Journal of Toxicology and Environmental Health, Part B

Critical Reviews

ISSN: (Print) (Online) Journal homepage: www.tandfonline.com/journals/uteb20

A review of the toxicology of oil in vertebrates:

what we have learned following the Deepwater
Horizon oil spill

Ryan Takeshita, Steven J. Bursian, Kathleen M. Colegrove, Tracy K. Collier,

Kristina Deak, Karen M. Dean, Sylvain De Guise, Lisa M. DiPinto, Cornelis J.
Elferink, Andrew J. Esbaugh, Robert J. Griffitt, Martin Grosell, Kendal E. Harr,
John P. Incardona, Richard K. Kwok, Joshua Lipton, Carys L. Mitchelmore,
Jeffrey M. Morris, Edward S. Peters, Aaron P. Roberts, Teresa K. Rowles,
Jennifer A. Rusiecki, Lori H. Schwacke, Cynthia R. Smith, Dana L. Wetzel,
Michael H. Ziccardi & Ailsa J. Hall

To cite this article: Ryan Takeshita, Steven J. Bursian, Kathleen M. Colegrove, Tracy K. Collier,
Kristina Deak, Karen M. Dean, Sylvain De Guise, Lisa M. DiPinto, Cornelis J. Elferink, Andrew J.
Esbaugh, Robert J. Griffitt, Martin Grosell, Kendal E. Harr, John P. Incardona, Richard K. Kwok,
Joshua Lipton, Carys L. Mitchelmore, Jeffrey M. Morris, Edward S. Peters, Aaron P. Roberts,
Teresa K. Rowles, Jennifer A. Rusiecki, Lori H. Schwacke, Cynthia R. Smith, Dana L. Wetzel,
Michael H. Ziccardi & Ailsa J. Hall (2021) A review of the toxicology of oil in vertebrates: what we
have learned following the Deepwater Horizon oil spill, Journal of Toxicology and Environmental
Health, Part B, 24:8, 355-394, DOI: 10.1080/10937404.2021.1975182

To link to this article: https://doi.org/10.1080/10937404.2021.1975182

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JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH, PART B
2021, VOL. 24, NO. 8, 355–394
https://doi.org/10.1080/10937404.2021.1975182

REVIEW

A review of the toxicology of oil in vertebrates: what we have learned following

the Deepwater Horizon oil spill
Ryan Takeshitaa, Steven J. Bursianb, Kathleen M. Colegrovec, Tracy K. Collierd, Kristina Deake, Karen M. Deanf,
Sylvain De Guiseg, Lisa M. DiPintoh, Cornelis J. Elferinki, Andrew J. Esbaughj, Robert J. Griffittk, Martin Groselll,
Kendal E. Harrm, John P. Incardonan, Richard K. Kwoko, Joshua Liptonp, Carys L. Mitchelmoreq, Jeffrey M. Morrisr,
Edward S. Peterss, Aaron P. Robertst, Teresa K. Rowlesu, Jennifer A. Rusieckiv, Lori H. Schwackea, Cynthia R. Smitha,
Dana L. Wetzelw, Michael H. Ziccardix, and Ailsa J. Hally
a
Conservation Medicine, National Marine Mammal Foundation, San Diego, California, United States; bDepartment of Animal Science, Michigan
State University, East Lansing, Michigan, United States; cCollege of Veterinary Medicine, Illinois at Urbana-Champaign, Brookfield, Illinois,
United States; dZoological Pathology Program, Huxley College of the Environment, Western Washington University, Bellingham, Washington,
United States; eCollege of Marine Sciences, University of South Florida, St. Petersburg, Florida, United States; fLethbridge, Alberta, Canada;
g
Department of Pathobiology and Veterinary Sciences, University of Connecticut, Storrs, Connecticut, United States; hOffice of Response and
Restoration, NOAA, Silver Spring, Maryland, United States; iDepartment of Pharmacology and Toxicology, University of Texas Medical Branch,
Galveston, Texas, United States; jMarine Science Institute, University of Texas at Austin, Port Aransas, Texas, United States; kDivision of Coastal
Sciences, School of Ocean Science and Engineering, University of Southern Mississippi, Gulfport, Mississippi, United States; lRSMAS, University
of Miami, Miami, Florida, United States; mURIKA, LLC, Mukilteo, Washington, United States; nNOAA Environmental Conservation Division,
Northwest Fisheries Science Center, Seattle, Washington, United States; oDepartment of Health and Human Services, National Institute of
Environmental Health Sciences, National Institutes of Health, North Carolina, United States; pBoulder, Colorado, United States; qUniversity of
Maryland Center of Environmental Science, Chesapeake Biological Laboratory, Solomons, Maryland, United States; rHealth and Environment
Division, Abt Associates, Boulder, Colorado, United States; sDepartment of Epidemiology, LSU School of Public Health, New Orleans, Louisiana,
United States; tAdvanced Environmental Research Institute and Department of Biological Sciences, University of North Texas, Denton, Texas,
United States; uNOAA Office of Protected Resources, National Marine Fisheries Service, Silver Spring, Maryland, United States; vDepartment of
Preventive Medicine and Biostatistics, Uniformed Services University, Bethesda, Maryland, United States; wEnvironmental Laboratory of
Forensics, Mote Marine Laboratory, Sarasota, Florida, United States; xSchool of Veterinary Medicine, One Health Institute, University of
California, Davis, California, United States; ySea Mammal Research Unit, Scottish Oceans Institute, University of St Andrews, St Andrews, UK

ABSTRACT KEYWORDS
In the wake of the Deepwater Horizon (DWH) oil spill, a number of government agencies, Oil toxicity; Deepwater
academic institutions, consultants, and nonprofit organizations conducted lab- and field-based Horizon oil spill; wildlife
research to understand the toxic effects of the oil. Lab testing was performed with a variety of toxicology; Gulf of Mexico;
fish, birds, turtles, and vertebrate cell lines (as well as invertebrates); field biologists conducted fish; birds; sea turtles; marine
mammals; human health
observations on fish, birds, turtles, and marine mammals; and epidemiologists carried out
observational studies in humans. Eight years after the spill, scientists and resource managers
held a workshop to summarize the similarities and differences in the effects of DWH oil on
vertebrate taxa and to identify remaining gaps in our understanding of oil toxicity in wildlife and
humans, building upon the cross-taxonomic synthesis initiated during the Natural Resource
Damage Assessment. Across the studies, consistency was found in the types of toxic response
observed in the different organisms. Impairment of stress responses and adrenal gland function,
cardiotoxicity, immune system dysfunction, disruption of blood cells and their function, effects on
locomotion, and oxidative damage were observed across taxa. This consistency suggests con­
servation in the mechanisms of action and disease pathogenesis. From a toxicological perspec­
tive, a logical progression of impacts was noted: from molecular and cellular effects that manifest
as organ dysfunction, to systemic effects that compromise fitness, growth, reproductive potential,
and survival. From a clinical perspective, adverse health effects from DWH oil spill exposure
formed a suite of signs/symptomatic responses that at the highest doses/concentrations resulted
in multi-organ system failure.

CONTACT Ryan Takeshita [email protected] National Marine Mammal Foundation, 2240 Shelter Island Dr. Ste. 200; San Diego, CA 92106,
United States
Supplemental data for this article can be accessed on the publisher’s website.
© 2021 The Author(s). Published with license by Taylor & Francis Group, LLC.
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-
nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built
upon in any way.
356 R. TAKESHITA ET AL.

Table 1. Summary of reported effects of DWH oil exposure on vertebrate systems, life stages, and responses. Effects are dependent on
oil type, exposure concentration and duration, exposure route, and species/life-stage. Although the focus is mainly on toxicological
effects, we include some physical effects of oil, particularly in birds, turtles, and humans. Workshop participants provided their expert
opinions on relative weights of evidence for effects on a given system. Red symbols denote the taxa in which the most significant
effects on the system have been reported or there is a large amount of evidence for effects on the system. Black symbols denote the
taxa in which there is some limited evidence for an effect. Cells with no text indicate no data are available for that system/taxon
combination. The studies included under the behavioral “system” are a collection of tested effects in whole animal “behaviors”, but the
etiologies of the response impairments likely differ and mechanistically may belong to other physiological systems. Downward arrows
represent a decrease in the observations/effects; upward arrows represent an increase. HPI: hypothalamus-pituitary-interrenal axis;
HPA: hypothalamus-pituitary-adrenal axis; ROS: reactive oxygen species; LPO: lipid peroxidation.
Stage/System/
Response Taxa

Fish Turtles Humans

Birds Marine

Mammals
Development and
early survival
(Section 1)
Deformities ↑
Reproduction
(Section 2)

Possible transgenerational Reproductive success Variability in hatching Reproductive success ↓

effects ↓ success Fetal distress
Reproductive success ↓ Parental care ↓
Nest abandonment
↑
Hatching success ↓
Endocrine
(Section 3)

Possible HPI dysfunction HPA dysfunction Possible HPA dysfunction Impaired stress response Impaired stress
– probable HPA response
dysfunction
Adrenal gland disease
Respiratory
(Section 4)

Gill damage Cough/dyspnea Observed asphyxiation Moderate-severe lung Respiratory

DNA single strand breaks in Air sacculitis disease disease
gill. Open-mouthed Bronchopneumonia
Observed asphyxiation breathing
Maximal metabolic rate ↓
Aerobic scope ↓
Cardiovascular
(Section 5)

Cardiotoxicity in early life Damage to myocytes Possible effects indicated by Possible cardiac Heart attack risk
stages Myocardial changes in hematology morphometric ↑
Disruption to K+ and Ca2+ contractility ↓ and blood chemistry abnormalities and Palpitations ↑
ion fluxes Arrhythmia cardiac fibrosis Acute chest
Stroke volume ↓ Possible dilative pain
Cardiac output ↓ cardiomyopathy
Cardiomyocyte shortening
during stimulation ↓
Neurological/
Sensory/
Behavioral
(Section 6)
(Continued)
 JOURNAL OF TOXICOLOGY & ENVIRONMENTAL HEALTH, PART B 357

Table 1. (Continued).
Stage/System/
Response Taxa
Visual acuity ↓ Flight control ↓ Mental health ↓
Olfaction ↓ Take off speed ↓ Dizziness,
Critical swim speed ↓ Flight length ↑ nausea,
Swim performance ↓ Foraging time ↓ migraine ↑
Prey capture ability ↓ Flight strategy
Thigmotaxis ↑ change
Group cohesion ↓ Lethargy
Risk taking behavior ↑ Heat-seeking
behavior
Nutritional/ Gastrointestinal/Urinary
(Section 7)

Altered gut microbiome Food consumption Gastrointestinal

changes symptoms ↑
Slower refueling
post-exercise
Hematochezia
Renal ductular and
tubular hypertrophy
and mineralization
Plasma urea and uric
acid ↑
Kidney weight
(normalized to body
weight) ↑
Hepatobiliary
(Section 8)

Hepatic lesions Liver weight Some indication of liver

Biomarkers of hepatic (normalized to body damage
activity ↑ weight) ↑
Integument/ Thermoregulation
(Section 9)

Some evidence for skin lesion Hypothermia Hyperthermia when covered Limited in vivo evidence Dermal symptoms
prevalence correlated to oil Feather damage ↑ in oil that PAH cause skin ↑
exposure Preening time ↑ cell damage
Energetic flight costs
↑
Feather plucking ↑
Gross thickening of
dermis
Immune
(Section 10)

Immune-associated gene White blood cell T cell dysfunction

expression ↓ changes
Mortality following
pathogen exposure ↑
Circulatory
(Section 11)

Oxidative stress measured in

circulating blood
DNA single strand breaks in Anemia coagulopathy
blood
Metabolism
(Section 12)

(Continued)
358 R. TAKESHITA ET AL.

Table 1. (Continued).
Stage/System/
Response Taxa
Growth rate over extended Foraging time ↓ Cellular damage oxidative Body mass ↓
time ↓ Energetic flight costs stress ↑
Cellular damage (apoptosis, ↑ Antioxidant responses ↑
oxidatative stress) Slower refueling DNA damage
Cellular membrane lipid Exercise-flight
peroxidation from ROS (LPO) induced exhaustion
measured in plasma) ↑ Creatine kinase ↑
Aspartate
aminotransferase ↑
Cellular Damage
(multiple organ
systems)
(All sections)
Apoptosis, oxidataive stress↑ Cytochrome P450 Oxidative stress ↑
enzymes induced Antioxidant responses ↑
Glutathione and DNA damage
glutathione
reductase induced

Introduction 2018, included multi-disciplinary researchers from

a broad array of study taxa. The workshop had the
Between April and July 2010, the Macondo well
following specific goals –
blowout/Deepwater Horizon (DWH) oil spill
resulted in release of more than 636 million L of
● Collate and compare the results of exposure
oil into the northern Gulf of Mexico (GoM). The
and effect (toxicity) studies at various marine
resulting oil slicks covered over 112 million km2 in
trophic levels;
the upper surface waters (Colwell 2014, 2018;
● Report commonalities and differences among
DWH Natural Resource Damage Assessment
effects on diverse species/life stages in labora­
Trustees 2016). Since the spill, a Natural Resource
tory and field studies; and
Damage Assessment (NRDA), along with a breadth
● Summarize the current state of knowledge fol­
of research projects funded by the GoM Research
lowing research arising from the response to
Initiative (GoMRI), have produced a large body of
the DWH oil spill.
information on the exposure to and potential toxi­
city of DWH source and weathered crude oil and of
Here we provide a review and summary of the
the associated polycyclic aromatic hydrocarbons
workshop findings, along with additional rele­
(PAHs) to marine vertebrates (DWH NRDA
vant literature produced in the wake of the
Trustees 2016). These include studies and reviews
DWH oil spill.
on fish (e.g., Pasparakis et al. 2019), birds (e.g.,
A variety of DWH-related studies have docu­
Bursian et al. 2017a; Dean and Bursian 2017), mar­
mented impacts on survival, fecundity, and popula­
ine mammals (e.g., Takeshita et al. 2017), turtles (e.
tion dynamics in different species inhabiting the
g., Mitchelmore, Bishop, and Collier 2017) and
GoM that were within the footprint of the DWH
humans (e.g., Croisant and Sullivan 2018), but to
oil spill (e.g., McCann et al. 2017; McDonald et al.
date little effort has been put into surveying the
2017a, 2017b; Mullin et al. 2017; Schwacke et al.
effects of DWH oil across all of these vertebrate
2017; Wallace et al. 2017; Walter et al. 2014).
taxa.
However, the purpose of the workshop (and this
GoMRI was established to investigate the subsequent review) was to focus on the toxicologi­
impacts of oil, dispersed oil, and dispersant on cal aspects of DWH oil spill research in vertebrate
GoM ecosystems. As part of this mission, GoMRI species both during and after the event (i.e., inves­
sponsored a workshop to discuss and synthesize the tigations on the adverse physiological and patholo­
newly acquired knowledge on the toxicology of oil gical “sub-lethal” effects of the oil, rather than
in vertebrates. The workshop, held in October mortality and morbidity per se) (Table 1). The
Table 2. High level summary of toxicological study designs to describe the exposure and effects of DWH oil by taxon group. A major outcome of the workshop was that researchers and
decision makers need to carefully consider the nature of each field/laboratory study’s design, exposure/dose considerations, and context when comparing across experiments/field efforts
and to estimates of exposure during the event (comparing these factors across the literature is beyond the scope of this review). Typically, health assessments were conducted and/or
endpoints were measured on a similar time scale as the duration of exposure, however some tests investigated delayed exposures. This table only refers to studies cited in the body of this
review; please refer to the citations in the text for more information about specific studies.
Internal
Field or Duration of measure of
Taxon laboratory Life stages Exposure route(s) exposure Oil type Concentration or dose known? Other environmental factors exposure?
Fish Laboratory Early life Waterborne Hours to days WAF, HEWAF, CEWAF Water concentrations measured UV and sunlight, No
stages DWH slick oil, crude oil temperature, salinity and
and PAHs dissolved oxygen
Juvenile Waterborne and intraperitoneal Hours to weeks HEWAF, CEWAF, DWH slick Water concentrations measured Hypoxia No
and Oiled sediment > month with 1 oil, PAHs, DWH Sediment and water Pathogenic bacteria Yes
adult month recovery surrogate oil concentrations for PAH
Sub- period monitored
adult
Cells (in Waterborne Hours WAF, DWH source and slick Water concentrations measured NA
vitro) oil,
Field Adult Waterborne Months to multi- DWH slick oil Water concentrations measured No
year
Birds Laboratory Adults Ingestion and “dermal”, plus Days DWH weathered oil Yes, higher than turtle exposures No
incidental dermal for ingestion
exposures
Field Adults Ingestion and “dermal” (inferred) Months to multi- DWH oil No Yes
year
Turtles Laboratory Juveniles Ingestion Days to weeks DWH slick oil Yes, lower than bird exposures Yes
(surrogate
turtle species)
Laboratory Hatchlings WAF/CEWAF Days No
(loggerhead
hatchlings)
Field Juveniles Ingestion and dermal, plus Months DWH oil Estimated using qualitative scale, Yes (for some
and inhalation. then extrapolated to quantitative studies)
adults ranges
Marine Laboratory Cells Waterborne Weeks WAF, CEWAF Yes N/A
Mammals (in
vitro)
Field All life Inhalation, dermal, ingestion, Years DWH oil No No
stages aspiration (inferred)
Humans Field Adults Inhalation, some dermal and Months DWH oil Yes, estimated for inhalation No
possible ingestion (inferred)
JOURNAL OF TOXICOLOGY & ENVIRONMENTAL HEALTH, PART B
359
360 R. TAKESHITA ET AL.

DWH oil spill resulted in a wide range of vertebrate due to the cryptic nature of marine species,
species being exposed to the same source oil, albeit challenges with regard to the study of long-
at different concentrations, stages of weathering, term effects, and absence of baseline health
and exposure durations. data, in addition to ethical, logistical and fund­
Cross taxa comparisons are perhaps more rele­ ing constraints that have governed the studies.
vant than comparisons across studies with different For example, investigations on the potential
oil types and sources, although there are efforts to effects of DWH oil on endangered sea turtles
standardize experiments across the fields (e.g., have been limited to lab exposures with either
King, Elliott, and Williams 2020; Hodson et al. un-releasable sea turtle hatchlings (Harms et al.
2019; Adams et al. 2017; Mitchelmore et al. 2020; 2019) or surrogate species such as red-eared
Engel et al. 2017). However, workshop participants sliders Trachemys scripta elegans and snapping
repeatedly emphasized the need to appropriately turtles Chelydra serpentina (Mitchelmore et al.
contextualize the comparability of data and the 2015). For lab tests, the study designs and meth­
limitations of the various approaches/methods, odologies, including the type of oil, concentra­
especially in relation to exposure and dose across tion, duration of exposure, choice of native vs
the studies (Table 2). For some species such as sea surrogate species, life stage, exposure route, and
turtles, birds, and cetaceans, information from ear­ reporting of analytical chemistry, might also
lier studies/reviews is included to provide connec­ make cross-study comparisons difficult, espe­
tions about specific endpoints/systems and oil cially when attempting to compare the findings
toxicity. Throughout the discussion, oil exposure to field studies.
refers to whole DWH oil, unless specifically stated The evidence for physical and toxicological
otherwise (for example, PAH-only lab exposures). effects are organized by target system and this
Although oil spill response actions can inadver­ review follows this organization (Table 1). The
tently result in toxicological impacts or complica­ assembled scientists used their expert judgment to
tions, discussion of the combined impacts of oil and provide an indicative level of confidence and con­
dispersant is limited here, as in the case of expo­ sensus regarding the degree to which the scientific
sures to dispersed oil. However, robust literature on evidence supported a conclusion that DWH oil
the effects of COREXIT on organisms is available affected a particular system and taxonomic group
(e.g., Anderson et al. 2011). To maintain the focus (see Table 1) and developed conceptual models/
of the review, investigations concentrated on PAH- impact pathways as a means of synthesizing the
based toxicity. The specific toxicology of other che­ information (Figures S1-S4).
mical contaminants resulting from the DWH spill,
such as heavy metals, was excluded but workshop
Exposure of vertebrates to DWH oil
participants acknowledged that these effects cannot
be isolated in situations with whole oil exposures. The different types, magnitudes, durations, and
However, the physical effects of oil, such as fouling combinations of vertebrate exposure to DWH oil,
of bird feathers, typically in the context of juvenile/ in addition to any other physical, biological, and
adult birds and turtles. Where relevant, studies that chemical stressors, were likely to affect the compar­
include investigating the effects of multiple envir­ isons of toxicity across studies and taxa (Table 2).
onmental stressors in addition to oil, such as the However, as the main objective was to investigate
effects of temperature and sunlight, were included. common mechanisms, effects, and outcomes of oil
There are limitations to the comparisons that toxicity, the group of experts agreed to avoid letting
can be made across taxa in an effort to identify the overwhelming details of exposure derail the
commonalities, pathways, target organs and tox­ discussions. Even with the breadth and depth of
icological endpoints. Clearly there are differences the research associated with DWH, the question
that are attributed to ecological niches, trophic of how exposure influences toxicological outcome
levels, habitats, and life-history strategies of the is a major gap in our collective understanding of
different genera, as well as critical physiological oil’s impacts on wildlife and humans due to the
differences. However, there are also limitations complex nature ofthe 1) duration and the
 JOURNAL OF TOXICOLOGY & ENVIRONMENTAL HEALTH, PART B 361

geographic scale of the spill, 2) variety of habitats, At the sea surface, rising oil created an extensive
species, and life-stages affected, and 3) increasing surface slick and subsurface plume that, upon land­
number of sub-lethal oil effects at the different fall, covered the coastline with oil. In addition to
levels of biological organization. Thus, the variety embryonic and larval invertebrates and fish coming
of DWH oil toxicity exposure studies reflect the into contact with the slick and sheen, sea turtles and
multi-faceted fate and transport of the DWH oil. marine mammals encountered surface oil when sur­
As source oil ejected into the GoM from the facing to breathe, feed, and/or rest. Birds were also
riser at the sea floor, it immediately mixed with exposed to surface oil when landing on the water/
sea water (and dispersants, once subsea applica­ coastline or foraging for prey, resulting in oily plu­
tion was in place) to produce droplets and dis­ mage. Thus, many lab studies exposed animals to
solved oil components. Plumes of this DWH oil naturally weathered slick oils (e.g., “slick A”)
mixture then moved with the ocean currents. skimmed from the ocean surface during DWH
Similar mixtures of dissolved oil and oil droplets response activities (see Forth et al. 2017 for a
formed at the surface underneath the oil slick, description and comparison of the oils used in the
driven partially by wave action and aerial applica­ NRDA toxicity testing program). Several research
tion of dispersants. Many of the toxicological stu­ groups specifically measured the effects of surface
dies focused on the effects of waterborne oil on sheen on ichthyoplankton, including the additional
plankton, invertebrates, and fish, particularly negative effects of ultraviolet [UV] light. Other
focusing on: 1) negatively-buoyant early life- groups investigated exposure to other taxa, including
stage invertebrates and fish in the surface mixing a surrogate-species study on whole oil ingestion via
zone, and 2) the likely sublethal effects to juvenile esophageal gavage tubes with snapping turtles and
and adult fish, including an assessment of how red-eared sliders, and studies on the negative effects
exposure to oil droplets may differ from exposure of DWH oil on bird species found in the GoM due to
to dissolved oil components alone (e.g., Morris, ingestion of oil-contaminated prey as well as oiled
Lay, and Forth 2015). These lab experiments gen­ plumage. Although these experiments had similar
erally used precisely controlled conditions and delivery mechanisms, the types of oils were differ­
concentrations as verified by analytical chemistry ent (for example, natural vs. artificial weathering)
of water-accommodated fractions (WAFs) of oil and the final total dose was much higher in the oil-
using either high-energy mixing (HEWAFs) with contaminated prey for birds compared to the turtle
a blender or stir-plate or chemically assisted mix­ gavage protocol, thus these doses can only be com­
ing (CEWAFs) using dispersants. pared to inferred oil exposures in the field. A sum­
Over time, waterborne oil components settled mary of the different approaches to determine the
to the deep-sea floor, often due to the formation of impact of the oil on the major taxonomic groups is
oil and bacteria/particulate matter aggregates presented in Table 2. During the workshop, lab
termed marine snow. As the remaining surface results were also compared to data on living and
oil moved closer to coastlines, natural mixing dead, wild animals collected during field wildlife
and tidal action drove oil into shallow water sedi­ response efforts for sea turtles (Stacy et al. 2017)
ment. Several groups conducted a variety of tests and birds (Harr et al. 2017b; Wallace et al. 2017),
on benthic infauna, shrimp, and fish to under­ and health assessments of temporarily captured
stand how concentrating oil on the sea floor may common bottlenose dolphins (Tursiops truncatus
impact fauna, including sub-lethal effects on older truncatus) (Schwacke et al. 2017; Smith et al. 2017),
life-stages (e.g., Brown-Peterson et al. 2017, 2015a; as well as information from stranded birds (Fallon et
Lotufo et al. 2016; Morris, Lay, and Forth 2015). al. 2018), turtles (Stacy et al. 2017), and dolphins
Similar to the water accommodated fractions, con­ (Venn-Watson et al. 2015). These investigations
ditions of these exposures may typically be con­ relied upon extrapolated and inferred exposures
trolled in the lab and measured using analytical based upon field measurements or remote sensing
chemistry including standardized mixing proto­ data. However, many of the lab studies employed
cols to infuse sediment with various concentra­ field-collected data about oil weathering and con­
tions of oil. centration to design and/or ground-truth/verify lab
362 R. TAKESHITA ET AL.

exposure tests and results. Human studies included column, but their resilience may vary (Philiber et
in our discussions relied upon reconstructed expo­ al. 2019; Wobus et al. 2015), particularly between
sures to crude oil and dispersed oil (e.g., Stewart et saltwater and freshwater species. In combination
al. 2018) and self-reports (Rusiecki et al. 2018). with oil exposure, UV radiation from sunlight exhi­
Despite the variety of species, exposure scenar­ bits synergistic ability to enhance the effects of
ios, and additional stressors, a noteworthy set of PAHs, known as photoinduced toxicity (Bridges
consistent toxic effects was found for DWH oil et al. 2018), which is a particular risk for transpar­
across the literature likely driven in part by: 1) ent eggs. Experiments with mahi-mahi
focusing on studies with one crude oil source, albeit (Coryphaena hippurus) embryos, both early (Alloy
at various stages of weathering, 2) using standar­ et al. 2016) and later in development (Sweet et al.
dized methods for mixing oil and water or sedi­ 2017), determined that exposing them to WAFs of
ment, including analytical chemistry slick oil collected during the DWH spill, together
characterization and conducting lab exposures with increasing levels of natural sunlight, signifi­
time, duration and concentration and 3) investigat­ cantly reduced the proportion that hatched and
ing a multitude of biological endpoints at various altered embryo buoyancy and metabolic rates.
levels of organization from numerous sublethal However, there may be different effects due to any
effects to mortality on various biological systems. discrepancies between UV spectra of natural sun­
light versus artificial UV exposure systems (Lay et
al. 2015). A similar effect on larval mortality was
Systemic and physiological effects of oil on also detected in red drum (Sciaenops ocellatus), an
vertebrates economically and ecologically important estuarine
species, and spotted seatrout (Cynoscion nebulosus)
The workshop considered the evidence for tox­
(Alloy et al. 2017), with the latter species being
icological impacts of DWH oil by broad phy­
more sensitive. These findings highlight the impor­
siological system; any affected systems and
tance of assessing the concentrations of PAHs asso­
responses where findings were reported across
ciated with toxicity on fish embryos in relation to
more than one taxon are summarized in Table
levels of UV (Lay et al. 2015). Evidence of inter­
1. There was also evidence for DWH oil's
active effects between temperature, salinity and
adverse effects on behavioral responses, life
PAHs on both hatching and embryo mortality in
stage impacts, and on effects at the molecular
Gulf killifish (Fundulus grandis) was reported by
and cellular level that may be common across
Rodgers et al. (2018a). However, effects were not
different physiological systems. Where data
consistent and depended upon relative salinity and
were available by vertebrate taxonomic group,
temperature combinations.
the findings of the studies are considered for
The type of oil is also a key toxicity factor as
each taxon fish, birds, turtles, marine mammals,
weathering of oil results in products with differ­
and humans. Here, our conversations and avail­
ent compositions (Forth et al. 2017; Morris, Lay,
able literature are summarized in the order of
and Forth 2015). Weathered oil was more lethal
consideration at the workshop.
to mahi-mahi embryos, on a total PAH basis,
than source oil based on 96 hr median lethal
Development and early survival concentrations (45.8 µg/L compared to 8.8 µg/L
total PAH) (Esbaugh et al. 2016). These differ­
Early life stages and juveniles across taxa may be ences may be related to the amount of dissolved
more susceptible to the effects of oil due to their ≥ three-ringed PAHs in the oil although source
immaturity and developing physiologies. and weathered oil initiated similar LC50s in red
drum (Khursigara et al. 2017). A difference
Fish between weathered oil and source oil was also
Pre-hatch. The buoyant eggs of many fish species found in bay anchovies (Anchoa mitchillis) in
are likely to be at risk from the influence of oil which the LC50s were lower in embryos exposed
exposure due to their distribution in the water to more weathered fractions of DWH oil
 JOURNAL OF TOXICOLOGY & ENVIRONMENTAL HEALTH, PART B 363

(O’Shaughnessy et al. 2018). Despite differences Turtles

in weathering, concentration often remains the Field and lab studies demonstrated no marked
critical predictor of effects. For example, a gen­ impact on mortality and deformity rates after turtle
ome-wide gene expression study in Gulf killifish egg exposure to oil. After the 1979 Ixtoc 1 blowout
determined that transcriptional responses only at in the Bay of Campeche, Mexico, lab studies with
higher concentrations of oil exposure were pre­ loggerhead turtle (Caretta caretta) eggs and field
dictive of field-observed responses in the sensitive studies of Kemp’s Ridley turtle eggs (Lepidochelys
early life stages in addition to causing DNA kempi) indicated that exposure to oil (not from
damage in mature fish (Pilcher et al. 2014). DWH) reduced embryo and hatchling survival
Exposure of Gulf killifish embryos (< 24 hr post- and produced developmental deformities in those
fertilization) to HEWAF resulted in mortality that that survived. Exposure conditions were important
was exacerbated by simultaneous hypoxia or in determining severity of the effect: non-weathered
increased temperature (Rodgers et al. 2018a). oil was more toxic (Fritts and McGehee 1982).
Post-hatch. Once eggs have hatched, the survival DWH oil exposure in surrogate sea turtle species
of the larvae is dependent upon the specific devel­ such as common snapping turtles also diminished
opmental window during which the larvae are hatching success and increased developmental
exposed to oil. For example, Bay anchovies exposed deformities (Bell, Spotila, and Congdon 2006; Van
to HEWAF and CEWAF displayed different sensi­ Meter, Spotila, and Avery 2006), although these
tivities at two developmental stages. Young larvae were not seen by Rowe, Mitchelmore, and Baker
at 5 days post hatching were more sensitive than (2009). In studies using non-DWH oil, altering the
older larvae at 21 days post hatching (Duffy et al. physical characteristics of the nesting substrate
2016). However, Duffy et al. (2016) concluded that and/or physical smothering of the egg surface can
lethal concentrations in acute (24 hr) exposure impact eggshell respiratory function and hence
experiments were not sufficient for predicting embryo survival depending upon the particular
effects in the wild or among species. Similarly, part and proportion of the egg becoming fouled
Brewton, Fulford, and Griffitt (2013) observed (Phillott and Parmenter 2001).
that DWH oil produced reduced growth in young
spotted seatrout, but CEWAF initiated more
Reproductive system
adverse effects in larvae while HEWAF resulted in
greater number of adverse effects in juveniles. Many aspects of the reproductive system are sus­
Exposure to oiled sediment produced developmen­ ceptible to the toxic effects of contaminants, includ­
tal malformations including yolk sac and pericar­ ing the developing gonads, embryos, or through
dial edema, spinal defects, and tissue degeneration hormonal disruption. In addition, these outcomes
in zebrafish embryos (Raimondo et al. 2014). Gulf affect the survival of the offspring with additional
killifish larvae (< 24 hr post-hatch) exposed to potential for long-term effects where contaminants
HEWAF for 48 hr displayed decreased survival are teratogenic. Due to the complexity of this sys­
and development was negatively affected, but tem and various stages at which effects and impacts
hypoxia and high temperature each enhanced might be observed, a conceptual model was pro­
adverse effects of HEWAF on development and duced (Supplementary Information, Figure S1),
mortality (Serafin et al. 2019). illustrating the various stages of the reproductive
Oil in sediment may also be toxic to epibenthic cycle for different taxonomic groups, where effects
juvenile fish. In southern flounder (Paralichthys were reported (details of the model are provided in
lethostigma) experimentally exposed to oil- the figure legend).
contaminated sediments from Louisiana, mortality
rates of juveniles were increased with both concen­ Fish
tration and duration of exposure (Brown-Peterson Egg production. An investigation to determine
et al. 2017) and gill abnormalities and hepatic the combined effects of chronic hypoxia and
lesions were observed in fish exposed to the most dissolved PAHs on egg production in sheeps­
contaminated sediments. head minnow (Cyprinodon variegatus) found
364 R. TAKESHITA ET AL.

significant reduction under all treatments fertilization. Several developmental endpoints in

(Hedgpeth and Griffitt 2016), but the greatest the F1 generation were altered including reduced
decrease was noted when fish were exposed to weight and length. Both exposed generations dis­
hypoxic conditions in combination with a played deficits in prey capture compared to con­
blended oil and water mixture and an oil, trol F1 and F2 generations and correlations with
water, and chemical dispersant mixture. tissue levels of PAHs provided evidence that these
However, significant reductions were only effects were associated with PAH exposure. A
detected when hypoxia was included as a factor, similar study design demonstrated that environ­
suggesting again that other stressors and prevail­ mental conditions such as hypoxia and low sali­
ing environmental conditions such as dissolved nity might enhance developmental abnormalities
oxygen need to be considered. in unexposed sheepshead minnows born from
parents experimentally exposed to HEWAF
Reproductive capacity. Reproductive effects of oil (Jasperse et al. 2019c). Bautista and Burggren
on female spotted seatrout captured from (2019) reported that with adult zebrafish exposed
Mississippi coastal waters following the DWH oil to DWH oil through their diet, F1 larvae showed
spill were assessed using a gonadosomatic index both beneficial and maladaptive traits, likely
(GSI) and investigating ovarian development and attributed to epigenetic transgenerational
spawning frequency (Brown-Peterson et al. 2015b). inheritance.
Overall, post-DWH spill fish displayed lower GSI
values than those collected prior to the oil spill, Birds
particularly at the beginning of the reproductive Reproductive capacity. Prior to the DWH oil spill,
season. The most striking finding was the effect on a variety of studies established that oil exposure
spawning frequency, which was markedly reduced affects reproductive capacity in birds, by redu­
post-spill, from approximately every 4.5 days to 13.5 cing mating behaviors, reproductive success, and
days. Carr et al. (2018) examined the gonads of Gulf parental care, as well as increasing nest aban­
killifish one year after the DWH spill trapped at two donment (Barros, Alvarez, and Velando 2014;
impacted regions in Barataria Bay and one unim­ Fernie et al. 2018; Golet et al. 2002; King,
pacted site in East Texas. The GSI in males from the Elliott, and Williams 2020; Leighton 1993;
unimpacted area was twice that of males from the Walton et al. 1997). While experimental investi­
impacted site while testicular germinal epithelium gations of reproductive success such as egg lay­
thickness was 2.7-fold smaller at the impacted site. ing, hatching success, deformity estimates, and
Carr et al. (2018) suggested that exposure to oil and fledging success were not conducted immediately
dispersants may therefore adversely affect testicular following the DWH oil spill, Burger (2018) con­
function in these fish. Experimental exposure of ducted population- and colony-based estimates
sheepshead minnows to HEWAF under different of reproductive success (Burger 2018). Nesting
oxygen and salinity conditions demonstrated that phenology differed by oiling category for brown
HEWAF exposure significantly lowered egg produc­ pelican (Pelecanus occidentalis), snowy egret
tion and egg fertilization rate, but only under (Egretta thula), tricolored heron (Egretta trico­
hypoxic and hypoxic with low salinity scenarios, lor), laughing gull (Leucophaues atricilla), and
suggesting that environmental conditions might black skimmer (Rynchops niger), with the varia­
directly modulate reproductive toxicity of oil expo­ tion related to proportions of birds breeding
sure in fish (Jasperse et al. 2019a). earlier or later than peak nesting time. Burger
(2018) suggested that there was no apparent
Generational effects. Transgenerational effects evidence that reproductive success to fledging
were reported in experimentally oil-exposed was affected in the year following the spill with
sheepshead minnows (Jasperse et al. 2019b). Two the caveat that multi-year follow up may provide
generations of offspring from fish dosed with data on the long-term consequences of chronic
HEWAF were examined. The F0 generation exhib­ oil exposure.
ited altered egg production and decreased
 JOURNAL OF TOXICOLOGY & ENVIRONMENTAL HEALTH, PART B 365

From 2008 to 2010, brown pelican nesting habitat (such as nesting beaches) or prey base
success varied across years, but was lowest in (reviewed in Wallace et al. 2020). Loggerhead turtle
2010, corresponding to higher habitat losses fol­ nest densities on three NW Florida beaches in 2010
lowing the spill (Walter et al. 2013). Brown were reduced by 43.7% (95% CI: 10-65%) relative to
pelicans can nest on open ground; however, expected nesting rates in the absence of a spill and
they prefer elevated platform nests in shrubs. its associated clean-up (Lauritsen et al. 2017). These
Walter et al. (2013) observed that nesting suc­ reductions were attributed to both direct (e.g., mor­
cess was positively correlated to nest height, and tality from oil and response activities) and indirect
in some cases was negatively associated with nest (e.g., deterrence of nesting) effects related to the
density. In 2010, all 52 nesting attempts on DWH incident, particularly the high level of dis­
Wine Island (Louisiana) were relegated to turbance in the nesting beach areas resulting from
ground level and resulted in total abandonment response activities preventing females from coming
prior to hatching (Walter et al. 2013). ashore (Lauritsen et al. 2017).
Reproductive failure due to habitat loss may
result in adaptation to new nesting locations
Endocrine system
and partially account for lack of evidence for
reproductive losses in colonial nesters in 2011. The endocrine system is an important target system
for many contaminants, including PAHs, as many
Marine Mammals are known to be endocrine disrupters, often
Reproductive capacity. Much of the information mimicking the effects of hormones through recep­
about the reproductive effects of oil in viviparous tor binding (Lee et al. 2017). The hypothalamus-
vertebrates comes from field studies of marine pituitary-inter-renal (HPI) axis is an interacting
mammals. Lane et al. (2015) reported on the regulatory system governing the release of cortisol
early follow up of common bottlenose dolphins that is critical in how fish respond to many envir­
exposed to DWH oil that were temporarily cap­ onmental stressors and social structure. The HPI
tured for health assessments. Only 2 of the 10 axis is analogous to the hypothalamus-pituitary-
pregnant females produced viable calves com­ adrenal (HPA) axis found in mammals, birds, and
pared to a previously reported success rate of turtles, which also serves as an important regulator
83% (Wells et al. 2014). Kellar et al. (2017) con­ of stress response and a modulator of neuroendo­
tinued the investigation of reproductive success in crine-immune interactions (Parent et al. 2011). A
two northern GoM bottlenose dolphin stocks and conceptual model of the endocrine system in the
again found significantly lower rates of success context of this review and potential effects of oil is
when compared to unexposed reference stocks. illustrated in Supplementary Information,
Rates for both GoM stocks were 19.4% compared Figure S2.
with 64.7% for control stocks. In addition, in the
years immediately following the DWH oil spill Fish
there were elevated numbers of dead stranded Hypothalamus-pituitary-inter-renal axis.
perinatal bottlenose dolphins in the oil spill foot­ Khursigara, Ackerly, and Esbaugh (2019) reviewed
print and evidence of a higher prevalence of fetal evidence for interactions between oil exposure and
lesions, including fetal distress (87 vs 27%), when environmental stressors such as hypoxia, tempera­
compared to stranded perinatal dolphins exam­ ture, salinity and acid-base balance in fish through
ined from unexposed regions (Colegrove et al. the HPI. Findings suggest that oil exposure puts
2016). fish at a competitive disadvantage, although the
mechanism through which this is acting is not
Turtles clear. Reddam et al. (2017) also indicated that the
Reproductive capacity. Sea turtles are vulnerable to glucocorticoid stress response is stimulated in toad­
oil and associated oil spill response activities for a fish (Opsanus beta) exposed to PAHs. Evidence
number of reasons, including direct physical foul­ from in vivo and in vitro experiments indicated
ing and toxicity of oil and indirect impacts to their that there may be internalization or
366 R. TAKESHITA ET AL.

downregulation of the melanocortin 2 receptor in al. 2013). However, Lamb, O’Reilly, and Jodice
response to PAH exposure. This receptor mediates (2016) indicated that chronic stress of this habitat
the action of adrenocorticotrophic hormone destruction has been impacting nestling success in
(ACTH) and exposed fish were no longer able to subsequent years.
mount a second response when subjected to stress­
ful conditions associated with crowding. Marine Mammals
Glucocorticoids. One of the most striking findings
Birds following the DWH spill was its impact on adrenal
Glucocorticoids. A case study of northern gannets function in bottlenose dolphins (Schwacke et al.
(Morus bassanus) breeding in Eastern Canada 2014). Dolphins temporarily captured in an oil-
investigated the impact of PAHs on circulating impacted area (Barataria Bay, Louisiana) displayed
prolactin and corticosterone, two hormones that exceptionally low serum concentrations of two key
are involved in metabolism and mediation of the adrenal hormones, cortisol and aldosterone, when
stress response and influence reproduction. Franci compared to concentrations found from prior dol­
et al. (2014) reported that 23.5% of the birds had phin health assessment studies across multiple sites
overwintered in the GoM in 2010-2011 during the (Schwacke et al. 2014). Many of these animals were
time of the DWH oil spill, but found no apparent not able to mount an expected acute stress response
evidence for effects of oil on hormones or body following the capture event, which should include
mass. However, studies on house sparrows (Passer elevated serum cortisol and potentially aldosterone
domesticus) demonstrated an impaired stress levels. These findings were reinforced by the
response after ingestion of DWH oil (Lattin et al. pathology results among the dolphins found dead
2014). The sparrows’ ability to elevate corticoster­ following the spill (Venn-Watson et al. 2015).
one in response to both a standardized stressor and Adrenal tissue examined histologically showed
an injection of ACTH was impaired following 4 that a high proportion (33%) exhibited thin adrenal
weeks of exposure to a 1% crude oil diet. In addi­ cortices, compared to 7% in dolphins stranding
tion, a second house sparrow study demonstrated outside the area affected by the spill. A follow-up
tissue-specific changes in the density of glucocorti­ study carried out 3–4 years post-spill demonstrated
coid receptors following 6 weeks of ingestion expo­ that impaired stress response persisted for at least 4
sure to 1% weathered crude oil, including lower years after the disaster (Smith et al. 2017).
receptor numbers in liver, high numbers in fat,
and no marked changes in kidneys, muscle, spleen, Turtles
or testes (Lattin and Romero 2014) Hypothalamic-pituitary-adrenal axis (HPA). No
Feather corticosterone and nestling body condi­ marked differences in baseline corticosterone con­
tion were measured in 3- to 4-week-old brown centrations were found in either surrogate sea turtle
pelicans nestlings along the GoM from 2013 to species (red-eared sliders and snapping turtles)
2015 (Lamb, O’Reilly, and Jodice 2016). Feather exposed via gavage for 14 days to DWH oil col­
corticosterone may be employed an indicator of lected from the ocean surface (“slick A”) at 100 and
chronic stressors, and in the case of nestling or 1,000 mg/kg (Mitchelmore et al. 2015). Alterations
fledging birds, chronic elevated stress might in concentrations of stress-induced corticosterone
impede development. While the study did not via ACTH with increasing oil dose were not
directly assess the impact of oil exposure on nest­ observed, although a non-significant trend to
ling health, data demonstrated a negative correla­ lower levels was detected in red-eared sliders
tion between body condition and increased feather (Mitchelmore et al. 2015). However, two red-
corticosterone such that nestlings from ground or eared sliders in the 1,000 mg/kg treatment failed
lower level nests exhibited higher feather corticos­ to respond to clinically normal corticosterone con­
terone and lower body condition. As discussed in centrations such that the potential for an impact to
the section on bird reproduction, brown pelicans in the HPA axis cannot be ruled out, especially given
some areas along the GoM lost optimal nesting sites the limited number of individuals, relatively short
producing reproductive failure in 2010 (Walter et exposure time of 14 days (compared to weeks and
 JOURNAL OF TOXICOLOGY & ENVIRONMENTAL HEALTH, PART B 367

months for studies in other reptiles and mammals), tolerant phenotypes remained chronically impaired
and inability to follow any delayed impacts following a 24 hr oil exposure bout. Zhang et al.
(Mitchelmore et al. 2015). (2017) concluded that this was due to inferior
hypoxia resistance through the glycolytic metabolic
pathway at the oiled gill, in hypoxia tolerant fish.
Respiratory system

The respiratory system is susceptible to acute and Birds

chronic toxic effects of airborne pollutants, includ­ In western sandpipers (Calidris mauri) orally
ing the vapor phase of crude oil components, par­ dosed with artificially weathered DWH oil at con­
ticulate PAHs, and volatile organic compounds centrations of 1 or 5 ml kg/body weight/day for 20
(VOCs) that are produced by large crude oil slicks. days, there was presence of pulmonary hemor­
A conceptual model of the respiratory system and rhage in the treated groups but not control, indi­
DWH oil effects by taxa is illustrated in cating damage to the lungs and a decreased ability
Supplementary Information, Figure S3. to exchange oxygen (Bursian et al. 2017b).
Dermally treated double crested cormorants
Fish (Phalacrocorax auritus) were noted to display sig­
Respiratory function. While the evidence that acute nificant dyspnea upon handling and examination.
oil exposure can impair cardiorespiratory function Control birds examined within 24 hr exhibited no
in larval fish is robust (Mager et al. 2014), the effects evidence of respiratory distress. Further, brady­
on later life stages were less well known before the cardia likely induced by the dive reflex was
DWH oil spill. Young fish (mahi-mahi, Atlantic noted in treated cormorants only. Histologically,
croaker [Micropogonias undulatus], and red hemorrhage (likely due to euthanasia) and inflam­
drum) experimentally exposed to DWH oil at mation were also present in wild-caught control
environmentally relevant concentrations exhibited groups; thus, respiratory lesions could not be
reduced maximal oxygen uptake, lower aerobic assessed in this study due to a low sample number
scope, and decreased swimming capacity (Harr et al. 2017b).
(Johansen and Esbaugh 2017). Swim performance Chicken hatchlings exposed in ovo to DWH
was affected at a lower PAH concentration whereas HEWAF airborne volatiles showed changes in
a 3-fold rise in exposure from 4 to 12 µg/L total cyp1a expression in lung epithelia that were indica­
PAH50 affected both movement and respiration. tive of PAH exposure (Dubansky et al. 2018). These
changes in cyp1a might potentially result in similar
Low oxygen tolerance. Hypoxia tolerance, consid­ effects on heart and lung function following in ovo
ered here as the critical oxygen threshold, was exposure to dioxins or PCBs (DeWitt et al. 2006;
investigated in Atlantic croaker experimentally Kopf and Walker 2009).
exposed to non-weathered crude oil (Pan et al.
2018). Fish exposed to 10 and 23 µg/L total PAH Marine Mammals
showed a significantly reduced aerobic scope rela­ Respiratory system abnormalities. Schwacke et al.
tive to controls. This was driven exclusively by (2014) found a significantly higher proportion of
diminished maximal metabolic rate with no the bottlenose dolphins in Barataria Bay, Louisiana
marked effect on standard metabolic rate. In red following the DWH spill with lung abnormalities as
drum, hypoxic conditions and oil exposure resulted compared to dolphins sampled in Sarasota Bay,
in additive reductions in aerobic scope compared to Florida. The Barataria Bay dolphins were 5-fold
either stressor alone (Ackerly and Esbaugh 2020). more likely to have moderate to severe lung disease,
Zhang et al. (2017) also suggested that this may not consisting of increased occurrence of alveolar inter­
be consistent among individuals, with hypoxia tol­ stitial syndrome, lung masses, and pulmonary con­
erant individuals being more susceptible. solidation. Corresponding to data from live health
Individual European sea bass (Dicentrarchus lab­ assessments, bottlenose dolphins stranding in the
rax) subjected to a hypoxia challenge test years immediately following the spill displayed a
responded differently. Interestingly, the hypoxia higher prevalence of primary bacterial pneumonia
368 R. TAKESHITA ET AL.

compared to non-exposed dolphins (22 vs. 2%) symptoms such as dyspnea, shortness of breath,
(Venn-Watson et al. 2015). A study among the and cough among responders exposed via inha­
same study animals using a noninvasive technique lation to oil compared to those not exposed.
for detection of exhaled breath metabolites found a Gam et al. (2018a, 2018b) investigated effects
significant relationship between pulmonary conso­ of inhalation oil exposure by measuring lung
lidation and metabolites consistent with chronic function using spirometry in 7,775 adults
inflammation as evidenced by products of lung enrolled in the GuLF STUDY, who participated
epithelial cellular breakdown and arachidonic acid in the response or who received training but
cascade metabolites (Pasamontes et al. 2017). were not hired. Overall, data demonstrated no
Pasamontes et al. (2017) concluded that the marked difference between the two groups.
increased degree of cellular breakdown products However, workers that handled oiled plants/
in the Barataria Bay dolphins were consistent wildlife or recovered dead animals exhibited
with, but not specific to, the proposed mechanism lower spirometry performance than unexposed
of chronic lung disease from aspirating or inhaling workers. Gam et al. (2018c) also found that
noxious agents. workers with high potential exposure to burn­
ing oil displayed reduced lung function 1 to 3
years after the oil spill based upon health
Humans
encounter data, but these effects were not
Respiratory system abnormalities. Several studies
apparent 4–6 years later (Gam et al. 2018b;
investigated the effect and risk of inhaled oil
Lawrence et al. 2020). These findings were simi­
spill emissions on the respiratory system in
lar to those from the US Coast Guard cohort
humans following the DWH event. The DWH
(Rusiecki et al. 2018) in which chronic respira­
Oil Spill Coast Guard Cohort Study (DWH-CG)
tory conditions, overall and specifically asthma,
, a survey-based study of US Coast Guard per­
were significantly elevated in responders report­
sonnel involved in the response (Rusiecki et al.
ing crude oil exposure compared to those with
2018), determined that more than half of study
no exposure in the 2 year period post-spill.
participants had been exposed to the oil
Of the community-based human studies, Peres
(Alexander et al. 2018). Coughing was the
et al. (2016) evaluated 2,126 adult women living
most prevalent symptom reported (19.4%), fol­
in Southern Louisiana and noted significant asso­
lowed by shortness of breath (5.5%) and wheez­
ciations between high exposure levels to DWH oil
ing (3.6%). An exposure–response relationship
and all 13 physical health symptoms assessed,
was evident between deployment duration and
with the strongest associations found for burning
all three symptoms before the well was capped
in the nose, throat, or lungs, sore throat, dizzi­
but only for coughing and wheezing post-
ness, and wheezing (all odds ratios > 4). The
capping. A similar pattern was noted for self-
women most financially impacted by the oil spill
reported exposure to crude oil via inhalation as
were significantly more likely to report wheezing
well as from other routes of exposure. Rates of
and other respiratory issues such as a stuffy,
reported respiratory symptoms were markedly
itchy, or runny nose. The Gulf Coast Health
stronger when participants reported exposure to
Alliance: Health Risks related to the Macondo
both oil and dispersant compared to oil alone.
Spill (GC-HARMS) longitudinal study of the
This large study (n=4,855) was able to control
communities impacted by the spill used a self-
for the effects of personal protective equipment
reporting approach to understand the physical
(PPE) and other exposures not often included
and mental health issues (Croisant et al. 2017).
in such retrospective surveys. In prospective,
Impacts on respiratory health were not reported
longitudinal analyses utilizing health encounter
separately but were included as part of the multi­
data to calculate incidence of respiratory con­
ple descriptive indicators of general health. Lung
ditions in the 5 years following the oil spill,
function, as assessed by physicians, was not sig­
Rusiecki et al. (2020) noted elevated incidence
nificantly different among the variably exposed
of sinusitis, bronchitis, asthma, and respiratory
communities studied. A GC-HARMS follow-up
 JOURNAL OF TOXICOLOGY & ENVIRONMENTAL HEALTH, PART B 369

study employed sophisticated analytical methods underlying toxicity in fish embryos. Following
to examine seafood samples collected over three these suggested modes of action, studies showed
years to address gaps in knowledge associated that DWH oil impaired contraction of myocytes
with human risk assessment due to petrogenic isolated from mahi-mahi at low PAH concentra­
PAH toxicity and communicated the findings to tions (Heuer et al. 2019), which explains observa­
the stakeholder communities involved in the tions of reduced stroke volume and diminished
longitudinal study (Jackson et al. 2019). cardiac output in mahi-mahi and cobia
(Rachycentron canadum) (Cox et al. 2017; Nelson
et al. 2017).
Cardiovascular system
MicroRNA (miRNAs) play a key role in
Effects induced by pollutants that target the heart embryogenesis and in regulation of other pro­
might be functional, such as lasting only for the cesses. Exposure to weathered and non-
duration of exposure, or irreversible, where the risk weathered oil suggested that slick oil more dif­
of which increases with dose and duration of expo­ ferentially altered miRNAs expression in mahi-
sure. Consequently, changes in the heart might mahi than treatment with source oil, regardless
result in both acute and chronic effects on an indi­ of developmental stage (embryonic vs larval
vidual’s fitness. development stages) (Diamante et al. 2017). In
the analysis of the targets, disruption of the
Fish cardiovascular system pathways at later develop­
Cardiac failure in early life stages. Developing fish mental stages was highlighted. Comparable
are particularly vulnerable to the effects of dissolved miRNA changes were also observed in a similar
PAHs at the low ppb range, and thus early life exposure study of larval red drum where target
stages may be widely impacted following major oil genes were also identified as being those
spills (e.g., Travers et al. 2015). Following the DWH involved in development and functioning of the
spill, research focused on determining the mechan­ nervous system (Xu et al. 2019). This approach,
isms of previously observed cardiotoxicity on early using next generation sequencing and in-depth
life stages (Incardona 2017). Brette et al. (2014) bioinformatics analyses, found that targets were
assessed the impact of field collected DWH oil predominantly involved in neuro-cardio system
samples on in vitro cardiomyocyte preparations development processes and associated key sig­
dissociated from the hearts of adult blue fin tuna naling pathways such as axonal guidance signal­
(Thunnus orientalis) and yellowfin tuna (T. alba­ ing, cAMP-response-element-binding protein
cares). Four environmental samples were used and signaling in neurons, calcium signaling, and
included source oil, artificially weathered oil (by nuclear-factor-of-activated T cells signaling in
heating at 90° to 105°C) and two skimmed oil cardiac hypertrophy. Significant cardiac morpho­
samples. The approach was to examine the effects logic effects were seen consistent with differen­
of these solutions on excitation-contraction (EC) tially expressed gene transcripts, particularly late
coupling using electrophysiological and Ca2+ ima­ in development (Xu et al. 2017). In addition,
ging techniques. Effects on action potential dura­ alterations in cardiac gene expression in devel­
tion in cardiomyocytes were observed, which oping mahi-mahi exposed to slick oil, but not
correlated closely with the concentrations of three- source oil, were consistent with phenotypic
ringed PAHs in the samples. The functional effects changes such as reduced heart rate and pericar­
on rhythmicity suggested that components of crude dial edema (Xu et al. 2016).
oil interfere with EC coupling, which links electrical Following the findings that crude oil disrupts EC
excitation to contraction in cardiomyocytes. DWH coupling in developing fish hearts, Sorhus et al.
oil exerted significant effects on K+ channel inhibi­ (2016) examined the influence of dispersed oil on
tion and on the voltage-dependent properties of cardiac function and morphogenesis, characterized
cardiac Ca2+ channels. These effects on the ion novel craniofacial defects, and investigated asso­
channels that are important in the contractility of ciated gene expression. Even short duration expo­
cardiomyocytes may indicate the mechanism sures at low concentrations were sufficient to
370 R. TAKESHITA ET AL.

produce cardiac and craniofacial abnormalities. output was reduced by 70% in larval red drum
The specific nature of the abnormalities suggested (Khursigara et al. 2017), driven by reduced stroke
that the target many be precursor cells in which ion volume rather than bradycardia. The results also
channels are directly or indirectly affected. The data demonstrated that sensitivities and target organs
appear to support a unifying hypothesis involving were similar in this estuarine species as were
depletion of intracellular calcium that results in found in pelagic fish.
several downstream organogenesis pathways being
disrupted.
Consequences of cardiac damage. The physiological
Cardiovascular stress may be assessed using
outcomes of changes in cardiac development and
morphometric analyses of heart form and function
cardiovascular function were investigated in mahi-
(Incardona, Collier, and Scholz 2004). Edmunds et
mahi. Swimming performance was affected in both
al. (2015) found that mahi-mahi embryos exposed
juvenile and adult fish (Mager et al. 2014, 2018;
to field-collected DWH oil during embryogenesis
Stieglitz et al. 2016a) likely through reductions in
exhibited contractility, looping, and circulatory
myocyte shortening, stroke volume, cardiac output,
defects. The type and degree of morphometric and
and stroke work (Nelson et al. 2016). Data demon­
cardiac-specific molecular responses was dose-
strate that oil exposure can result in sublethal car­
dependent with differences in sensitivity due to age.
diac effects in adult pelagic fish.
Kirby et al. (2019) found that acute crude oil
Cardiac function. In addition to cardiac failure,
exposure altered mitochondrial function and ade­
effects of oil on cardiac function may also be tem­ nosine diphosphate (ADP) affinity in cardiac mus­
perature dependent, as Perrichon et al. (2018) cle fibers from mahi-mahi. These observations are
found that higher temperatures resulted in greater in contrast to studies on red drum cardiac muscle
number of bradycardias in larval mahi-mahi but (Johansen and Esbaugh 2019) where no marked
reduced the occurrence of hematoma and severity effect on mitochondria were detected, although
of edema. effects on red muscle mitochondria were reported
Effects on fast-swimming predatory fish were of (see metabolism section below).
particular concern due to the high aerobic demand
of species such as tuna and amberjack (Incardona et
al. 2014). These species also displayed concentra­ Birds
tion-dependent effects on cardiac function and Cardiac structure and function. Oral and dermal
heart failure with circulatory disruption, pericardial dosing studies in double-crested cormorants,
edema, and other secondary malformations. These laughing gulls, western sandpipers, and homing
effects were independent of the consequences of pigeons (Columba livia) were conducted to assess
weathering on the DWH oil to which the embryos the physiologic effects of artificially weathered
were exposed. In a study with mahi-mahi, Esbaugh DWH oil (Bursian et al. 2017a). Following obser­
et al. (2016) reported that the weathering increased vation of enlarged, flaccid hearts during necropsy
oil toxicity and that pericardial edema correlated of the cormorants, laughing gulls, and homing
with acute lethality. pigeons, cardiac biomarkers were included in the
Cardiac effects were detectable even at low expo­ suite of endpoints for dermal exposure of cormor­
sure levels (<1 ppb) in some species, suggesting low ants to artificially weathered DWH oil. Oil expo­
thresholds for developmental cardiotoxicity in fish sure induced significant systolic myocardial
(Incardona et al. 2015). Even transient embryonic dysfunction as assessed with echocardiography
exposure at low concentrations was sufficient to (Harr et al. 2017c). It was concluded that the
induce delayed toxicity. Adult zebrafish exposed changes were indicative of a possible dilated
to oil as embryos also showed subtle changes in cardiomyopathy. Arrhythmias, particularly bra­
heart shape and swimming performance (Hicken dycardia, were found in all treated birds.
et al. 2011). Common toxicological responses in the Cardiac damage to fish affecting the EC coupling
cardiovascular system were seen in radically differ­ mechanism and calcium cycling, combined with
ent species of fish larvae. For example, cardiac the significant rise in plasma-ionized calcium in
 JOURNAL OF TOXICOLOGY & ENVIRONMENTAL HEALTH, PART B 371

the oil-exposed birds may suggest a common footprint (19%) (Personal communication, B.
mechanism that warrants further investigation Linnehan). It is unclear whether cardiac morpho­
as a pathogenic mechanism of disease. Not metric abnormalities/lesions are driven directly by
only did DWH oil initiate cardiac abnormalities oil exposure, or as secondary effects from inhaled/
in susceptible developing life stages, as demon­ aspirated oil damaging the lungs (or some combina­
strated in fish, but the oil also produced clini­ tion of both).
cally significant alterations in adult birds after
three weeks exposure (Harr et al. 2017c). Among
Humans
double-crested cormorants orally dosed with 5
Cardiac function. In humans, some preliminary
or 10 ml artificially weathered DWH oil kg/body
findings are suggestive of an elevated risk of
weight/day for 21 days or exposed by 6 dermal
cardiac effects, with increases in palpitations
applications of 13 ml oil to breast and back
and chest pain. In a self-reporting health study
feathers every 3 days, gross cardiac lesions
(Croisant et al. 2017), the proportion of respon­
including thin walls and flaccid musculature
dents reporting hypertension was higher in the
were detected in both groups of birds and myo­
oil-exposed communities than the control com­
cardial fibrosis in a few of those dermally
munity. Strelitz et al. (2018) noted that indivi­
exposed (4 out of 13). At no time was myocar­
duals working on the spill for more than 180
dial infarction found upon complete necropsy of
days and who stopped working due to heat
all birds in the studies.
exhibited an increased risk of non-fatal heart
attack. After 5 years, DWH oil spill workers
Marine Mammals
exposed to total hydrocarbon levels >0.3 ppm
Although there were no published studies of the displayed a 62–81% higher hazard for heart
cardiovascular system in marine mammals exposed attack compared to workers with the lowest
to DWH oil at the time of the workshop, a few studies exposure levels (Strelitz et al. 2019b). Further,
have been completed in the last year. Linnehan et al. residential proximity to the spill and duration
(2020) found that marine mammals (managed in San of clean-up work were associated with a sug­
Diego) and wild common bottlenose dolphins (in gested 29-43% higher hazard of heart disease
Sarasota, Florida and Barataria Bay, Louisiana) dis­ events (Strelitz et al. 2019a).
played a similarly high prevalence (approximately Cardiovascular conditions and symptoms
90%) of systolic heart murmurs, with maximal inten­ The DWH-CG Study evaluated longer term car­
sity typically in the sternal cranial and left cranial diovascular conditions among Coast Guard
areas of the heart. However, three dolphins in responders. In prospective, longitudinal analyses
Barataria Bay also exhibited medium mitral regurgi­ using health encounter data to calculate incidence
tation and moderate to severe lung disease; veterinar­ of respiratory conditions in the 5 years following
ians gave all three individuals a guarded to poor the oil spill, Denic-Roberts et al. (2020) demon­
prognosis based upon all of the health assessment strated elevated incidence of cardiovascular condi­
data available. In a separate study using echocardio­ tions, such as hypertension and palpitations,
graphy, oil-impacted dolphins in Barataria Bay among responders exposed via inhalation to oil,
showed several differences in cardiac structure, compared to those not exposed.
including thinner interventricular septa, thinner left
ventricular walls, smaller left atria, and higher pre­
valence of tricuspid valve prolapse and thickening Central nervous system (neurological and sensory
(Personal communication, B. Linnehan). including behavioral and psychological)
Veterinarians diagnosed two of the Barataria Bay
dolphins with pulmonary arterial hypertension. The influence of oil on the central nervous system
Dead, stranded dolphins from areas affected by (CNS) can be profound since the consequences
DWH oiling also exhibited a higher rate (p = 0.002) impact so many downstream effectors and sensory
of cardiac fibrosis (46%) compared to stranded dol­ functions. These include neurobehavioral impacts,
phins at locations outside of the DWH oil spill
372 R. TAKESHITA ET AL.

effects on the senses of smell and sight, potential of respond. The implications of this investigation
neuronal injury, and psychological impacts (at least are that predator avoidance behavior might be
in humans). modified by oil exposure in the wild. In a similar
study with mahi-mahi, unexposed juveniles
Fish avoided high concentrations of DWH oil (27.1
Behavior. Using male Siamese fighting fish (Betta µg/L), but exposed individuals did not. As with
splendens), Bautista et al. (2019) demonstrated damselfish, oil exposure did not significantly
that a 4-week dietary exposure with DWH oil affect amplitude or duration of response as mea­
produced an increase in aggressive behavior, as sured by the electro-olfactogram (Schlenker et al.
well as decrease in nest building, testis mass, and 2019a).
brain mass compared to unexposed fish. When
exposed to WAFs, fish including red drum, Vision. mRNA and miRNA expression analysis in
Atlantic croaker, and coral reef fish from the several marine species exposed to slick oil reported
Pomacentridae and Lethrinidae families showed impacts on pathways involved in visual function.
elevated risk-taking behavior, an impaired ability Disruption of these pathways affected retinal histol­
to capture prey, reduced sheltering behavior, ogy as well as visual acuity (as determined by opto­
diminished social behavior, and decreased volun­ motor response) in a PAH dose-dependent manner
tary movement speed and distance traveled in mahi-mahi (Xu et al. 2018), red drum, and
(Armstrong et al. 2019; Johansen and Esbaugh sheepshead minnows (Magnuson et al. 2018). A
2017; Rowsey et al. 2019). Transcriptomics studies subsequent study using slick oil and zebrafish
identified potential mRNA and microRNA path­ determined that disruption of these gene expres­
ways that are consistent with neurological and sion pathways and visual acuity were consistent
sensory disruptions, including disrupted structure with a dose-dependent loss of glial cells supporting
and function of synapses and nervous tissue (Xu et the neuronal network in the retina (Magnuson et al.
al. 2019, 2017). 2020). These data suggest that exposure to oil may
disrupt eye development and function across a
number of fish species.
Olfaction. There were clear effects of oil expo­
sure on olfaction in fish (Cave and Kajiura Birds
2018), an area largely unexplored prior to the Behavior. Perez et al. (2017a, 2017b, 2017c) using
DWH oil spill. Studies in Atlantic stingrays homing pigeons as a surrogate for migratory birds,
(Hypanus sabinus) reported an average decrease demonstrated that flight behavior might be altered
in magnitude of the olfactory response by 45.8% following oil application to feathers. Homing
after 48 hr exposure to oil mimicking the con­ pigeons were trained to a variety of flight scenarios.
centrations found in the coastal regions. Flight behaviors were examined before and after oil
Olfaction in this species is particularly important application of artificially weathered DWH oil on
in all aspects of their life history, including feed­ flight and tail feathers (20% total coverage and
ing and mate and predator detection. Behavior equal to only 1% of the bird’s body weight). For
and olfaction following oil exposure were also the longest flights studied (161 km) (Perez et al.
examined in bicolor damselfish (Stegastes parti­ 2017b), after a single oil application, pigeons
tus); chemical alarm cue was used to test the showed a 2.6-fold rise in flight duration compared
response of exposed and unexposed fish to flights prior to oil application, and their flights
(Schlenker et al. 2019b). Controls avoided the took longer than control birds during the experi­
cue as expected, whereas exposed fish did not. mental flights. The distance flown by oiled birds
In addition, the response to several cues was was on average 28 km greater than controls and
assessed using an electro-olfactogram. Exposed showed decreased route efficiency. Perez et al.
fish were less likely to detect the chemical (2017b) suggested that this altered behavior may
alarm cue; however, the amplitude or duration be due to the potential for increased lift along a
was not markedly affected when they did ridgeline and to reduce exposure to predation. In a
 JOURNAL OF TOXICOLOGY & ENVIRONMENTAL HEALTH, PART B 373

second study using a shorter distance and addi­ (Deepwater Horizon Natural Resource Damage
tional post-oiling flights, Perez et al. (2017c) noted Assessment Trustees 2016; Mitchelmore,
changes in flight behavior that continued for 35 Bishop, and Collier 2017).
days post-oiling, including more time spent
stopped (approximately 3-fold greater compared
to pre-oiling). In pigeons oiled multiple times, Humans
Perez et al. (2017a) found longer flight times com­ Psychological effects. The psychological effects of
pared to baseline pre-oiling flights and reduced the DWH oil spill on humans was the subject of
weight between flights due to lower food consump­ several key studies involving both community
tion. Data suggest reduced refueling capacity (see exposed and occupationally exposed cohorts.
section on metabolism below), but may also be Bell, Langhinrichsen-Rohling, and Varner
attributed to more time spent preening during (2018) reported that post-traumatic stress symp­
their downtime, as is common for lightly oiled toms (PTSS) increased rapidly in the Gulf coast
birds. The results indicate that light oiling might community and was higher among those who
affect behavior in order to compensate for altered noted direct contact with the oil compared to
integrity of flight feathers. those with no contact (Cherry et al. 2017). A
Maggini et al. (2017b) studied the effects of oiling longer-term study, involving 314 participants
on takeoff of western sandpipers following light oil interviewed directly following the spill and at
application to wing and tail feathers. This applica­ the second-year time point, indicated that the
tion represented 20% of total body surface but only occurrence of mental health symptoms including
5% of visible oil surface of the bird with wings depression and PTSS did not diminish over time
folded and was used to mimic a potential oiling and were similar at both time points. Mental
event initiated by a bird landing on water. health issues and modest decreases in neurobe­
Maggini et al. (2017b) employed accelerometry to havioral functions were also detected in the Gulf
determine that, in the first 0.4 sec of flight, the Long-term Follow-up Study (GuLF STUDY)
distance traveled by oiled birds was 29% less than (Kwok et al. 2017; Quist et al. 2019) that
prior to oiling and at 10° less of an angle. Maggini et involved 8,969 clean-up workers and 2,225 non-
al. (2017b) postulated that this slowdown might workers, and adverse mental (and physical)
make these individuals more prone to predation effects were significantly worse for participants
than unoiled conspecifics and result in the use of that were exposed to both the DWH oil spill and
less productive, but safer, refueling sites, further Hurricane Katrina (Lowe et al. 2019).
diminishing the likelihood of successful migration. The DWH-CG Study evaluated acute neuro­
logical and mental health symptoms among
Turtles Coast Guard responders during their response
Behavior. It is not just the chemical toxicity of to the DWH oil spill. Increased prevalence of
oil that results in impact to oil-exposed organ­ headaches, lightheadedness, difficulty concentrat­
isms: physical miring in oil might also severely ing, numbness/tingling sensation, blurred vision,
hinder movement, leading to behavioral and memory loss/confusion was associated with
changes and alterations in predator/prey rela­ elevated frequency of crude oil exposure via
tionships and ultimately mortality (reviewed in inhalation and via skin contact (Krishnamurthy
Wallace et al. 2020). During the DWH incident, et al. 2019; Rusiecki et al. 2018). Exposure to
sea turtles were found physically coated by oil both crude oil and oil dispersants yielded asso­
with heavy fouling – the most readily apparent ciations appreciably greater in magnitude than
and immediate harmful effect observed for crude oil alone (Krishnamurthy et al. 2019).
(Deepwater Horizon Natural Resource Damage Wang et al. (2020) found elevated prevalence of
Assessment Trustees 2016; McDonald et al. anxiety and depression among responders
2017b; Stacy 2012). Indeed, survival of turtles reporting longer oil spill response work duration
fouled at the highest category documented was and intensity, increasing exposure to crude oil,
determined to be unlikely without intervention and physical symptoms.
374 R. TAKESHITA ET AL.

The Women and Their Children’s Health Study Turtles

(WaTCH) administered telephone interviews to a Oil ingestion in sea turtles was documented during
population-based sample of 2,842 women who the DWH incident rescue efforts (Stacy 2012).
were questioned regarding their mental health Previously, retention times of oil in the GIT of turtles
and domestic conflict as well as their exposure to was estimated to be approximately 9 days but this
the oil spill (Rung et al. 2016). Over 28% reported study demonstrated that it was <48 hr in Kemp’s
symptoms of depression, 13% severe mental dis­ ridley and loggerhead sea turtles (Mitchelmore et al.
tress, and 16% a rise in the number of fights with 2015). The estimated amounts of oil in the upper
their partners with an associated increase in the digestive tract of these turtles were used to calculate
intensity of those conflicts. Reported exposure to environmentally relevant daily doses (100 or 1,000
the DWH oil spill was a significant predictor of mg/kg) for a surrogate sea turtle oil toxicity study
these outcomes. Mental health issues and memory (Mitchelmore 2012a; Mitchelmore, C. L. 2012b). In
loss were also significant issues among wives of this study juvenile snapping turtles and red-eared
clean-up workers (Rung et al. 2015). In a latent sliders were orally dosed daily (100 or 1,000 mg/
profile analysis of post-traumatic stress disorder kg) to the oil commonly fingerprinted coating sea
(PTSD) in women from the WaTCH study, turtles from the DWH incident, namely, Slick A oil,
Nugent et al. (2019) found that women in the for 14 days. Diagnoses were based upon individual
more symptomatic classes were more likely to organism evaluation of hematological, blood che­
have been impacted by the DWH oil spill com­ mistries, and histological data and showed evidence
pared to asymptomatic classes. in the snapping turtles of treatment related dehydra­
tion, GI protein loss, or malabsorption, and in the
red-eared sliders there were some cases of moderate
Gastrointestinal system subacute gastritis/gastroenteritis in the 1,000 mg/kg
slick A DWH treatment group (Mitchelmore et al.
The gastrointestinal tract (GIT) is the target organ
2015). In addition, Harms et al. (2019) reported
for many ingested pollutants, with a large surface
significant differences between treatments and con­
area where mucosal and deeper damage might
trols (with greater differences in the combined oil/
occur. Substances absorbed through the GIT then
dispersant exposures) in a number of relevant clin­
travel through the bloodstream and possess the
ical chemistries analytes in experimentally-exposed
potential to exert adverse effects on other systems.
hatchling loggerhead sea turtles, including total pro­
tein, albumin, globulin, potassium, and sodium,
Birds reflecting loss of electrolyte and hydration home­
Common loons (Gavia immer; caught in coastal ostasis consistent with decreased seawater consump­
Louisiana from 2011 to 2015) with higher blood tion and dehydration. Harms et al. (2019) also noted
PAH concentrations had lower body mass com­ a failure to gain weight in dispersant- and oil/dis­
pared to birds with lower circulating PAH concen­ persant combination-exposed hatchlings. In contrast
trations (Paruk et al. 2016). Evidence indicated that to the DWH laboratory oil studies, many of the listed
this may be attributed to nutrient malabsorption effects were not observed in loggerhead and Kemp’s
but suggested that more data are needed due to ridley sea turtles exposed to crude oil during the
species differences in the tolerance and metabolism DWH spill and/or may be discerned from capture
of PAH compounds. While not assessed directly, and transport stress (Stacy 2012; Stacy et al. 2017).
Dean et al. (2017) suggested that oral exposure of
cormorants to artificially weathered DWH oil Humans
might impact the GIT resulting in malabsorption The DWH-CG study reported a significant ele­
based upon reduced feed intake and body weights. vation (prevalence ratios > 1) in several acute
In addition, Harr et al. (2017b) reported anecdotal gastrointestinal symptoms following exposure to
evidence of abnormal excreta in the orally- and oil including nausea, diarrhea, stomach pains,
dermally-dosed cormorants, indicating that oil and constipation (Rusiecki et al. 2018).
impacts absorption and integrity of the GIT. Interestingly, the prevalence ratios were higher,
 JOURNAL OF TOXICOLOGY & ENVIRONMENTAL HEALTH, PART B 375

particularly for diarrhea, stomach pains, and Birds

constipation, among those exposed to both oil Changes in liver oxidative stress endpoints (i.e.,
and dispersant. total antioxidant capacity) were reported in western
sandpipers dosed orally with artificially weathered
DWH oil (1or 5 ml/kg bw/day for 20 days).
Hepatic system Absolute liver weights in oil-exposed sandpipers
were also higher compared to controls (Bursian et
As the site of detoxification, the liver is often
al. 2017b). Data suggested that the sandpipers
damaged by exposure to pollutants, including oil.
increased their overall antioxidant capacity in the
Liver injury covers a wide range of effects including
liver in response to oil exposure. Increased liver
hepatic necrosis, lipid accumulation (steatosis), or
weights in response to oil exposure was detected
hepatobiliary dysfunction.
in cormorants and laughing gulls, suggesting ele­
vated weight is the result of compensatory meta­
Fish bolic responses (Harr et al. 2017b; Miller, Peakall,
Menhaden (Brevoortia sp.) exposed to DWH oil in and Kinter 1978; Peakall et al. 1989).
Barataria Bay (n=18) exhibited increased preva­ Horak et al. (2017) observed hepatotoxic effects of
lence of hepatic lesions involving necrosis and ingested oil on laughing gulls that were orally dosed
hypertrophy compared to those inhabiting a con­ with artificially weathered DWH oil (5or 10 ml/kg
trol region (n=16) in Delaware Bay, New Jersey bw/day) for 27 days. Hepatic total glutathione, oxi­
(Bentivegna et al. 2015). In 48% of the Barataria dized glutathione, and reduced glutathione rose sig­
Bay fish, there was evidence of fibrosis not nificantly, as did relative (% body weight) liver
detected in control fish. Bentivegna et al. (2015) weights. Double-crested cormorants orally dosed
concluded that liver and stomach lesions are indi­ with artificially weathered DWH oil (5 or 10 ml/kg
cative of exposure over a longer period and the bw/day) over a 21-day period showed dose-related
potential for permanent damage, reducing their elevation in total glutathione, oxidized glutathione,
overall survival probability. Jones et al. (2017) and reduced glutathione, while superoxide dismutase
also demonstrated that hepatic gene expression and glutathione peroxidase were significantly
patterns were significantly changed in sheepshead reduced. Further, these birds exhibited significant
minnows experimentally exposed to different decreases in other liver enzyme activities and clinical
WAFs. chemistry endpoints indicative of diminished hepatic
A multi-year study of coastal fish [red snapper function (Dean et al. 2017). Livers collected at
(Lutjanus campechanus) and gray triggerfish necropsy from these birds showed induction of
(Balistes capriscus)] between 2011 and 2014 both CYP1A4/1A5 enzymes as measured by assays
found elevated hepatic biomarkers including for benzyloxyresorufin O-debenzylase (BROD),
ethoxyresorufin O-deethylase (EROD), glu­ EROD, methoxyresorufin O-demethylase (MROD),
tathione transferase, and glutathione peroxidase and pentoxyresorufin O-depentylase (PROD)
activities (Smeltz et al. 2017). Levels of EROD (Alexander et al. 2017).
activity declined over the 4-year period with Double-crested cormorants exposed to oil via
livers from gray triggerfish exhibiting signs of feather preening demonstrated abnormal plasma
fatty liver and fluorescent substances similar to markers associated with liver function compared
PAHs. to orally dosed birds, as well as markedly
Juvenile southern flounder experimentally enlarged livers (Cunningham et al. 2017; Dean
exposed to a sediment-oil mixture for 32 days and Bursian 2017; Harr et al. 2017b). Dermally
displayed histopathologic changes in liver (and exposed birds were estimated to have consumed
gill) tissues of fish exposed to more than 8 mg/ approximately 0.9 ml of artificially weathered
kg tPAH50 (the sum of 50 individual PAHs) DWH oil/kg bw/day, which was significantly
with signs of hepatic intravascular congestion lower than the dose levels for the oral dosing
and vacuolation (Brown-Peterson et al. 2015b). study, and thus differences in hepatotoxicity
may be attributed to dose effects.
376 R. TAKESHITA ET AL.

Turtles Fish
Hepatic exposure and effects of DWH oil were There is some evidence that DWH oil contamina­
evident in some field-collected sea turtles, as bile tion correlates with increases in skin lesions in
metabolite levels were elevated (Ylitalo et al. 2017; some fish species. Anecdotal reports from fisher­
Ylitalo, Collier, and Stacy 2015). Similar dose- men motivated Gulf-wide cruises by Murawski et
dependent elevations in bile metabolites were al. (2014), which documented an elevated preva­
also seen in both species in the surrogate study lence of skin lesions in red snapper and other GoM
(Mitchelmore et al. 2015). Further, a rise in bile fish species near the DWH wellhead compared to
protein concentrations in snapping turtles later years. During laboratory exposures of juvenile
exposed to 1,000 mg/kg slick A DWH oil sug­ southern flounder, Bayha et al. (2017) noted bloody
gested that there may have been reduced intake lesions on and near fins only in fish exposed to oil-
or assimilation of food (Mitchelmore et al. 2015). laden sediment, but sample size was small and did
A 14 day-exposure to slick A oil at 1,000 mg/kg not quantify the prevalence.
resulted in significant elevations in oxidative stress
and antioxidant compensatory responses in the Birds
liver tissue in red-eared sliders evidenced as Bird feathers are uniquely adapted for flight, buoy­
increases in total antioxidants and total, reduced, ancy, and body temperature maintenance.
and oxidized glutathione levels. Only elevations in Constant preening helps to maintain integrity of
total antioxidant levels were evident in liver tissue flight, contour, and down feathers. Oil not only
of the snapping turtle, highlighting difference damages feather integrity, but can also act as a
between turtle species (Mitchelmore et al. 2015). skin irritant (Jessup and Leighton 1996) and pro­
Interestingly, the lack of compensatory antioxi­ duce behavioral changes in preening. Infra-red
dant responses may be the reason why there was imaging and implanted body temperature trans­
evidence for oxidative damage in this species. mitters were used to determine how repeated appli­
cation of DWH oil to the feathers of double-crested
Marine Mammals cormorants affected body temperature regulation
There was some evidence of effects of oil exposure on (Cunningham et al. 2017). Matted feathers and
the hepatobiliary system in bottlenose dolphins loss of feather integrity were observed following
(Schwacke et al. 2014). Abnormal values for two or the first oil application. Skin discoloration was
more of the liver enzymes measured were reported found by the 2nd to 3rd application, and extensive
among 19% of the dolphins live captured in Barataria feather plucking, particularly of down feathers, was
Bay, LA compared to none detected among those noted in the majority of oil-exposed cormorants
captured in Sarasota Bay, FL. Toxic liver damage after the final oil application (Cunningham et al.
was also suspected in several bottlenose dolphins 2017). The skin at necropsy was discolored and
that stranded in the oil spill footprint following the thickened, but it was not possible to assess ade­
spill (Venn-Watson et al. 2015). However, the preva­ quately by standard histopathologic techniques.
lence of dolphins with hepatobiliary effects decreased Forward-looking infrared (FLIR) images taken of
over time and were not significantly different in the the front and back of oiled and control birds
exposed compared to unexposed dolphins captured throughout the study showed that thermal conduc­
in 2013 and subsequently (Smith et al. 2017). tance (heat loss) increased on the head, neck, back,
and breast of oiled birds over the course of the
study, indicating both the spread of oil over the
Integumentary system
body with preening and detrimental effects of loss
The skin is vulnerable to the toxic effects of chemi­ of down feathers and feather integrity of contour
cals through direct contact. It is the barrier against feathers on heat loss in this diving bird.
many external pollutants and whilst it works effec­ Horak et al. (2020) externally oiled ring-billed
tively against some, other substances may penetrate gulls (Larus delawarensis) with weathered DWH
quite readily. However, following the DWH spill oil, with 7 ml applied to the breast, wing tips, and
few studies focused on dermal effects. tail feathers for three consecutive days, and
 JOURNAL OF TOXICOLOGY & ENVIRONMENTAL HEALTH, PART B 377

collected feathers. Thermography imagery was col­ system, its components, and where impacts of oil
lected weekly for 4 weeks to investigate feather exposure were reported is depicted in Figure S4
structure (quantified using a barbule clumping (Supplementary Information).
index) and thermoregulatory ability (characterized
by internal body temperature and external surface Fish
temperature). Post-oiling feather clumping was sig­ Host resistance. The effects of oil on the immune
nificantly higher in oiled and rehabilitated (that is system were studied in red snapper, both alone and
washed with detergent on day 8 or 9) birds com­ in conjunction with exposure to the fish pathogen
pared to controls, but steadily declined over time in Vibrio anguillarum (Rodgers et al. 2018b). The
both groups. However, feather microstructure in expression of five immune-related gene transcripts
rehabilitated birds was indistinguishable from con­ were investigated in various combinations with/
trols within three weeks of washing, whereas the without oil and with/without pathogen. All five
feathers of oiled birds were still significantly immune genes were upregulated in the oil-
clumped a month post-oiling. External tempera­ exposed groups after 8 days exposure but were
tures for rehabilitated birds did not differ from downregulated or displayed no marked differences
controls within a week of rehabilitation. with controls after 10 or 17 days. These immune-
associated gene expression levels fell sharply from
Marine Mammals day 8 to day 10, with only one cytokine gene
Recently, Wise et al. (2018) used WAF of Alaskan remaining up-regulated until day 17. Rodgers et
oil and CEWAF to determine that although WAF al. (2018b) emphasized the need to understand the
was not cytotoxic to sperm whale (Physeter macro­ many factors that modulate immune gene expres­
cephalus) skin cells in vitro, there was some chro­ sion and whilst some responses may be conserved
mosomal damage. CEWAF was more cytotoxic and among species, there are likely to be species differ­
genotoxic than WAF, which appeared to be due to a ences. Nevertheless, if oil affects the immune
rise in total levels of PAHs in CEWAF than WAF. response to bacterial infection, particularly across
Studies conducted prior to the DWH oil spill multiple immune pathways, the outcomes for indi­
demonstrate that oil acts as a skin irritant in ceta­ vidual animals and populations are likely to be
ceans (Jessup and Leighton 1996). critical.
Bayha et al. (2017) conducted a similar study
with southern flounder but exposing juvenile
Humans
fish to oiled sediment with/without V. anguil­
Effects of DWH oil on the skin were investigated
larum. Flounder exposed to oil prior to bacter­
among workers in direct contact with oil during
ial challenge exhibited a 94% mortality within
the clean-up operations. Prevalence of acute der­
48 hr whereas those challenged with the patho­
mal symptoms including skin rashes or itching
gen only had a < 10% mortality. These results
was elevated among responders with increasing
were linked to oil-induced immunosuppression:
exposures to crude oil (PR=1.87; 95% CI: 1.45-
the oil-exposed cohort demonstrated reduced
2.40 for high vs low crude oil exposure). The
levels of the major fish antibody class, IgM,
risk of long-term dermal conditions in the 2
and an overall downregulation of genes
years post-DWH was elevated in oil spill respon­
involved in immune function, response to sti­
ders vs. non-responders (RR=1.21) (Rusiecki et
mulus, and hemostasis. Thus, PAHs sequestered
al. 2018).
in sediments may exert long-term adverse
health impacts on benthic species.
Immune system
The immune system can be highly sensitive to Genetic markers of immune effects. Jones et al.
exposure from pollutants resulting in increased (2017) exposed sheepshead minnows to two con­
susceptibility to infection, induced allergies, and centrations of HEWAF, a chemically enhanced
autoimmunity. A conceptual model of the immune fraction, and Corexit 9500 dispersant for 7 and
378 R. TAKESHITA ET AL.

14 days. Immune-related gene sub-networks parameters (Harms et al. 2019). No significant

were impacted across all treatment groups, espe­ differences were found in total white blood cell
cially the high HEWAF group. In the 7-day or differential white cell counts among treatment
treatment, most pathways were down regulated groups, although this study was necessarily lim­
but in the 14 day experiment the opposite was ited to small sample sizes that may have restricted
the case. Innate immune processes were most the power to detect effects.
affected, such as macrophage and granulocyte
function. To a lesser extent some pathways relat­
Marine Mammals
ing to T and B cell functioning were also
Immune function. Immune responses, both
affected.
through functional in vitro assays and blood ana­
lyses from exposed dolphins, were notably asso­
Birds
ciated with exposure to DWH oil in live captured
Oil-induced oxidative damage of proliferative
bottlenose dolphins (De Guise et al. 2017). There
hemoprogenitors in bone marrow has long been
was a consistent increase in T and B lymphocyte
documented in mammals and, more recently,
proliferation among animals in Barataria Bay, LA
decreased cell mediated immune response was
compared to those in Sarasota Bay, FL. Although
noted in birds (Olsgard et al. 2008). Dean et al.
cytokine concentrations were not significantly dif­
(2017) reported that double crested cormorants
ferent, some key patterns were compatible with
dosed orally with artificially weathered DWH oil
responses found in other oil-exposed species. The
demonstrated a significant decrease in total white
balance of cytokines suggested a Th2 response con­
blood cell, heterophil, and eosinophil concentra­
sistent with intra-cellular infections and changes in
tions during the course of the 21-day study.
B cell functions that may affect responses to extra-
However, other white blood cell types were not
cellular bacterial infections. The largest effects were
markedly different between exposed and unex­
seen among dolphins from Barataria Bay that was
posed birds and reduced in both groups. In the
sampled in 2011 with evidence of a reduction in
same study, the oral high-dose group consistently
those effects with time since the spill.
showed smaller and fewer inflammatory lesions
In vitro exposure studies were also carried out on
throughout the body, including kidneys, liver,
lymphocytes from bottlenose dolphins to elucidate
heart, pancreas, and throughout the GIT than did
the effects of oil and dispersant on different lym­
either the control or low-dose group (Harr et al.
phocyte subtypes as markers of innate and adaptive
2017b). Briggs, Gershwin, and Anderson (1997)
immunity (White et al. 2017). Both T and B cell
suggested that oil toxicity exerts more impact on
proliferation were enhanced following exposure to
cell-mediated immune responses than antibody-
oil at the higher levels. In the chemically enhanced
mediated responses; however, in this study only
mixtures, the opposite response was detected. The
measurements of cell-mediated immune function
combination of responses led White et al. (2017) to
were white blood cell and differential counts. Thus
conclude that adaptive immune reduction may
interpretation of the specific effects of oil are some­
result in enhanced susceptibility to infection but
what limited. The design of the study limited
that elevated natural killer cell activity may be in
assessment of other immune system endpoints.
some way advantageous in increasing viral surveil­
For example, changes in lymphocyte concentra­
lance ability.
tions in the avian exposure investigations were
noted but not explored thoroughly with prolifera­
tion and function studies. Further research is Circulatory system
warranted.
Hematotoxicity may be initiated by many different
Turtles pollutants resulting in reduction in the production
Clinicopathologic abnormalities were studied in and function of the oxygen-carrying red cells: the
experimentally exposed hatchling loggerhead sea erythrocytes.
turtles that included some immune cell
 JOURNAL OF TOXICOLOGY & ENVIRONMENTAL HEALTH, PART B 379

Fish the months following the DWH oil spill exhibited

Effects on erythrocytes. Fifty-seven adult, mixed sex signs of oxidative injury to erythrocytes as indicated
red drum, caught in six oil-contaminated and two by the presence of Heinz bodies. Packed cell volume
reference sites where no oil was observed along the (of circulating erythrocytes) was lowered by as much
Louisiana coastline were sampled for blood analysis as 19% compared to reference populations and there
2 years after the oil spill (Harr et al. 2018). A was evidence of a regenerative hematologic response
reference interval for red drum packed cell volume as indicated by increases in reticulocytes by as much
was established (42–62%) from fish at the two as 40% compared to reference populations. Further,
reference sites, and 18% of the fish sampled at birds with no visible oiling captured in the impacted
contaminated sites exhibited anemia (<42%), area displayed apparent anemia suggesting that it
while no anemic fish were captured at the reference was not possible to assess oil-induced effects from
sites, 2 years after the oil spill when little to no oil visible signs of oiling alone.
was visible.
Turtles
Birds Effects on erythrocytes. Previous studies of petro­
leum toxicity in field or laboratory experiments
Effects on erythrocytes. Anemia and abnormal ery­ demonstrated alterations of some blood cell para­
throid morphology were reported in double-crested meters (Lutcavage et al. 1995; Vargo et al. 1986).
cormorants experimentally exposed to artificially However, no apparent evidence of hemolytic ane­
weathered DWH oil both orally and dermally mia was observed in oiled DWH turtles (Stacy
(Harr et al. 2017a). Anemia was mildly regenerative 2012; Stacy et al. 2017). Further, there was no
but inadequately compensated, indicating decreased evidence of anemia or abnormal erythroid mor­
bone marrow production. This study documented phology in any of the turtles in the DWH oil sur­
that avian Heinz body structure and/or organelle rogate turtle study (Mitchelmore et al. 2015). All
damage is significantly structurally different than turtles (control and oiled groups) showed evidence
found in mammals. The classic button appearance of inflammation that may have been due to the
of mammalian Heinz bodies is almost never found gavage tube used to conduct the oral dosing and
in birds even in blood samples from birds with thus all inflammatory responses were removed
biomarkers indicating severe oxidative damage from consideration due to this complication.
(Bischoff, Harr, and Barron 2021). Therefore, con­
firmation by electronic microscopy is often required.
Collecting anticoagulated whole blood samples in 2– Marine mammals
3% glutaraldehyde is recommended because such Effects on erythrocytes. Schwacke et al. (2014) noted
samples, if appropriately stored in a cool dark some cases of anemia and inflammation in dol­
place, can be archived for years. Further, coagulo­ phins from areas affected by DWH oiling.
pathy, suspected due to lack of clotting noted at Decreased hemoglobin levels in 4 out of 32 dol­
necropsy in orally dosed laughing gulls and cormor­ phins in oiled Barataria Bay, Louisiana were found
ants both orally and dermally exposed to oil was compared to 0 out of 26 dolphins in unoiled
confirmed using activated clotting times in double Sarasota Bay, Florida. The reticulocyte counts of
crested cormorants and pigeons dosed with artifi­ the anemic dolphins were all greater than the max­
cially weathered DWH crude oil. Coagulopathy imum count from the Sarasota Bay population.
results in blood loss through the GIT (hematochezia)
and other vascular leakage, which might directly
Metabolism, energetics and biomechanics
result in anemia. Often with extravascular hemor­
rhage, protein values decrease when compensated. An outcome of the systemic toxic effects of oil
Fallon et al. (2018), using a less rigorous measure­ exposure, particularly damage to the cardiovascular
ment technique reported that American oystercatch­ system, may be downstream impacts on metabolic
ers (Haematopus palliates), black skimmers, brown rate and energetics with indirect consequences for
pelicans, and great egrets (Ardea alba) captured in survivorship.
380 R. TAKESHITA ET AL.

Fish Birds
Oxygen consumption and metabolic demand. Oil Energetic effects. The energetic costs of migratory
and ultraviolet (UV) exposed mahi-mahi embryos flights may be extremely high particularly for
displayed enhanced rates of oxygen consumption small migratory birds such as the western sandpi­
for extended periods prior to hatching compared to per that breed in the Arctic and overwinter in
controls (Pasparakis et al. 2017). There was also a coastal habitats of North, Central and South
significant correlation between oxygen consump­ America (Morrison et al. 1993; Nebel et al.
tion, embryo sinking rates, and onset of negative 2002). In sandpipers with artificially weathered
buoyancy. DWH oil applied to their feathers, Maggini et al
Johansen and Esbaugh (2019) exposed red (2017a; 2017c) found that light and moderate oil
drum to PAH mixtures for 24 hr and compared exposure increased metabolic cost of flight up to
results to samples from unexposed control fish. It 22% and 45% respectively compared to control
was postulated that the reductions in critical swim birds. Flight control decreased which would result
speed despite maintenance of maximum meta­ in elevated duration of migration and might alter
bolic rate in exposed fish were due to impaired reproductive failure and mortality rates. In terms
mitochondrial function in swimming and cardiac of kinematic parameters, light and moderately
muscles. Whilst Johansen and Esbaugh (2019) oiled birds flying slowly in a wind tunnel had
found no evidence for effects of mitochondrial larger wingbeat amplitudes than controls, while
dysfunction in cardiac muscle, impairment was moderately oiled birds showed greater wingbeat
observed in red muscle. Oil exposed mitochondria frequencies at all flying speeds due to poorer lift
from red drum muscle tissue suggested a reduc­ and increased drag. Maggini et al. (2017b) esti­
tion in ATP generation. However, doses used to mated that this enhanced energetic cost may result
induce impairment were at the upper end of the in stopover delays of approximately 1 to 8 days per
range reported during the DWH oil spill. Chub stopover for a total potential delay of 9 to 45 days
mackerel (Scomber japonicus) exposed to weath­ for western sandpipers to reach their Arctic breed­
ered oil as a WAF for 72 or 96 hr were studied in a ing grounds. If oil ingestion caused impairment of
swim tunnel respirometry system (Klinger et al. GIT function (Leighton 1993), this delay would be
2015). Energetic demand increased in all fish in further exacerbated and might exert catastrophic
response to oil exposure at 96 hr. Evidence indi­ population impacts due to reproductive failure at
cated that the rise in metabolic demand might be the breeding grounds.
attributable to energetic cost of detoxification. Multiple metabolic pathways associated with
However, studies with mahi-mahi (Mager et al. energy production were impaired in double-
2014; Stieglitz et al. 2016b), cobia (Nelson et al. crested cormorants dermally exposed to oil such
2017), and red drum (Johansen and Esbaugh 2017) that 20% of their surface area was lightly oiled
showed no marked impact of oil exposure on (Dorr et al. 2019). Both plasma and liver metabo­
resting or standard metabolic rate. lomes were affected compared to controls indicat­
Social competition was affected by crude oil ing potential impacts to thermoregulation, cardiac
exposure in red drum through reduced aerobic function, and hematologic parameters. Modeling of
scope (the difference between basal metabolism seasonal changes in the thermoregulatory cost of
and maximum capacity for oxygen transport, i.e., oiling in double-crested cormorants based upon oil
standard metabolic rate compared to maximum application to feathers (Cunningham et al. 2017)
metabolic rate) (Khursigara, Johansen, and demonstrated that the resting metabolic rate
Esbaugh 2018). This endpoint is predictive of social (RMR) following application of 13 to 78 g of artifi­
dominance in these gregarious fish and fish cially weather DWH MC252 rose by 31 to 76% over
exposed to oil were more likely to be subordinate winter and 29 to 73% during the breeding season
than expected demonstrating that physiological (Dorr et al. 2020). Although body weight of cor­
constraints affect social status and behavior with morants oiled in the lab might be maintained by
secondary effects on ecological fitness increased food consumption (Cunningham et al.
 JOURNAL OF TOXICOLOGY & ENVIRONMENTAL HEALTH, PART B 381

2017), wild birds were estimated to require more for sanderlings in Louisiana, but not for red knots;
than 2 hr per day of additional foraging time (Dorr however, both species departed the PAH contami­
et al. 2020). nant sites later than normal. Multiple factors such
Basal metabolic rates (BMRs) of western sandpi­ as migration patterns, food supply, and other con­
pers at 27oC and metabolic rates under thermal taminants may also have played a role. These con­
stress conditions (sliding scale down to −3oC) clusions were supported by the results of a dosing
over a 12 hr period were tested in respirometry study in which sanderlings were administered no,
chambers. Oil applied to the back and breast feath­ low, medium, or high doses of PAH ranging from 0
ers to a total of 20% body coverage did not result in to 1260 µg total PAH/kg bw/day (Bianchini and
significant changes in thermal conductance, but Morrissey 2018). Consistent with other studies,
birds that were oiled 3 days before testing exhibited mass gain was found to be lower compared to
lower body temperatures at the time of testing and controls in all groups.
lost more body weight than other birds. In addition, Bonisoli-Alquati et al. (2020) used a microar­
birds exposed to oil for 3 days before respirometry ray transcriptomic approach in liver samples to
displayed changes in blood chemistries consistent investigate genome-wide gene expression
with damage to the loop of Henle, evidenced as changes in wild Seaside Sparrows (Ammospiza
increased urea, decreased sodium, and albumin, as maritima) exposed to oil in saltmarshes. Data
well as increases in markers of oxidative stress demonstrated that as well as inducing liver
including reduced and total glutathione, superox­ hypertrophy, energy homeostasis was impacted
ide dismutase, and malondialdehyde ± through changes in gene expression encoding
4-hydroxyalkenals. molecules associated with energy regulation and
Using homing pigeons as a surrogate for the lipid biosynthesis.
effects of DWH oil on bird flight, Perez et al.
(2017b) reported that birds externally oiled with
artificially weathered DWH oil either once or mul­ Summary and Conclusions
tiple times, (1) took significantly longer to return
home, (2) lost more weight during flight, (3) were When organisms are exposed to chemical contami­
unable to replenish their energy stores despite ade­ nants, the resulting adverse effects can manifest in a
quate food supply, and (4) showed reduced body variety of ways depending on the species, life-stage,
weight over time. Body weight was likely lower due individual life history, nature of the exposure, and
to both enhanced expenditure of energy in longer countless other variables. Despite this variation,
flights with damaged feather integrity and there is consistency among the DWH toxicity test­
decreased calorie intake due to diminished appetite ing and field observation results including data
and possible compromised GIT function. The con­ from DWH NRDA field studies, the DWH litera­
clusion was that even partially oiled birds were ture (laboratory and field studies) outside of the
likely to display poorer body condition and an NRDA program, and the established oil/petroleum
elevated risk of reproductive failure and subsequent toxicity literature beyond DWH.
mortality.
● From a taxonomic perspective, many of the
Ecosystem damage at staging sites is a vital issue
mechanisms of action and the resulting disease
for migratory species such as sanderlings (Calidris
pathways are conserved across species and
alba) and red knots (C. canutus), as refueling affects
taxa. For example, the effects on cardiovascular
individual fitness, reproductive success, and survi­
development, structure, and function, and the
val during migration. These species were the sub­
reports of cardiac symptoms and disease
ject of a study into differences in fuel loads and
appear similar across multiple taxa
fueling rates at two sites, one of which contained
● From a toxicologic perspective, there is a logi­
PAH-contaminated sediments (Louisiana). Plasma
cal progression following exposure routes lead­
metabolite profiles and fattening index scores indi­
ing to molecular and cellular damage/
cated that pre-migratory fueling rates were slower
mechanisms that manifest as organ disease,
382 R. TAKESHITA ET AL.

finally resulting in reduced fitness, growth, Cardiovascular effects were one of the most
reproductive potential, and survival. For exam­ apparent common endpoints across taxa – most
ple, flounder exposed to oil in the sediment intensely studied in fish, but also reported for
have reduced antibody production, are more birds and emerging evidence for effects in mam­
susceptible to infection, demonstrate reduced mals. Of note are recent studies showing similar
growth and oxygen transport capacity, can findings between marine mammals and humans for
develop skin lesions, and eventually die due cardiovascular effects. In addition, oxidative stress
to the combined effects of DWH oil exposure, and damage endpoints were also a commonly
immune dysfunction, and a bacterial observed effect. The finding of impaired stress
challenge. response in marine mammals prompted investiga­
● From a clinical perspective, the breadth of tions across other taxa, resulting in positive find­
adverse health effects and clinical signs asso­ ings for an association in birds and fish.
ciated with DWH oil exposure are due to var­ The large body of work that has been published
ious combinations of molecular/cellular on the toxic effects of oil on vertebrates since the
damage in multiple organ systems. By applying DWH oil spill has made a major contribution to the
the knowledge gained from sublethal studies of toxicological knowledge base. The field studies
the pathogenesis of oil-related disease, further were often based in the same regions, the Gulf
impacts from oil exposure can be better under­ States most impacted by the oil, particularly
stood. For example, HPA axis abnormalities Louisiana and Mississippi allowing for greater com­
and adrenal gland damage in bottlenose dol­ parability. Investigators examined effects at all
phins result in abnormal steroid hormone con­ trophic levels, often within the same food chain.
centrations and electrolyte imbalances, and The associated experimental exposure, and many of
likely contribute to immunosuppression and the in vitro studies, were also closely linked to the
reproductive failure. fieldwork using oil collected during the spill, both
early in the event and following weathering. This
It is clear that not every organism exposed to oil also increased confidence in the comparability of
will experience all of the adverse health effects the results.
presented in the results summarized above. It is The findings (summarized in Table 1) indicate
likely that each individual might suffer from some critical commonalities and mechanisms that
various combinations and severities of negative are also likely to be linked across systems, particu­
impacts, some more detrimental than others. larly through impacts on signaling processes. These
However, all the organisms exposed to DWH data may be useful in identifying and informing
oil may be forced to allocate resources to deal data gaps regarding oil toxicity in other, less-
with the spill-related injuries. Some will even­ studied taxa/species. The pathways summarizing
tually recover, but some may succumb to their how the reproductive, endocrine, respiratory, and
injuries, potentially impacting their population. immune systems are impacted are illustrated in
Laboratory results and field analyses demon­ Supporting Information Figures S1 – S4. Evidence
strate that exposure to DWH oil might result from the 5 taxa provides new information on repro­
in a suite of mechanistically derived toxicological ductive, endocrine, respiratory, and immune
responses and impairments to homeostasis effects. Evidence of impacts on the other systems
occurring across multiple taxa, resulting from remain important and should not be excluded
the conserved physiological processes across ver­ when considering the likely effect of future oil
tebrate taxa. Although not the focus of the spills. This summary puts the pathways for effects
workshop or this review, workshop participants into the vertebrate-wide context where the evi­
did note that many physiological systems are dence-base is most compelling.
conserved between invertebrate and vertebrate This synthesis indicates that petroleum and its
taxa, and that there is a good deal of research many constituents, through direct as well as indir­
on invertebrates that is consistent with the ect routes of exposure, when released into the mar­
research discussed here. ine environment produce widespread adverse
 JOURNAL OF TOXICOLOGY & ENVIRONMENTAL HEALTH, PART B 383

health effects at both the individual and population ● How do we move from characterizing and
levels. Notwithstanding the caveats associated with quantifying sublethal impacts to population-
making comparisons across taxa where the nature level effects? How does the field integrate
of exposure including oil type, concentration/dose, work from toxicologists and population mode­
duration, and route could be the reasons for lers? Can cross-taxa studies help inform how
observed differences whereby effects are seen in individuals’ exposure to oil may impact beha­
one taxon but not in another, the pathways and vioral and social structures?
toxicological impacts of DWH oil can result in ● How does mild, moderate, and severe multi-
long-term changes in the abundance and distribu­ organ systems damage impact overall health,
tion of marine wildlife. survival, and reproduction?
The workshop participants also discussed key ● How do we best approach standardized, com­
outstanding data gaps in our collective understand­ parable field studies with multiple stressor
ing of the toxicology of oil in vertebrates, as we exposure scenarios with both natural and
attempt to move on from DWH and prepare for anthropogenic stressors?
the next oil-related disaster. The questions ● How should managers and researchers
included: update the pre-DWH conceptual model of
dispersants with the post-DWH research on
● How do we simultaneously address the concepts both dispersant toxicity and dispersed oil
of environmental exposure (e.g., detecting dose toxicity?
and its patterns) and evaluating toxic exposure ● How can negative results from laboratory and
for injury/damages to natural resources (e.g., field studies be appropriately reported and
correlating exposure with biological endpoints/ integrated into our collective understanding
biomarkers) during an event? of oil toxicity?
● How do we ensure that we have appropriate ● Can we develop standards for surveys and
baseline (i.e., pre-spill) data? This was identified health assessments of wildlife during and
as an especially difficult challenge for assessing after an oil spill, especially in the context of
human exposure and toxic effects, given the characterizing and quantifying NRDA injuries
difficulty in ramping up research studies in the and losses?
wake of DWH (although the DWH-CG Study
has been able to account for preexisting condi­ The interpretation of toxicological effects follow­
tions via health encounter data). ing such large-scale events requires scientific
● How can managers comprehensively charac­ inference. Our ability to assess the injuries across
terize the type, magnitude, and duration of an ecosystem in the wake of environmental disas­
ephemeral exposures during future oil spills/ ters is naturally limited in terms of timing, spatial
events as quickly as possible, rather than coverage, our existing knowledge of the contami­
opportunistically “chasing the oil”? nants and affected resources, our lab and statistical
● How can researchers and resource man­ capabilities, budget, and political will. Therefore,
agers compare/replicate laboratory expo­ in order to describe and estimate the potential
sures with inferences and limited data sets total impacts of toxic releases, scientists and policy
on field conditions/exposures during an makers must combine the available site-specific
event? data with the literature to draw taxonomic and
● How do researchers balance studying/inter­ mechanistic/functional inferences about effects
preting acute observations with inferences that may not be directly studied (or where studies
about chronic effects from prior/ongoing resulted in inconclusive findings). As many of
exposures? How can they determine what is these systems are conserved across taxa, our ability
truly an acute observation when signs/symp­ to postulate based upon conserved physiologic
toms and disease are compounded by chronic systems across taxa while considering the unique
effects? biological aspects of organisms is critical to char­
acterizing a holistic assessment of impacted
384 R. TAKESHITA ET AL.

resources. Future studies to investigate the com­ Alexander, C. R., M. J. Hooper, D. Cacela, K. D. Smelker, C. S.
monalities and differences in oil toxicity among Calvin, K. M. Dean, S. J. Bursian, F. L. Cunningham, K. C.
vertebrates require robust combinations of study Hanson-Dorr, K. E. Horak, et al. 2017. CYP1A protein
expression and catalytic activity in double-crested cormor­
designs involving laboratory-, field-, and survey- ants experimentally exposed to deepwater Horizon
based approaches. Mississippi Canyon 252 oil. Ecotoxicol Environ. Saf.
142:79–86. doi:10.1016/j.ecoenv.2017.02.049.
Alexander, M., L. S. Engel, N. Olaiya, L. Wang, J. Barrett, L.
Acknowledgments Weems, E. G. Schwartz, and J. A. Rusiecki. 2018. The deep­
water horizon oil spill coast guard cohort study: A
This research was made possible by a grant from The cross-sectional study of acute respiratory health
Gulf of Mexico Research Initiative. The authors would symptoms. Environmental Research 162:196–202.
like to thank Dr. Nancy Kinner, Missy Gloeker, and doi:10.1016/j.envres.2017.11.044.
Jesse Ross (University of New Hampshire) for their help Alloy, M., D. Baxter, J. Stieglitz, E. Mager, R. Hoenig, D.
facilitating and participating in the workshop, as well as Benetti, M. Grosell, J. Oris, and A. Roberts. 2016.
Michael Feldman, Evonne Tang, and Dr. Charles Wilson Ultraviolet Radiation Enhances the Toxicity of Deepwater
for their participation in the workshop. We would also Horizon Oil to Mahi-mahi (Coryphaena hippurus)
like to thank Dr. Brian Stacy for his participation in the Embryos. Environmental Science & Technology 50
workshop and for providing helpful reviews of the manu­ (4):2011–17. doi:10.1021/acs.est.5b05356.
script. This publication is UMCES contribution No. Alloy, M., T. R. Garner, K. Bridges, C. Mansfield, M. Carney,
6045 and Ref. No. [UMCES] CBL 2022-008. This is H. Forth, M. Krasnec, C. Lay, R. Takeshita, J. Morris, et al.
National Marine Mammal Foundation Contribution 2017. Co-exposure to sunlight enhances the toxicity of
#314 to peer-reviewed scientific literature. naturally weathered Deepwater Horizon oil to early lifestage
red drum (Sciaenops ocellatus) and speckled seatrout
(Cynoscion nebulosus). Environmental Toxicology and
Chemistry 36 (3):780–85. doi:10.1002/etc.3640.
Funding
Anderson, S. E., J. Franko, E. Lukomska, and B. J. Meade.
This work was supported by the Gulf of Mexico Research 2011. Potential Immunotoxicological health effects follow­
Initiative. ing exposure to COREXIT 9500A during cleanup of the
Deepwater Horizon oil spill. Journal of Toxicology and
Environmental Health, Part A 74 (21):1419–30.
doi:10.1080/15287394.2011.606797.
Declaration of Interest and Disclaimers Armstrong, T., A. J. Khursigara, S. S. Killen, H. Fearnley, K. J.
No potential competing interest was reported by the authors. Parsons, and A. J. Esbaugh. 2019. Oil exposure alters social
All opinions expressed in this paper are the authors’ and do group cohesion in fish. Scientific Reports 9 (1):13520.
not necessarily reflect the policies and official views of the doi:10.1038/s41598-019-49994-1.
Uniformed Services University, the Department of Defense, Barros, A., D. Alvarez, and A. Velando. 2014. Long-term
the United States Coast Guard, the Department of Homeland reproductive impairment in a seabird after the Prestige oil
Security, or the National Oceanic and Atmospheric spill. Biology Letters 10 (4):20131041. doi:10.1098/
Administration. rsbl.2013.1041.
Bautista, N. M., T. Pothini, K. Meng, and W. W. Burggren.
2019. Behavioral consequences of dietary exposure to crude
oil extracts in the Siamese fighting fish (Betta splendens).
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