Of the endpoints examined with PCB
exposure, the most difficult to interpret for female reproduction are those that also rely on the
partner, such as fertility/fecundity—information on the male partner is not always available, and
the numerous ways these endpoints are parameterized makes it difficult to harmonize findings
across studies (Kafan et al.. 2021: Hipwell et al.. 2019: Smarr etal. 20171. Animal studies can
supplement the human database by including a wider array of measurable reproductive endpoints
and can be designed to evaluate female- and male-only exposures and exposure of both members of
the mating pair.

Of the studies that evaluated PCB exposure and female reproductive endpoints over the
lifespan, 126 were human and 143 were other mammalian studies (see Figure 26). In some cases,
multiple publications described different endpoints evaluated in the same study population
(e.g., the LIFE study). Most human studies of female reproductive endpoints measured PCBs in
blood (including cord blood) (see Figure 26). Less commonly, PCBs were measured in breast milk
(Rennertetal. 2012: Brucker-Davis etal. 2010: Cao et al. 2008: Khanjani and Sim. 2007: Gladen et
al. 20001. follicular fluid fAl-Hussaini etal. 2018: Bloom et al. 2017: Petro et al. 20121. adipose
tissue (Pollack etal. 2021: Ploteau et al. 2017: Ploteau et al. 2016: Martinez-Zamora etal. 2015:
Trabert et al. JO I r>: tUick Louis etal. 2012: Oin etal. 2010: Whitcomb et al. 20051 or placenta
fPloteau etal. 2017: Ploteau et al. 2016: Martinez-Zamora etal. 2015: T rabert et al. 2015: Buck
Louis et al. 2012: Oin et al. 20101. Some studies characterized PCB exposure using work history
(Taylor etal. 1989: Tavlor et al. 19841. residence in PCB-contaminated apartments (Kofoed et al.
20211. or reported fish consumption (Lambertino et al. 2011: Mendola et al. 1997: Mendola et al.
19951. Nonhuman mammalian studies included a wide range of experimental designs and life
stages of exposure (see Figure 26), including four studies that investigated transgenerational PCB
exposure and female reproductive development and fertility for up to three generations through
the maternal lineage fKrishnan etc ; ishnan et al. 2018: Mennigen et al. 2018: Steinberg

et al. 20081.

Age at beginning (menarche) and end (menopause) of menstruation was studied in human
populations with PCB exposure (Marks etal. 2021: Attfield etal. 2019: Grindler et al. 2015: Croes
et al. 2014: Den Hond et al. 2011: Leiis et al. 2008: Chao et al. 2007: Denham etal. 20 ; nek et
al. 2004: Vasiliu et al. 2004: Cooper etal. 2002: Den Hond et al. 2002: Gerhard et al. 19981.
Prospective ascertainment for both endpoints is preferred—for menarche, this could mean
querying girls (or their parents) as young as 6 years of age, while for menopause, women might be
queried beginning at age 40-45 years. Retrospective ascertainment could lead to measurement

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error that could be more pronounced with increasing time elapsed. Four studies evaluating age at
menarche were prospective cohort studies fMarks etal. 2021: Attfield et al ; is etal. 2008:
Vasiliu etal, 20041. while the remainder evaluated age at menarche retrospectively or cross-
sectional ly fCroes et al.. 2014: Den Hond etal. 2011: Chao et al. 2007: Denham etal. 2005: Den
Hond et al. 2002: Gerhard et al. 19981. Among the studies that evaluated age at menopause, one
was cross-sectional (Grindler etal. 20151. one was conducted within a case-control study of breast
cancer (Cooper et al. 20021. and one was conducted within a prospective cohort of women
accidentally exposed to polybrominated biphenyls fBlanck et al. 20041. All studies included a wide
age range (women younger than 40 years, up to age 74 or older) and relied on self-report of
menstruation occurrence. The mammalian database included three studies in rats that evaluated
reproductive aging, measured as the onset of persistent vaginal estrus (a syndrome of premature
anovulation) (see Figure 26).

Nine human studies [five cross-sectional fCroes etal. 2014: Den Hond et al. 2011: Wolff et
al. 2008: Den Hond et al. 2 ; lessen et al. 20011. four cohort (Windham etal. 2015: Su etal.
2012: Leiis etal. 2008: Gladen et al. 20001] evaluated PCB exposure and markers of female
pubertal onset other than age at menarche, such as age at first breast development, age at first
pubic hair development, and Tanner stage of breast and pubic hair development (Marshall and
Tann 9), in children aged 6-19 years. Most studies assessed Flemish/Dutch populations

fCroes et al. 2014: Den Hond etal. 2011: Leiis et al. 2008: Den Hond etal. 2002: Staessen etal.
20011. which might have been exposed to PCBs primarily via waste incineration fBremmer etal.
19941. In nonhuman mammalian studies, the onset of female puberty (measured as the age at
vaginal opening or first estrous) was evaluated in 22 studies in rats and one study in guinea pigs,
including four studies that evaluated transgenerational exposures fKrishnan et al. 2019: Krishnan
et al. 2018: Mennigen et al. 2018: Steinberg et al. 20081 (see Figure 26). The timing of puberty in
rodent models is closely tied to body weight, with delays in puberty resulting from decreases in
body weight, so comparison of body weight in control vs. treatment groups in these studies can
help distinguish potential direct effects on puberty from a generalized delay in growth. PCB
exposure and body weight in early life have been evaluated frequently in rodent models (see
Section 3.3.3).

Thirty-three human studies and one study in rhesus monkeys evaluated endometriosis and
PCB exposure (see Figure 26), although some human studies were related analyses conducted in
the same study population. Eleven of the studies were cross-sectional, one was a cohort, and the
remainder were case-control (see Figure 26). One important consideration for this health endpoint
is that the most accurate ascertainment is based on surgical assessment (e.g., laparoscopy).
Common clinical classification systems include those developed by the American Fertility Study [as
used in, e.g., fBuck Louis et al. 20051] and the American Society for Reproductive Medicine [as used
in e.g., (Buck Louis et al. 2012: Niskar etal. 20091], All but two studies (Neblettetal, 2020:

Fierens etal. 20031 ascertained endometriosis using surgical assessment. However,

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misclassification is still a concern, even with these standardized staging systems ( Weiss.

20001. Few studies evaluated other gynecological disorders; one evaluated self-reported
"gynecologic disorders" without further detail (Nakamoto etal. 20131. while six studies evaluated
uterine fibroids (Wesselinketal. 2021: Neblett et al, 2020: Trabert et a ; mbertino et at,

2011: Oin etal. ; lerhard etal. 19991. three studies evaluated polycystic ovary syndrome
(Neblett etal, 2020: Yang et al. 2015: Vagi etal. 20141. one evaluated adenomyosis (Heilier et al.
20041. and one evaluated pelvic inflammatory disease (Neblett et al. 20201.

Sixteen human studies and 32 studies in other mammals (see Figure 26) measured sex-
steroid or gonadotropin levels in females across the lifespan and PCB exposure. Studies of these
hormones are particularly important because all female reproductive endpoints described here are
related via the synthesis, production, secretion, or metabolism of sex-steroid hormones. The human
database included one case-control study, seven cross-sectional studies, and eight cohort studies
(see Figure 26). All used standard laboratory methods for hormone measurement Eight studies
evaluated hormones in nonpregnant adult women (Lambertino etal. 2021: Pan etal. 2019: Gallo et
at. 2018: Guo etal. 2018: Perskv et at. 2011: Windham etal. 2005: Gerhard et al. 1999: Gerhard et
al. 19981. with specific information about the timing of collection and menstrual cycle status for
premenopausal women, which is crucial to the interpretation of the results. Although some
variation occurred in the suite of female reproductive hormones evaluated in these adult
populations, most included FSH, LH, and E2 [e.g., (Pan et al.! ; alio etal. 2018: Guo etal.
2018: Mivashita et al. 2018: Kristensen et al. 20161], Two studies evaluated reproductive
hormones in cord blood at delivery (Warembourg et al, 2015: Takser et al, 20061. while two others
evaluated hormones in children 6-9 years of age fRennert et al. 2012: Su et al. 20121. The
measurement of the specific hormones in these younger female populations was less consistent, but
both Kennertetal. (20121 and Su et al. f20121 included assessments of E2, testosterone, and others.
The mammalian toxicological database consisted of 32 studies in monkeys, rats, mice, mink, rabbits,
and guinea pigs (see Figure 26). More than half these animal studies evaluated F1 females that had
been exposed during development, including four studies evaluating transgenerational exposures
(Krishnan et al. 2019: Krishnan etal. 2018: Mennigen et al. 2018: Steinberg et al. 20081. The
hormone measurements varied across nonhuman mammalian studies, including plasma or serum
levels of E2, progesterone, testosterone, dehydroepiandrosterone (a precursor to other sex-steroid
hormones), FSH, and LH, as well as urinary measurements of estrogen and androgen metabolites.
Female anogenital distance, a measure hypothesized to reflect androgenic activity in utero, was
investigated in 4 human studies and 15 studies in other mammals (see Figure 26). The human
health implications of changes in anogenital distance remain unclear, although some evidence
indicates a longer anogenital distance in women might be associated with presence of polycystic
ovary syndrome fSanchez-Ferrer etal. 20171.

Twelve human studies evaluated menstrual cycle irregularities, and six evaluated ovulation
(see Figure 26). Nonhuman mammalian toxicology studies evaluated irregularities in the menstrual

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cycle (rhesus or cynomolgus monkeys) or estrous cycle (rats, mice, guinea pigs, or cows) or
ovulation (rhesus monkeys, rats, mice, rabbits, or mink) (see Figure 26). Some studies also
measured sex-steroid hormones or gonadotropins as discussed above, which are integral to the
maintenance of the menstrual/estrous cycle and ovulation and are therefore useful for interpreting
these endpoints [e.g., (Kristerisen etal. 2016: Dickerson etal. 2011: Windham etal. 2005: Meerts
et al, 2004a: Gerhard etal. 1999: Backlin etal. 1997: Arnold et al, 1993: Truelove et al, 1990:

Allen et al, 1980: lonsson et al. 1975)]. More than half the human studies of menstrual cycle
irregularities were cross-sectional (see Figure 26). All but one fBuck Louis etal. 2011al of the
human studies evaluating menstrual cycle length ascertained endpoint information via self-report;
this raises the concern for measurement error (lukic et al. 2007: Small etal. 20071 although such
error likely would not differ by exposure status. About half the nonhuman mammalian studies
evaluated estrous cyclicity in female rats that had been exposed during development (see
Figure 26), including 2 transgenerational studies fMennigen et al. 2018: Steinberg et al. 20081.
Ovulation as measured in nonhuman mammalian studies (e.g., ovulation rates or number of corpora
lutea) included evaluations with both adult and developmental exposures.

Numerous human studies evaluated fertility of the woman or the couple (see Figure 26),
including studies evaluating time to pregnancy [e.g., (Hwang eta ; ick Louis etal. 2013:

Chevrier et al. 2013: Yang et al. 2008: Axmon etal. 2006: Cole etal. 2006: Toft et al. 2005: Axmon
et al. 2004: McGuinness et al. 2001: Buck etal. 20001] or other measures of couple fertility, such as
fertilization rate among couples undergoing IVF [e.g., fYounglai et al. 20021] or pregnancy rate
among couples planning conception [e.g., (Hwang et al. 20191], However, as noted above, these
studies are difficult to interpret due to the difficulties in disentangling potential effects attributable
to exposure status for each partner; a notable exception is the LIFE study in which exposure
information was ascertained for each partner (Buck Louis et al. ). The mammalian toxicology

literature might help fill this gap, as 68 studies evaluated maternal-only exposure and pregnancy or
conception rate (measured as the ability to become pregnant, implantation rates, litter size, or litter
number) (see Figure 26), including three transgenerational studies fKrishnan etal. 2018:

Mennigen et al. 2018: Steinberg et al. 20081. Female fertility was evaluated in a wide range of
species (rhesus monkeys, rats, mice, mink, rabbits, gerbils, ferrets, cows, or swine) (see Figure 26)
and was the most commonly measured female reproductive endpoint in the mammalian toxicology
literature. Additionally, nine studies evaluated the fertility of mating pairs in rats or mice (see
Figure 26).

Thirty-four human studies and 25 studies in other mammals (rhesus monkeys, rats, mice,
mink, guinea pigs, ferrets, or cows) evaluated gestational length, including studies of preterm birth
(see Figure 26). Most human studies were cohort studies from various countries. Two studies
evaluated Yusho or Yu-Cheng patients. Eleven studies evaluated preterm birth as a dichotomous
endpoint (Kofoed et al. 2021: Neblettetal. 2020: Bell et al. 2019: Wu et al. 2011: Woityniaket al.
2010: Tsukimori et al. 2008: Khaniani and Sim. 2007: Longnecker et al. 2005: Ribas-Fito et al.

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2002: Berkowitz etal. 1996: Wassermann et al. 19821. which has clear clinical relevance. However,
recent research indicates that there might be no threshold for the effect of gestational age on
adverse outcomes later in life (Clark etal. 2009: Zhang and Kramer. 20091. which suggests
evaluation of gestational length as a continuous endpoint might provide a more sensitive approach
to understand potential effects of chemical exposures. Exposure measures used in studies of
gestational length and preterm birth spanned a variety of time points; most assessed exposure
during pregnancy, while some evaluated exposure within hours or days of delivery (including
measures in cord blood, placenta, or dried blood spots) fBell et al. 2019: Tang et al. 2018: Wu et al.
2011: Brucker-Davis etal. 2010: Wang et al. 2005: Lucas etal. 2004: Ribas-Fito et al. 2002: Fein et
al. 19841 or during early infancy (including measures in breast milk) (Brucker-Davis et al. 2010:
Khanjani and Sim. 20071. One study evaluated exposure on the basis of "current" blood measures;
time since pregnancy was not reported (Neblettetal, 20201. For these end points, the most relevant
time window for exposure is during pregnancy.

Pregnancy-related disorders were also reported in a few human and other mammalian
studies. In humans, there were four studies of preeclampsia (see Figure 26). One nonhuman
mammalian study reported the incidence of dystocia (i.e., difficult or obstructed labor) fCurran et
al. 2011b). and three studies reported vaginal bleeding during pregnancy (Lundkvist and Kindahl.
1989: Lundkvist et al. 1987: Brezner et al. 1984). Although these are severe conditions important
for public health, the likelihood these databases would support a strong hazard identification
conclusion is low.

Two epidemiological studies evaluated PCB exposure and mammographic breast density
fLee et al. 2020: Rusiecki et al. 20201: evaluations of mammary gland differentiation and cell
proliferation were also conducted in one rodent study fBrown and Lamartiniere. 19951. Sexual
behavior and histopathological evaluations of the uterus, ovaries, and vagina were evaluated only in
nonhuman mammalian studies with no human equivalent (see Figure 26). Female sexual behavior
was assessed in 18 studies in rats, gerbils, or mink. About half these studies reported only simple
measurements of mating incidence or frequency, but four studies in rats assessed specific
behavioral indicators of sexual receptivity such as lordosis or latency measurements (Colciago et
al. 2009: Steinberg et al. 2007: Chung et al. 2001: Chung and Clemens. 19991. and five studies in
rats evaluated sociosexual behavior (i.e., allowing females to choose among stimulus animals with
different sex or hormonal status) (Hernandez Scudder et al. 2021: Hernandez Scudder et al. 2020:
Topper etal. 2019: Krishnan etal. 2018: Reillv et al. 2018). Changes in sexual behavior are often
indicative of hormonal dysregulation but might also be relevant to the evaluation of nervous system
function (see Section 3.3.11). Only one epidemiological study evaluated reproductive organ size
(uterine length) (Su et al. 2012). By contrast, reproductive organ (e.g., ovary or uterus) weights
were widely reported among nonhuman mammalian studies, with fewer studies reporting
histopathology of these organs (see Figure 26). Organ weights are considered less informative
endpoints due to their nonspecific nature, whereas histopathology can be a relatively sensitive

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measurement. Maternal body weight changes, which were measured in many studies that evaluated
female fertility [e.g., fYang et al. 2009: Kostvniak et al. 2005: Kava et al. 2002: Brunstrom et al.
2001: Arnold etal. 2000: Haiw et al.. 1999: Lilienthal et al.. 1990: Welsch. 1985: Talcott and Roller,
1983: Thomas and Hinsdill, 19801]. can indicate both maternal toxicity and fetal toxicity, so
adjusting for gravid uterine weight can be used to help distinguish potential maternal and
intrauterine effects (U.S. EPA. 1991). None of the available studies adjusted for gravid uterine
weight; therefore, the maternal body-weight measurements have limited utility for female
reproductive hazard identification but could be useful as an indicator of potential overt toxicity
when interpreting other endpoints in a study.

Overall, the database of human and nonhuman mammalian studies is likely sufficient to
support hazard identification for PCB exposure and female reproductive endpoints. In humans, the
endpoints of endometriosis and gestational length have been the most studied. Female fertility was
by far the most studied endpoint in the mammalian toxicology literature, but a relatively large
number of studies also evaluated other endpoints that can provide further support for assessments
of potential human health hazard.

Ninety-five human and 131 other mammalian studies (see Figure 26) evaluated PCB
exposure and male reproductive endpoints over the lifespan. In some cases, multiple publications
described different endpoints evaluated in the same human study population [e.g., a cohort of
Swedish fishermen, e.g., (Rignell-Hydbom etal. 2005b: Rignell-Hydbom et al. 2005a: Rignell-
Hvdbom et al. 20041] or subsequent follow-up information from a prospective cohort [e.g., the
Russian Children's Study, e.g., (Mi'nguez-Alarcon et al. 2017: Burns et al. 20161], Most human
studies of male reproductive endpoints used biomarkers to characterize PCB exposure, with
varying numbers of PCB congeners measured in blood (see Figure 26). Less commonly, PCBs were
measured in breast milk (Desalegn et al. 2021: Krysiak-Baltvn etal. 2012: Rennertetal. 2012:
Brueker-Davis et al. 2008: Cao etal. 2008: Khanjani and Sim. 2007: Gladen etal. 2000). adipose
tissue (Koskenniemi et al. 2015: Cok etal. 2009: Cok etal. 2008). placenta (Su et al. 2012: Gladen
et al. 20001. or seminal fluid fLin et al. 2021: Magnusdottir et al. 20 ; ;ati etal. 2002: Stachel
et al. 1989: Bush et al. 1986). or characterized using a JEM (Rocheleau et al. 2011).

Endpoints related to each other through the framework of the testicular dysgenesis
syndrome (i.e., cryptorchidism, hypospadias, anogenital distance, secondary sex ratio) fSkakkebaek
et al. 2001) were evaluated in both humans and other mammals (see Figure 26). In general, the
studies of cryptorchidism and hypospadias are few and tend to have a small number of cases, which
limits the robustness of the overall findings. Male anogenital distance was investigated in 4 human
studies and 14 other mammalian studies (see Figure 26). The human health implications of
observed changes in anogenital distance remain unclear, although some evidence indicates shorter
anogenital distance in men is associated with reduced semen quality fMendiola etal. 20111.

Altered anogenital distance is also associated with an endocrine disrupting impact of other
chemical exposures (Kahn et al. 2020). Secondary sex ratio, which is the ratio of male to female

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offspring at birth, is a measure of endocrine regulation and disruption during early stages of
development This endpoint was evaluated in 13 human studies and 40 other mammalian studies
(see Figure 26). Because secondary sex ratio is a simple endpoint to assess, fairly large sample sizes
are available. However, the impact and meaning of these results should be interpreted within the
context of data on other clinically relevant endpoints associated with endocrine disruption and
reproductive development.

Eleven human studies focused on timing of male pubertal development (see Figure 26). Of
these, six evaluated PCBs with adrenarche and gonadarche only fBurns et al. 2016: Den Hond etal.
2011: Humbletetal. 2011: Korrick et al. 2011: Staessen etal. 2' ; iden et al. 20001. while five
others also included hormone measurements (Croes et al. 2014: Grandiean et al. 2012a: Su et al.
2012: Den Hond etal. 2002: Mol et al. 2002). and one additionally reported semen parameters
(Mol et al. 2002). Assessment of testicular function is not part of routine examinations in
prepubertal males. One recent paper suggests that assessment of anti-Mullerian hormone (AMH;
not measured in these studies), inhibin B (measured in Den Hond et al. (20021. Grandiean etal.
f2012al. and Metier ), and testicular volume (measured in Den Hond et al. f20021.

Grandiean etal. f2012al. Korrick et al. f20111. and Meiier et al. (2012)1. all relatively noninvasive,
could be useful for evaluating puberty disorders and primary testicular damage in prepubertal boys
and that early diagnosis might be amenable in preventing infertility in adulthood (Condorelli etal.
2018). The mammalian toxicology database on male pubertal development consists of 15 studies in
rats (see Figure 26), 10 of which also evaluated sex hormone levels fKrishnan et al. 2019: Topper
et al. 2019: Krishnan et al. 2018: Mennigen et al. 2018: Gillette etal. 2017: Walker etal. 2014:
Dicker son etal. 2011: Yang etal. 2009: Lilienthal et al. 2006: Meerts et al. 2004al and one of
which additionally reported on sperm concentration fYangetal. 20091. Most available studies
evaluated development of the male reproductive system after gestational exposures (see
Figure 26), and endpoints evaluated included preputial separation and testicular descent.

Among studies that focused on adults (past puberty), many reported semen (volume) and
sperm (concentration, motility, and morphology) parameters or serum levels of reproductive
hormones (see Figure 26). Some overlap occurred, as eight studies reported both types of
endpoints (Petersen etal. 2018: Vitku etal. 2016: Petersen etal. 2015: Vested et al. 2014: H an gen
et al. 2011: Rignell-Hvdbom et al. 2004: Richthoff et al. 2003: Mol et al. 20021. Although many of
these studies were cross-sectional (see Figure 26), a few were prospective in nature; for example,
the Russian Children's Study evaluated PCB levels measured in mid-childhood, with reproductive
endpoints measured up to 10 years later [e.g., (Minguez-Alarcon etal. 20171], Among the cross-
sectional studies, many recruited participants from infertility clinics, which could limit the
generalizability of findings [e.g., (Paul et al. 2017: Vitku etal. 2016: Abdelouahab etal. 2011:
Hauser et al. 20021], However, others were conducted among samples with a range of PCB
exposure potential, such as Swedish military conscripts (Richthoff etal. 2003) and populations
exposed to PCBs through fish consumption [e.g., (Rignell-Hydbom et al. 2005a: Rignell-Hvdbom et

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at. 2004: Perskv et at. 20011]. For semen and sperm parameters, it is important to consider factors
such as place of collection, number of samples collected, abstinence time before collection, and use
of standardized laboratory protocols (Cirillo etal. 2011: Brazil et at. 2004: Cohn et at. 20021.
Important confounders for semen and sperm parameters can include age and percent body fat, as
these are both related to PCB exposure and infertility. Many of the studies of semen and sperm
parameters, including those in well-characterized samples of individuals [e.g., (Toft et at. 2006:
Rignell-Hvdbom et at. 2004: Hauser etal.. 20031]. did include age and BMI (along with other
potential confounders) in their analyses and, importantly, requested abstinence of two or more
days. Timing is also important for hormone measures. For example, morning collection is
recommended to account for diurnal variation in serum testosterone concentrations. Studies
generally used accepted laboratory protocols for hormone analysis, and although samples were not
always consistently collected during morning hours, consideration of timing was often described
[e.g., fVitku etal.. 2016: Petersen etal.. 2015: Schell etal.. 2014: H an gen et at. 20111],

The mammalian toxicological database for PCB exposure and reproductive hormones and
sperm measures consists of 47 and 24 studies, respectively (see Figure 26). Studies that evaluated
reproductive hormone levels used several strains of rats and mice, guinea pigs, swine, and rhesus
monkeys. Reproductive hormones measured in these studies included testosterone, progesterone,
E2, LH, and FSH. Nonhuman mammals were exposed to PCBs during all stages of development,
including gestational, peripubertal, and sexually mature life stages. Studies that measured sperm
parameters also used a variety of mammalian models, including rats, mice, and rhesus monkeys,
and most exposed peripubertal or sexually mature animals (see Figure 26). Endpoints considered
in these studies included sperm count, motility, production, concentration, abnormalities, and in
vitro fertilizing ability.

Three human studies evaluated male infertility and PCB exposure (see Figure 26). Although
numerous studies of couple fertility and fecundity were identified, relatively few considered
paternal PCB exposure along with maternal exposure, including studies conducted among male
partners in the New York State Angler Cohort fBuck et at. 20 ; :k etal.. 19991 and the LIFE
study (Hwang etal.. 2019: Zhang etal.. 2019: Buck Louis etal.. 20131. Only one cross-sectional
study evaluated erectile dysfunction (see Figure 26). The mammalian toxicology database on male
fertility endpoints consists of 15 studies evaluating implantations, mating and pregnancy index,
litter size and number in unexposed females mated to exposed males (see Figure 26). Experimental
models used in these studies include rats, mice, mink, and rhesus monkeys.

Measures of reproductive organ size and weight can be used to detect changes in levels or
responsiveness to reproductive hormones (Dent et al ; bert et at. 20141. There were 8
human studies that evaluated reproductive organ size in males, by measuring testicular volume.
One of these was conducted in very young children (< 2 years of age) fMeiier et at. 20121. while the
remaining studies evaluated testicular volume as a measure of pubertal development (Burns et at.
2016: Grandiean et at. 2012a: Humblet et at. I: I .Quick etal. *'M I: i uni Hond et at. 2002: Mol

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et at. 2002: Staessen et at. 20011. Seventy-two studies evaluated PCB exposures and reproductive
organ weights in a variety of species and strains of mammals, including mice, rats, rabbits, rhesus
monkeys, mink, guinea pigs, ferrets, voles, and swine (see Figure 26).

Additional male reproductive endpoints evaluated only in nonhuman mammalian studies
with no human equivalent include sexual behaviors and histopathology (see Figure 26). Sexual
behaviors such as mating index, frequency of intromissions, and latency in ejaculations were
evaluated in 10 studies in rats, mice, or mink. Male reproductive organ histopathology was
evaluated in 33 studies that examined testes and accessory reproductive organs (e.g., prostate,
seminal vesicle, epididymis) in different species and strains of mammals, including rats, rabbits,
mice, guinea pigs, swine, rhesus monkeys, and mink. Studies that evaluated histopathology or organ
weights exposed mammals to PCBs during all stages of development, including gestational,
peripubertal, and sexually mature life stages.

Overall, the human and nonhuman mammalian databases are likely to provide sufficient
information to determine whether a hazard exists for male reproductive development, with the
most informative endpoints evaluated in humans being semen and sperm parameters and levels of
male reproductive hormones. Relatively few human studies examined paternal PCB exposure in
relation to fertility and fecundity, but this potential association was examined in 15 nonhuman
mammalian studies (see Figure 26). Reproductive organ weights and hormonal measures were the
most studied endpoints in the mammalian toxicology literature, but numerous studies using
diverse experimental models and designs evaluated other endpoints that can provide further
support for hazard assessment and could address gaps in the human database.

3.3.14. Respiratory

The respiratory system includes the upper respiratory tract (nose, nasal cavity, sinuses,
larynx, and trachea) and lower respiratory tract (lungs, bronchi and bronchioles, and alveoli).
Through gas exchange in the lung, the respiratory system supplies oxygen to the blood, where it is
transported to the tissues, and removes carbon dioxide carried in the blood from the tissues.
Respiratory health is assessed through measurements of pulmonary structure (e.g., lung weight,
histopathology, and chest radiography), pulmonary function (e.g., lung volume and air flow), or
respiratory symptoms (e.g., shortness of breath, cough, presence of sputum, and chest tightness).
The main measures of pulmonary function are determined by spirometry and include forced vital
capacity (FVC), forced expiratory volume in the first second of the forceful exhalation (FEV1), and
FEV1/FVC ratio; lung volume, diffusing capacity, and exercise testing are also common measures.
Other parameters of pulmonary health include measures of respiratory sounds, sputum analysis,
and blood gas tension. Respiratory endpoints related to asthma or infectious respiratory diseases
are discussed in Section 3.3.8. Environmental exposures to chemicals can cause impaired lung
development and function in children or diminished lung function in adults, and the effects of these
exposures might depend on individual response to oxidative stress and inflammation (Cao et at.
2016: Spann et at. 2016). Several factors can influence the potential for respiratory effects of

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exposure to chemicals, including sex, age, genetic factors, medical history (e.g., perinatal exposures
and outcomes, childhood asthma, and immune system health), active smoking, occupational or
ambient air pollution, diet (pro- and antioxidant intake), physical activity, and fitness (Cao et al.

20161.

Among the studies under consideration as relevant for PCB hazard identification, both
human and other mammalian studies evaluated respiratory endpoints (see Figure 4). Human
studies included inhalation or dermal exposure in occupational settings [e.g., (Kimbrough et al..

2015: Gustavsson and Hogstedt. 1997: Brown etal.. 1991: Fitzgerald etal.. 1989: Emmettetal.
1988b: Emmettetal.. 1988a: Gustavsson et al.. 1986: Lawton etal.. 1986: Brown and Tones. 1981:
Fischbein et al.. 19791] and in proximity to three chemical waste sites (Stehr-Greenetal., 19861.
oral exposure through ingestion of contaminated rice bran oil (Yusho patients) (Kanagawaetal..
2008: Nakanishi etal.. 2005: Tokunaga and Kataoka. 2001: Hirota etal.. 1995: Nakanishi et al.,
1985: Shlgematsu etal.. 19781. and general population exposures assessed in early life fAbellan et
al. 2019: Leiis etal.. 2018: Hansen etal.. 20151. Although most nonhuman mammalian studies
exposed animals by the oral route, exposure also occurred via injection, inhalation, and dermal
contact (see Figure 9). A few human studies assessed pulmonary function, histopathology, chest
radiography, respiratory sounds, and sputum analysis (see Figure 27). Related endpoints assessed
in nonhuman mammalian studies included pleural effusion, respiratory rate, blood gas tension,
pulmonary histopathology, and lung weight

Evidence Stream

Endpoint Category Human Other Mammal

Pulmonary Histopathology

Lung Weight

Respiratory Disease Mortality

Respiratory Symptoms

Pulmonary Function

Blood Gas Tension

Chest Radiography

Respiratory Sounds

Respiratory Illness History

Respiratory Rate

Sputum Analysis

Pleural Effusion

Number of Studies

_ 272

Figure 27, Overview of Human and Other Mammalian Respiratory Studies

Summary of the database of studies evaluating exposures to PCB mixtures and respiratory endpoints organized by
endpoint category. Lists of studies included in each count can be accessed via the online interactive version of this
figure (https://hawc.epa.gov/summarv/visual/assessment/100500282/QverviewAIIStudies/). Shading intensity
corresponds with the number of studies in each category, from 1 to 272, which is the maximum number of
nonhuman mammalian studies in any health endpoint category. The intent is to highlight not only differences in
the distribution of studies across respiratory endpoint categories but also to emphasize the number of respiratory
studies relative to the number of studies for other organs/systems.

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Of the human studies in the database, three assessed lung function in the general population
fAbellan et a ; its etal. 2018: Hansen etal. 20151. Hansen etal. (2015) examined prenatal
exposure to PCBs and allergic sensitization and lung function in 20-year-old offspring in a Danish
cohort of pregnant women. Abellan et al. (20191 examined prenatal exposure to PCBs and lung
function during childhood, while Leiis etal. (20181 assessed PCB serum levels and lung function in
adolescence, controlling for perinatal exposure to PCDD (polychlorinated dibenzodioxins). An
additional human study focused on respiratory symptoms in a small sample of participants living in
proximity to three chemical waste sites fStehr-Green et al. 19861. The remaining studies in the
database assessed occupational exposure to PCBs or were conducted among the Yusho cohort (see
Figure 5). These studies targeted populations exposed to much higher levels of total PCBs than the
general population; and, as Nakanishi etal. (20051 noted, PCDFs, not PCBs, have been shown to be
"the major causative agents of Yusho" in more recent studies (see Section 3.2.1). Additionally, of the
Yusho studies, only one was a longitudinal analysis fNakanishi etal. 20051. while the others were
cross-sectional analyses and thus less informative for PCB hazard identification.

Most of the 49 nonhuman mammalian studies (see Figure 4) were conducted in rodent
models such as rats, mice, and guinea pigs (see Figure 8). Seven studies used nonhuman primates
as their animal model. Nonhuman primates have the most similar respiratory system structure to
humans, which allows for the collection of endpoints such as pulmonary function tests (Miller etal.
2017a) that are unattainable using other mammalian models. Pulmonary histopathological
evaluation, which was conducted in 34 nonhuman mammalian studies across a variety of species
(see Figure 27, Figure 8), might be useful as a complement to data from human studies. Lung
weight, measured in 19 nonhuman mammalian studies, has been shown to be correlated with
histopathological changes fWahlstrom et al. 20131. which suggests that this marker is a useful
indicator for potential lung injury.

Some human studies only assessed respiratory disease mortality or respiratory
symptoms/illness history in the absence of other more specific measures of respiratory function
(Fitzgerald et al. 1989: Exxmiett et al. 1988b: Stehr-Green et al. 1986: Smith etal. 1982: Fischbein
et al. 1979). In nonhuman mammalian studies, measurements of blood gas tension and respiratory
rate were recorded (see Figure 27). Although these endpoints have been used to help diagnose
human patients with acute lung injury or acute respiratory distress syndrome, they are not the
most specific measurements of respiratory health. Collectively, these human and other mammalian
studies are less informative for PCB hazard identification because they capture a broad range of
conditions with potentially unrelated etiologies.

Overall, the human database is mostly limited to populations with high PCB exposure, some
with simultaneous exposures to other compounds that could contribute to potential effects.
However, the combined human and other mammalian database is likely to provide enough
information to draw conclusions about the potential for PCB exposure to cause respiratory effects,
especially at relatively high exposure levels.

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3.3.15. Urinary System

The kidney and lower urinary tract (ureters, bladder, and urethra) make up the mammalian
urinary system. The kidney primarily eliminates metabolic waste products but plays other
important physiological roles including control of body fluid volume, electrolyte regulation, protein
and hormone recycling, and other metabolic processes (Frazier etal. 2012: Tesch. 2010). The
lower urinary tract primarily transports (and stores) urine from the kidney for elimination fFrazier
et al, 2012).

In the kidney, pathophysiological responses to chemical exposures can range from
subclinical elevations in urinary or serum levels of certain biomarkers (e.g., creatinine) to frank
disease, including renal failure. Among the 29 human studies of PCB exposure and urinary system
endpoints (see Figure 4), four evaluated PCB exposures and frank disease. Two studies evaluated
diabetic nephropathy in NHANES participants (Everett and Thompson. 2016. 2014). while the
remaining studies evaluated self-reported kidney disease in a Japanese general population sample
(Nakamoto etal.. 2013) and diabetic end stage renal disease among American Indians (Grice etal.
20171. In this latter study, serum levels of numerous PCB congeners were measured and evaluated
using a nested case-control design. The prospective nature (PCBs collected at baseline, diabetes
status followed over 10 years) and large number of PCBs evaluated lend additional confidence that
this study can provide useful information about the potential for PCB exposure to affect kidney
function.

Although the number of human studies of the most severe endpoints is small, the results
can be evaluated in parallel with the results of studies in nonhuman mammals exposed to PCB
mixtures. In animals, kidney damage can be evaluated directly using histological methods, and
kidney histopathology is one of the most commonly evaluated urinary system endpoints in the PCB
database. However, investigations of diabetic nephropathy are unique to the epidemiological
database. Although diabetic animals can develop kidney disease that resembles human diabetic
nephropathy, currently available animal models cannot fully recapitulate diabetic renal changes
between humans and animals fAzushima et al. 2018: Velasquez etal. 19901. making this a
potentially promising yet challenging area of study.

Although nephropathy and kidney disease can be considered more severe manifestations of
kidney pathology, most of the human studies identified did not evaluate frank disease, but instead
measured biomarkers of urinary system function (see Figure 28). The most common biomarker
endpoints included serum levels of uric acid, urinary or serum creatinine, blood urea nitrogen
(BUN), and urinary albumin. All are used in clinical practice but might also be useful to detect sub-
or preclinical changes in kidney function in epidemiological studies fGounden et al. 2021:
Hernandez Scudder et al. 2021: Lopez-Giacoman and Madero. 2015). For example, increased
albumin levels are considered a sensitive marker of chronic kidney disease, although not specific to
a single cause. Increased BUN is likewise a general marker of decreased kidney function, but can
vary with diet, medication (steroid) use, and other factors. Creatinine is thought to be a more

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accurate proxy for glomerular filtration rate (GFR; considered a "gold standard" measure of kidney
function] than BUN, although it can vary widely within an individual depending on factors such as
diet and changes in muscle mass. Because of the potential lack of sensitivity and specificity of
individual biomarkers of renal function, studies evaluating multiple biomarkers (or ratios) [e.g.,
(Serdar et al.. 2014: Yoshimura etal.. 2005: EmmettetaL 1988a: LawtonetaL 1985: Baker et al..
1980: Fischbeinetal., 19791], might provide greater evidence for meaningful health outcomes
compared with studies only evaluating a single biomarker in isolation. A general consideration for
studies using biomarkers of urinary system function is that serum levels of PCBs could theoretically
be elevated due to reduced GFR that developed due to an unrelated cause. Prospective studies that
evaluate PCB exposure prior to development of any decrements of urinary system function are the
best way to address this concern, but most studies identified were cross-sectional in design (see
Figure 6). Biomarkers of renal function, including urinary or serum creatinine and BUN, also were
examined in 28 nonhuman mammalian studies, which can provide additional information useful for
evaluating potential causal relationships between exposure and effect (see Figure 28).

Evidence Stream

Endpoint Category

Human

Other Mammal

Kidney Weight

Kidney Histopathology

Serum Biomarkers of Renal Function

Urinalysis

Urinary Bladder Histopathology

Urinary System Mortality

Urine Output

Diabetic Nephropathy

Renal Disease/Renal Failure

Number of Studies

272

Figure 28. Overview of Human and Other Mammalian Urinary System Studies

Summary of the database of studies evaluating exposures to PCB mixtures and urinary system endpoints organized
by endpoint category. Lists of studies included in each count can be accessed via the online interactive version of
this figure (https://hawc.epa.gov/summarv/visual/assessment/100500282/QverviewAIIStudies/). Shading
intensity corresponds with the number of studies in each category, from 1 to 272, which is the maximum number
of nonhuman mammalian studies in any health endpoint category. The intent is to highlight not only differences
in the distribution of studies across urinary system endpoint categories but also to emphasize the number of
urinary system studies relative to the number of studies for other organs/systems.

Six human studies evaluated urinary system-related mortality (see Figure 28); all were
conducted among exposed workers and relied mainly on duration of employment as a proxy for
magnitude of PCB exposure. The study populations for these six analyses were sometimes

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overlapping but covered different periods. Causes of death evaluated included general death due to
disorders of the genitourinary system and more specific causes such as nephritis and renal
sclerosis.

In addition to the endpoints described above, studies of nonhuman mammals exposed to
PCB mixtures also evaluated kidney weight and urine composition and output (see Figure 28).
According to Craig etal. (20151. absolute kidney weight and renal histopathology are correlated,
making kidney weight a suitable marker to detect potential renal impacts from chemical exposure.
Measurements of urinary components relevant for assessing urinary system hazard included
urinary proteins, electrolytes, pH, blood, ketones, urea, and other excretory products
(e.g., sediment, casts). Urine output was infrequently studied following PCB exposure, limiting the
potential utility of these results for PCB hazard identification.

The bulk of available studies in the database evaluated PCB exposures and kidney structure
and function, but the urinary system also includes the urinary bladder. The lower urinary system
(ureter, bladder, urethra) is composed of similar tissue types (urothelium, connective tissue, and
muscle), which can be a primary target of xenobiotics but can also be altered by the production of
urinary solids fFrazier etal. 20121. Urinary bladder histopathology has been evaluated in eight
nonhuman mammalian studies (see Figure 28); five of these evaluated kidney and urinary bladder
histopathology together (Arnold et al. 1997: Schaeffer et al. 1984: Chu etal. 1980: latropoulos et
al, 1978: Koller and Zinkl. 1973). which allows for a limited assessment of potential linkages among
health endpoints observed across the full urinary system.

Multiple human and nonhuman mammalian studies evaluated urinary system endpoints.
Clinical evaluations of serum and urinary biomarkers of renal function are available from both
types of studies, providing a foundation for evaluating potential hazard for these endpoints. Other
important endpoints, like nephropathy and kidney disease/failure, were infrequently studied in
human populations. However, nonhuman mammalian studies offer supporting hazard information,
including evaluations of kidney weight and histopathology. In contrast, no human studies and very
few nonhuman mammalian studies evaluated endpoints related to the urinary bladder, which
represents an area of uncertainty that would benefit from further research.

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4. CONCLUSIONS

In this review, over 1,500 studies of humans and other mammals exposed to PCB mixtures
were mapped to 15 organs/systems. We identified 637 mammalian toxicological studies evaluating
endpoints in a variety of species exposed for different durations and at different life stages and 953
epidemiological studies conducted using diverse populations and methods. Although human and
other mammalian data are abundant for some organs/systems (e.g., hepatobiliary, nervous system,
and reproductive), some endpoints of great public interest (e.g., cardiovascular disease, autism)
have not been extensively studied in the context of PCB mixture exposure (see Table 31).

Table 3 provides a high-level summary of the endpoints in each organ/system that were
evaluated in human studies, along with preliminary assessments of the informativeness of each
database that consider the availability of both human and other mammalian studies. More
informative databases are more likely to support conclusive systematic reviews, while less
informative databases could be used to identify important topics for future research. Endpoints
identified as having low specificity might be most useful when evaluated in combination with other,
more informative measures. The anthropocentric focus of Table 3 was chosen for simplicity and
because endpoints grounded in strong human and other mammalian data provide the most
informative basis for hazard identification. However, endpoints evaluated only in animals can and
often do provide sufficient evidence to support the identification of hazards and analysis of dose-
response relationships critical for risk assessment (U.S. EPA. 2022). Notably, sparse data exist for
inhalation and dermal exposures in both humans and other mammals, representing important
areas of uncertainty that would benefit from further research, especially because these are highly
relevant human exposure routes.

There are several considerations that are important for interpreting this work. First, it
relies on publicly accessible published data. Supplemental search strategies (e.g., searching
reference lists of reviews, citation mapping, gray literature searches) were not extensively applied,
but technical experts did identify a few additional references for screening (n = 25). Historically,
scientific journals have often enforced publication length restrictions, sometimes leading to
incomplete reporting of study results. Potential selective reporting, where authors fail to mention
they conducted an evaluation or fail to report the results of an evaluation, is a factor to consider at

1This table provides an overview of the available data relevant for evaluating select endpoints within each
organ/system, with a focus on endpoints evaluated in human studies. Preliminary assessments of the potential
informativeness of each database are included, with availability of evidence from nonhuman mammalian studies
contributing to those assessments. Endpoints measured only in nonhuman mammalian models are not included
in this table to reduce the complexity of the analysis and to focus on the endpoints with the most direct human
relevance.

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the study evaluation step of a full systematic review. Furthermore, journals have been somewhat
reluctant to publish reports with primarily null results fMlinaric et al. 20171. and some work might
not have been published on the basis of decisions made by study sponsors or other factors fBero et
al, 20161. Publication bias exists when the reasons behind a failure to publish are associated with
the direction or magnitude of the effects observed fPwan etal, 2013: Dwan et al. 20081. Our
analysis of the PCB database included only published reports and did not address the potential for
publication bias. Future systematic reviews stemming from this work could consider using
statistical approaches to assess publication bias for studies of health endpoints and exposure to
PCB mixtures fDalton etal. 20161. Another caveat is that this evidence map is based only on full-
text screening and preliminary data extraction. Future analyses could include study evaluation and
full extraction of the data from subsets of studies relevant for specific research questions. These
additional review steps are needed to develop strong conclusions linking PCB exposure with
potential health effects. For example, full data extraction would be required to examine the
magnitude of exposure in animal studies relative to anticipated human exposures, which is an
important consideration for both hazard identification and dose-response assessment. Of note,
another challenge in conducting systematic reviews of large complex databases involves the use of
multiple systematic review tools, continual duplicate removal, and an ever-increasing literature
base as new studies are published each year.

The primary goal of this evidence map was to use systematic review methods to identify,
summarize, organize, and disseminate data relevant for characterizing potential human health
concerns from exposure to PCB mixtures. As an important part of this effort, we developed
interactive figures to help readers explore the available literature, including the ability to create
lists of references with customized combinations of study design features based on the specific
interests of the individual user. By sharing information from this SEM in this way, we hope to
provide a valuable tool that will both support future risk assessment work and highlight areas of
uncertainty that can be prioritized in future research to advance our understanding of PCB
mixtures and their potential effects on health.

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Table 3. Overview of the databases available for selected endpoint categories by organ/system

Organ/system

More informative endpoint
categories

Less informative endpoint categories

Notes

Cardiovascular

Blood pressure/Hypertension

IHD (including myocardial infarction)

Cerebrovascular disease (including stroke)

More data needed:

Atherosclerosis and other vascular diseases
Heart failure
Fetal heart rate

Low specificity or sensitivity.

Cardiovascular disease (NOS)

Subjective complaints

Cholesterol/triglyceride levels were
classified as hepatobiliary endpoints
(Section 3.3.7)

Dermal

Acne/Chloracne

Abnormal pigmentation

Dermal irritation (including eczema)

Hyperkeratosis

Nail deformities

More data needed:

Periodontal disease (including gingival

swelling/recession)

Scar formation

Low specificity or sensitivity.

"Skin problems"

Most human studies evaluated endpoints
at high PCB exposure levels

Atopic eczema was classified as an
immune endpoint (Section 3.3.8); dental
abnormalities were classified as
musculoskeletal endpoints (Section
3.3.10)

Developmental

Weight and size (early life)

More data needed:
Miscarriage/stillbirth
Birth defects

Low specificity or sensitivity.
Placental weight/histology

Measures of gestation length, pubertal
development, and endpoints associated
with testicular dysgenesis syndrome
were classified as reproductive endpoints
(Section 3.3.10)

Endocrine

Thyroid function

More data needed:

Thyroid disease

Adrenal gland function

Other endocrine organs and hormones

(including parathyroid endpoints)

Sex hormone levels were classified as
reproductive endpoints (Section 3.3.13);
insulin levels were classified as metabolic
endpoints (Section 3.3.9

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Organ/system

More informative endpoint
categories

Less informative endpoint categories

Notes

Gastrointestinal

(none)

More data needed:

Gastric ulcer
Colorectal polyps
Abdominal ultrasonography

Low specificity or sensitivity.

Abdominal pain

Nausea/vomiting

Changes in bowel habits

Bloating

Indigestion

Loss of appetite

Database limited for hazard assessment

Hematopoietic

WBC counts

Red blood cell counts/Hemoglobin

More data needed:

Anemia

Clotting function
Platelet counts

Low specificity or sensitivity.
Blood disease mortality

Measures of WBC function were
classified as immune endpoints (Section
3.3.8)

Hepatobiliary

Liver disease (including cirrhosis and
steatosis)

Serum biomarkers of liver function
Cholesterol/Triglyceride levels
Liver enzyme induction

More data needed:

Porphyria

Gallbladder and biliary endpoints

Low specificity or sensitivity.
Hepatomegaly

Immune

Immune suppression (including
susceptibility to infection, antigen-specific
antibody responses, WBC function, DTH)
Atopy (including allergies/asthma)

More data needed:

Autoimmunity (especially autoimmune disease
incidence)

Low specificity or sensitivity.

Nonspecific immunoglobulin levels
WBC counts

Immune organ size/weight

WBC counts were classified primarily as
hematopoietic endpoints (Section 3.3.6)

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Organ/system

More informative endpoint
categories

Less informative endpoint categories

Notes

Metabolic

Glucose homeostasis (including IR,
IGT/prediabetes, Type 2 diabetes mellitus,
gestational diabetes)

More data needed:
Metabolic rate

Low specificity or sensitivity.
Metabolic syndrome
Diabetes mellitus (NOS)
Overweight/obesity

Cholesterol/triglyceride levels were
classified as hepatobiliary endpoints
(Section 3.3.7); Type 1 Diabetes was
classified as an immune endpoint
(Section 3.3.8); diabetic nephropathy was
classified as a urinary system endpoint
(Section 3.3.15)

Musculoskeletal

Bone density/strength

Dental abnormalities (including enamel

defects and dental caries)

More data needed:

Arthritis

Low specificity or sensitivity.
Musculoskeletal complaints (including
muscle/joint pain, muscle weakness)

Most human studies evaluated endpoints
at high PCB exposure levels, especially in
fish-consuming populations

Rheumatoid arthritis was also classified
as an immune endpoint (Section 3.3.8)

Nervous System

Cognitive function

Attention, impulse control, externalizing
and internalizing behaviors
Executive function
Motor function/development

Following developmental exposures:
Social cognition and behavior
Auditory function

More data needed:

Brain aging disorders
Visual function
Olfactory function
Neurophysiology/neuroimaging
Following exposures during adulthood:
Social cognition and behavior
Auditory function

Low specificity or sensitivity.

Dizziness

Headache

Fatigue/level of consciousness
Neurological condition
Neurological disease mortality
Peripheral sensation or pain
Play behavior
Sleep problems

Ocular

Ocular swelling and irritation (including
periorbital edema, ocular discharge,
Meibomian gland enlargement,
conjunctivitis)

Most human studies evaluated endpoints
at high PCB exposure levels

Infectious forms of conjunctivitis were
classified as immune endpoints (Section
3.3.8)

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Organ/system

More informative endpoint
categories

Less informative endpoint categories

Notes

Reproductive

Sex hormone levels
Fertility

Sperm/semen parameters

Gestation length (including preterm birth)

Endometriosis

Pubertal development

Endpoints associated with testicular

dysgenesis syndrome (including anogenital

distance, hypospadias, cryptorchidism, sex

ratio)

More data needed:

Gynecological disorders other than
endometriosis

Pregnancy-related disorders (including
preeclampsia)

Menstrual cycle characteristics

Ovulation

Reproductive aging

Low specificity or sensitivity.

Erectile dysfunction

Measures of birth defects,
miscarriage/stillbirth, and placental
health were classified as developmental
endpoints (Section 3.3.3)

Respiratory

Pulmonary health and function (including
chest radiography, spirometry, respiratory
sounds, sputum analysis)

Low specificity or sensitivity.

Respiratory disease mortality
Respiratory illness history
Respiratory symptoms (e.g., shortness of
breath, cough/sputum, chest tightness)

Most human studies evaluated endpoints
at high PCB exposure levels

Asthma and infectious respiratory
diseases were classified as immune
endpoints (Section 3.3.8)

Urinary System

Biomarkers of renal function (including
markers measured in serum or urine)

More data needed:

Kidney disease/renal failure (including diabetic
nephropathy)

Urinary system components other than the
kidneys

Low specificity or sensitivity.

Urinary system mortality (NOS)

DTH = delayed type hypersensitivity; IGT = impaired glucose tolerance; IR = insulin resistance; IHD = ischemic heart disease; NOS = not otherwise specified; PCB
= polychlorinated biphenyl; WBC = white blood cell.

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Zhan^ \ \ iu x M
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APPENDIX A. QUALITY ASSURANCE FOR A
SYSTEMATIC EVIDENCE MAP FOR
POLYCHLORINATED BIPHENYL (PCB)
MIXTURES: EVALUATION OF NONCANCER
HEALTH ENDPOINTS AND EXPOSURES

This product is prepared under the auspices of the U.S. Environmental Protection Agency
(EPA) within the Office of Research and Development (ORD) in the Center for Public Health and
Environmental Assessment (CPHEA). EPA has an agency-wide quality assurance (QA) policy that is
outlined in the EPA Quality Manual for Environmental Programs (see CIO 2105-P-01.11 and follows
the specifications outlined in EPA Order CIO 2105.1.

As required by CIO 2105.1, ORD maintains a Quality Management Program, which is
documented in an internal Quality Management Plan (QMP). The latest version was developed in
2013 using Guidance for Developing Quality Systems for Environmental Programs (OA/G-1). A
National Center for Environmental Assessment (NCEA)/CPHEA-specific QMP was also developed in
2013 as an appendix to the ORD QMP. QA for products developed within CPHEA is managed under
the ORD QMP and applicableappendices.

This work was conducted under the U.S. EPA Quality Assurance program to ensure data are
of known and acceptable quality to support their intended use. Surveillance of the work by the lead
authors and programmatic scientific leads ensured adherence to QA processes and criteria, as well
as quick and effective resolution of any problems. The QA manager, lead authors, and programmatic
scientific leads have determined under the QA program that this work meets all U.S. EPA quality
requirements. This report was written with guidance from the CPHEA Quality Assurance Project
Plans (QAPPs; see table below). As part of the QA system, a quality product review is conducted
prior to management clearance. A Technical Systems Audit may be performed at the discretion of
the QA staff. This project underwent three quality audits in 2020, 2021, and 2022, with no major
findings. The report was subject to internal peer review by two CPHEA scientists and an
independent external peer review by three scientific experts. The reviews focused on whether all
studies were correctly selected, interpreted, and adequately described for the purposes of this
report. The reviews also covered quantitative and qualitative aspects of the report and addressed
whether uncertainties were adequately characterized.

A-l

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Title

Document number

Latest approval date

Program Quality Assurance Project Plan
(PQAPP) for the Integrated Risk Information
System (IRIS) Program

L-CPAD-0030729-QP-1-5

June 2022

Quality Assurance Project Plan (QAPP)
General Support of CPHEA Human Health
Assessment Activities

L-CPAD-0031961-QP-1-2

May 2022

Quality Assurance Project Plan (QAPP)
Support for the IRIS Toxicological Review of
Polychlorinated Biphenyls (PCBs): Effects
Other Than Cancer

L-CPAD-0031956-QP-1-2

July 2021

A-2

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v>EPA

United States
Environmental Protection
Agency

PRESORTED STANDARD
POSTAGE & FEES PAID
EPA

PERMIT NO. G-35

Office of Research and Development (8101R)
Washington, DC 20460

Official Business
Penalty for Private Use
$300

Recycled/Recyclable Printed on paper that contains a minimum of
50% postoonsumer fiber content processed chlorine free

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