Environmental Toxicology and Chemistry, Vol. 32, No. 1, pp.

3248, 2013
# 2013 SETAC
Printed in the USA
DOI: 10.1002/etc.2043

Global Climate Change

INTERACTIONS BETWEEN CHEMICAL AND CLIMATE STRESSORS: A ROLE FOR
MECHANISTIC TOXICOLOGY IN ASSESSING CLIMATE CHANGE RISKS
MICHAEL J. HOOPER,*y GERALD T. ANKLEY,z DANIEL A. CRISTOL, LINDLEY A. MARYOUNG,k
PAMELA D. NOYES,# and KENT E. PINKERTONyy

yU.S. Geological Survey, Columbia Environmental Research Center, Columbia, Missouri

zU.S. Environmental Protection Agency, Ofce of Research and Development, National Health and Environmental Effects Research Laboratory,
Mid-Continent Ecology Division, Duluth, Minnesota
Institute for Integrative Bird Behavior Studies, Department of Biology, The College of William and Mary, Williamsburg, Virginia, USA
kDepartment of Environmental Sciences, University of California, Riverside, California, USA
#Nicholas School of the Environment, Duke University, Durham, North Carolina, USA
yyCenter for Health and the Environment, University of California at Davis, Davis, California, USA
(Submitted 11 March 2012; Returned for Revision 8 May 2012; Accepted 13 August 2012)
Abstract Incorporation of global climate change (GCC) effects into assessments of chemical risk and injury requires integrated

examinations of chemical and nonchemical stressors. Environmental variables altered by GCC (temperature, precipitation, salinity, pH)
can inuence the toxicokinetics of chemical absorption, distribution, metabolism, and excretion as well as toxicodynamic interactions
between chemicals and target molecules. In addition, GCC challenges processes critical for coping with the external environment (water
balance, thermoregulation, nutrition, and the immune, endocrine, and neurological systems), leaving organisms sensitive to even slight
perturbations by chemicals when pushed to the limits of their physiological tolerance range. In simplest terms, GCC can make organisms
more sensitive to chemical stressors, while alternatively, exposure to chemicals can make organisms more sensitive to GCC stressors.
One challenge is to identify potential interactions between nonchemical and chemical stressors affecting key physiological processes in
an organism. We employed adverse outcome pathways, constructs depicting linkages between mechanism-based molecular initiating
events and impacts on individuals or populations, to assess how chemical- and climate-specic variables interact to lead to adverse
outcomes. Case examples are presented for prospective scenarios, hypothesizing potential chemicalGCC interactions, and retrospective scenarios, proposing mechanisms for demonstrated chemicalclimate interactions in natural populations. Understanding GCC
interactions along adverse outcome pathways facilitates extrapolation between species or other levels of organization, development of
hypotheses and focal areas for further research, and improved inputs for risk and resource injury assessments. Environ. Toxicol. Chem.
2013;32:3248. # 2012 SETAC
KeywordsAdverse outcome pathway

Acclimation

Weather

enough to routinely support integrated risk assessments. Hence,

there is a need to develop approaches and tools to better enable
consideration of potential interactions of toxic substances with
factors affected by GCC.
Risk assessments for toxic chemicals historically have relied
on apical, whole-organism end points directly related to key
demographic processes such as survival, growth, and reproduction. Data reecting mechanistic aspects of biological effects
of toxic chemicalssuch as altered gene or protein expressions, metabolite proles, and histopathologytypically have
received little or no direct use in either human or ecological risk
assessment. Yet, mechanistic information can help to address
fundamental uncertainties inherent to current risk-assessment
approaches, including those related to chemical effect extrapolations across species, endpoints and chemical structures, as
well as variations in risk outcomes across settings [12,13].
Importantly, understanding the biological pathways through
which chemicals exert their effects provides a means of assessing the impacts of mixtures with other chemicals, as well as
interactions of chemicals with nonchemical stressors. This is
directly relevant to evaluating potential interactions between
toxic chemicals and environmental conditions inuenced by
GCC. Because it is impractical, if not impossible, to collect
empirical data concerning all interactions between environmental
variables affected by GCC and chemicals in the environment
(including toxicants and toxins of concern as well as chemicals
lacking classication as contaminants), it is necessary to

INTRODUCTION

A variety of environmental variables inuenced by global

climate change (GCC) can directly or indirectly affect the health
of organisms. These variables include temperature, salinity, pH,
and penetration of ultraviolet (UV) radiation in aquatic environments. Global climate change is causing increases in the
severity and frequency of droughts and extreme precipitation
events, as well as regional-scale declines in air quality (e.g.,
increased ground-level ozone and particulate matter) in terrestrial systems [1,2]. Direct effects of these GCC-related changes
have been and continue to be characterized in biota, for
example, the potential inuence of temperature on distributions
of sh populations [36] and the timing of avian migrations to
nesting grounds and their concordance with appropriate prey
availability [79]. However, far less is known about the indirect
effects of variables affected by GCC on humans and the
environment, including the potential for interactions with toxic
chemicals. Factors such as temperature can greatly inuence
the toxicity of chemicals in a variety of taxa [10,11]. Other than
for a few species, chemicals, and endpoints, however, data
collected to date concerning the effects of changes in the global
climate on the toxicity of chemicals are not comprehensive
* To whom correspondence may be addressed
([email protected]).
Published online in Wiley Online Library
(wileyonlinelibrary.com).
32

Climate change and mechanisms of chemical toxicity

Environ. Toxicol. Chem. 32, 2013

develop predictive approaches to help assess where, when, and

how these interactions might inuence toxicity at organismal
and higher levels of organization and conclusions concerning
potential risk. To support these types of predictive approaches,
it is necessary to incorporate mechanistic data into the riskassessment process for evaluation of the potential inuence of
GCC on chemical toxicity.
A major impediment to the use of mechanistic data in risk
assessments has been an inability to clearly translate information collected at lower levels of biological organization (e.g.,
molecular, biochemical, and cellular responses) into endpoint
alterations that are meaningful to risk assessment, namely,
effects on individuals and populations. To address this limitation, Ankley et al. [14] described a conceptual framework
based on constructs called adverse outcome pathways (AOPs),
which depict linkages between molecular initiating events
(interaction of chemicals with biological targets) and the subsequent cascade of responses that occur across biological
levels of organization that culminate in impacts on individuals
(or populations) that can be used for assessing risk. The basic
concepts underpinning AOPs are not newvariations on the
theme have been captured to different degrees through constructs like mechanisms or modes of action and/or toxicity
pathways [14]. For example, the National Research Council has
recently proposed toxicity testing regimes centered on evaluations of biological perturbations along key toxicity pathways
using methods in computational biology and in vitro tests based
on human biology [15]. What the AOP concept provides is a
unied framework based on dening relevant linkages across

biological levels of organization in the context of applied risk

assessment. Since initial description of the AOP framework,
subsequent efforts have focused on further development and
application of the concept, including a Pellston conference
sponsored by the Society of Environmental Toxicology and
Chemistry in 2009 that specically addressed topics related to
the derivation of AOPs from existing and new data, incorporation of population modeling into the framework, and the use
of AOPs to better understand the resilience of systems and
extrapolation of chemical effects across species [1620].
In the present analysis, we describe adaptations of the AOP
concept and by extension mechanistic data as tools to help
identify potential adverse effects elicited by GCC and chemical
toxicant exposures. The ultimate goal of this effort is to develop
assessment approaches and tools that enable predictions of
when and how signicant interactions between chemical and
nonchemical stressors might be expected to occur, rather than
solely relying on collections of empirical data for different
combinations of stressors. Figure 1 shows a modication of the
AOP framework as originally depicted [14]. Notable modications include incorporation of an exposure component that
could be affected by GCC variables inuencing chemical fate,
transport, and bioavailability and consideration of internal
dosimetry (toxicokinetics), which also could be affected by,
for example, changes in temperature in poikilotherms [10]. In
considering this framework, it becomes apparent that there are
different relevant ways in which variables affected by GCC
could interact with chemicals in terms of producing adverse
effects.

Mechanis
c toxicity pathway

Toxicant

33

Adverse outcomes

Ini
a
ng toxicity events

Toxicant
Availability
Bioavailability
Biomagnica
on
Physico-chemical
proper
es (e.g.,
pKa, water/lipid
solubility, MW)

Uptake and
disposi
on

Molecular
interac
ons

Cellular
responses

Organ
responses

Organism
responses

Popula
on
responses

Absorp
on
Distribu
on
to target
organs,

ssues, uids
Metabolism
to more or
less bioac
ve
molecules
Excre
on

Receptor/ligand
interac
ons
DNA binding,
misrepair
Protein/lipid
oxida
on
Gene
upregula
on,
downregula
on

Cell injury,
death
Protein
deple
on,
produc
on
Altered
signaling
Enzyma
c
ac
va
on,
inac
va
on

Necrosis/inamma
on
Altered homeostasis
Altered
ssue & organ
development/func
on
Impaired thermal
regula
on
Altered hormone
produc
on/circula
on
Altered energe
cs

Lethality
Endocrine
dysfunc
on
Carcinogenesis
Chronic diseases
Impaired
reproduc
on
Impaired growth
and development
Compromised
immune func
on

Demographic
structure
Recruitment
Dispersal
Gene
c
changes
Ex
nc
on

Organism
responses

Popula
on
responses

Toxicant-induced
climate Sensi
vity

Climate change
parameter
Direct parameters
(temperature,
precipita
on,
salinity)
Indirect parameters
(hypoxia,
hyperthermia,
disease vectors,
food availability)

Detec
on and
signaling

Molecular
interac
ons

Peripheral and
central receptors
Central and
peripheral
endocrine/neural
signaling

Signal/receptor
interac
on
Molecular
cascades
Gene response

Climate-induced
toxicant sensi
vity

Cellular and organ responses

Metabolic and homeosta
c changes
Structural changes growth/resorp
on
Altered func
onal processes (e.g., water
and nutrient absorp
on/reten
on,
reproduc
ve cycles, etc.)

Altered feeding,
drinking, growth,
reproduc
on,
migra
on,
hiberna
on, etc.
Altera
on failure

Acclima
on via
changes in
physiology,
phenology or
home range
Ex
nc
on

Ini
a
ng acclima
on events

Climate change

Mechanis
c climate acclima
on pathway

Acclima
on outcomes

Fig. 1. Adverse outcome and climate acclimation pathways suggested for mechanistic assessments of contaminants and global climate change interactions.
Modied from Ankley et al. [14]. [Color gure can be seen in the online version of this article, available at wileyonlinelibrary.com.]

34

Environ. Toxicol. Chem. 32, 2013

One important dichotomy involves toxicant-induced

changes that alter the ability of an organism to respond to
GCC stressors (toxicant-induced climate susceptibility [TICS]),
in contrast to climate-induced toxicant sensitivities (CITS), the
scenario where GCC affects the toxicity of chemicals. Such
CITS scenarios produce altered or enhanced toxicity of
chemicals under climate change conditions that might not be
predicted in controlled laboratory testing or among natural
populations residing within or at the edge of their physiological
tolerance ranges. The former scenario (TICS) involves alterations caused by toxic chemicals that impact the ability of an
organism to acclimate to a stress introduced by GCC through
various biochemical, physiological, or behavioral responses.
These responses can be metabolic (hyperphagia, shivering,
estivation, and hibernation), structural (metamorphosis, tissue
resorption and growth), or homeostatic (water retention, ion
balance, nutrient absorption, and reproductive processes), and
can trigger associated behavioral changes (feeding, drinking,
reproduction, and migration; Fig. 1). Successful acclimation
allows survival in the face of environmental change, while
failure or environmental change beyond the ability of an
organism to acclimate can lead to loss of individuals or local
populations or even to species extirpation or extinction [21].
Neither contaminant effects on acclimation processes nor climate effects on contaminant toxicity may be obvious in laboratory studies carried out under carefully controlled conditions
that reduce testing variability and protect test animals from all
stressors but the test chemical.
In the present study, we present a number of real-world
examples illustrating how an understanding of mechanistic
toxicology supports integration of known or hypothesized
interactions between chemical and nonchemical/GCC stressors
into chemical risk assessments. We include examples relevant
primarily to ecological health and demonstrate how the framework shown in Figure 1 can be applied to either prospective or
retrospective risk assessments. Specically, we present several
scenarios where, based on established or plausible interactions
between chemical and GCC-related nonchemical stressors,
prospective assessments of risk can be developed that help to
identify potential adverse effects between existing or new
chemical exposure patterns and GCC stressors that have yet

M.J. Hooper et al.

to be investigated or fully documented. We also describe

retrospective situations in which observed impacts in humans
and wildlife can be dissected and diagnosed relative to toxic
pathways and mechanistic interactions between chemical and
nonchemical stressors. An understanding of toxic pathways in
one population or species can then serve as a basis for developing predictive models that can be applied in a generalized
manner, for example, at sites or in situations removed from
where initial observations were made.
As GCCchemical interactions might occur all along mechanistic toxicity pathways, case studies depict examples focusing
rst on exposure and the disposition of toxicants, followed by
examples depicting toxicodynamic interactions between chemicals, effect-associated receptors, and GCC. More complex
scenarios then demonstrate the interplay between CITS and
TICS and nally illustrate how retrospective analysis using
AOPs can help to explain observed GCC-associated toxicity
lacking a known causeeffect relationship.
ULTRAVIOLET-INDUCED PHOTOACTIVATION OF
POLYCYCLIC AROMATIC HYDROCARBONS

One manner through which environmental variables inuenced by GCC could affect contaminant toxicity involves direct
effects of the variable on chemical characteristics. The polycyclic aromatic hydrocarbons (PAHs) are a class of compounds
whose environmental concentrations, through pyrogenic events
such as forest res, are projected to increase as a consequence
of GCC [22]. The toxicity of PAHs can occur via a variety of
molecular initiating events and pathways. A PAH AOP of
particular relevance to GCC involves activation to reactive
species by ultraviolet (UV) radiation in sunlight, a process
termed photoactivated toxicity (PAT; Fig. 2). The intensity
of UV radiation, a key factor in determining PAH PAT, is likely
to be affected by variables altered by GCC [1,2]. These variables could include decreases in pH that can clarify water,
thereby increasing exposure of aquatic animals to UV radiation,
and increased inputs of dissolved or particulate organic carbon
to aquatic systems, which would effectively reduce UV penetration. Hence, specic inuences of GCC on UV intensity in
aquatic systems are likely to be site- and situation-specic.

Fig. 2. Adverse outcome pathway of the interaction of ultraviolet radiation with polycyclic aromatic hydrocarbons. With permission from Ankley et al. [14].
[Color gure can be seen in the online version of this article, available at wileyonlinelibrary.com.]

Climate change and mechanisms of chemical toxicity

However, through understanding the mechanisms by which

PAT occurs, it is possible to apply predictive models to the
assessment of the relative risk of PAH toxicity under GCC.
Almost 30 years ago researchers noted that toxicity of the
PAH anthracene to sh could be increased by an order of
magnitude or more through simultaneous exposure to sunlight
[23], and a wide array of studies since that time have documented similar effects with other PAHs in many different
aquatic species (for reviews, see [2426]). Ankley et al. [25]
provide an overview of different aspects of mechanisms of PAH
PAT and describe the derivation of an AOP specic for this
phenomenon, focusing on lethality in aquatic species (Fig. 2)
[14]. Here, we briey describe the pathway, with a particular
emphasis on mechanism-based models that enable prediction of
risk under scenarios of varying UV intensity and PAH concentrations, such as those that could occur as a consequence of
GCC. The initial step in PAT is uptake of PAHs by sensitive
species such as larval sh or pelagic invertebrates. Once in the
animal, some PAH structures can be activated through interactions with UV radiation in sunlight, typically in the UVA
portion of the spectrum (320400 nm). Models have been
developed that enable prediction of those PAHs likely to exhibit
PAT based on comparatively easily measured or calculated
structural characteristics [27]. The interaction of UV radiation
with accumulated PAHs involves elevation of the ground-state
molecule to excited singlet states, which can release excess
energy through a variety of mechanisms, including decay to
relatively longer-lived, triplet-state molecules capable of interacting with molecular oxygen to form reactive singlet oxygen.
Singlet oxygen can interact with a wide variety of biological
macromolecules (e.g., proteins, lipids), producing the damage
that results in PAT, which typically is manifested, at least in
short-term exposures, as lethality [25]. Critically, the occurrence
of PAT can be accurately modeled or predicted as a function of
the product of (internal) PAH dose and UV exposure [28].
Variations on this very basic UV
PAH relationship can be
incorporated into models such that the PAT of mixtures of PAHs
with varying phototoxic potency also can be predicted [29].
Our example concerning PAT has several noteworthy characteristics from the standpoint of assessment of interactions
between chemicals and variables inuenced by GCC. First, this
example clearly shows how information and models derived
from knowledge of toxicity mechanisms could be used to make
predictions of risk under changing environmental conditions.
Both key determinants of toxicity, PAH exposure and UV
intensity, could vary as a function of GCC, likely in a very
site-specic manner, so it is critical to have tools capable of
simultaneously assessing the possible consequences of alterations in either or both parameters. Based on past research,
enough is known about the physiochemical and biological
mechanisms of PAT that robust existing models could be
utilized for the purpose of assessing different risk scenarios
associated with GCC. This example also provides an illustration
of a possible adverse response that in some situations could well
be decreased by GCC. Specically, in situations where PAH
exposure is unchanged but UV penetration in aquatic systems
decreases due to increased precipitation and surface runoff, the
potential for PAT decreases.
TEMPERATURE AND SALINITY IMPACTS ON
CHEMICAL DISPOSITION

Beyond the accessibility or availability of chemical and

nonchemical stressors to organisms, environmental alterations

Environ. Toxicol. Chem. 32, 2013

35

with GCC have the potential to alter the biological disposition

(or toxicokinetics) of chemicals that can in turn inuence
internal exposure sites, concentrations, and durations. Toxicokinetic modications can lead to changes in organism-level
responses and eventually produce population-level impacts. In
our model AOP, this would be captured by alterations in
absorption, distribution, metabolism, and excretion (ADME)
of toxicants (Fig. 1). Understanding how ADME is impacted by
different GCC stressors, such as temperature and salinity in
aquatic environments, would help to identify mechanisms
involved with CITS and allow risk assessors to make predictions about geographical regions susceptible to these types of
interactions and other combinations of climatic changes and
toxicant exposures.
Some broad observations can be made regarding potential
climate effects on the uptake and disposition of chemical
contaminants [10]. For example, it has generally been observed
that uptake and elimination of toxicants increase as temperature
increases. Literature on the distribution of toxicants as impacted
by GCC factors is limited, and thus few general trends have
been described. Increases in two GCC-related variables, temperature and salinity, have been shown to enhance metabolism
to typically more, but in some cases less, toxic metabolites (see
Noyes et al. [10] for discussion). Two examples using the AOP
framework to illustrate how ADME mechanisms interact with
GCC stressors and lead to interactive effects are (1) alterations
in polychlorinated biphenyl (PCB) metabolism with increasing
temperatures, and (2) alterations of pesticide toxicity with
changes in temperature and salinity.
PCB uptake and disposition with rising ambient temperatures

Persistent organic pollutants, such as PCBs, are problematic

in that they can migrate thousands of miles from their original
point of release to high-latitude ecosystems. For example, the
Mackenzie River basin in northwestern Canada has been experiencing substantial warming trends and declining snow cover.
While atmospheric concentrations of PCBs have generally
declined in the Arctic with elimination and reductions in use,
increasing trends of contamination by more highly chlorinated
PCBs have been measured in Mackenzie River sediments and
the predatory arctic sh burbot (Lota lota) over a 30-year
collection period [30]. Study evidence suggests that increasing
primary production of algae from rising temperature and
declines in snow cover may increase partitioning of PCBs from
the water column, leading to increased contaminant bioavailability and transfer up the food chain.
Increasing trends of PCBs in biota are important because
environmental conditions being altered by GCC can also inuence the biological disposition of these compounds. Several
studies have shown that sh metabolize PCBs by cytochrome P450 (CYP) mixed-function oxidases to more toxic, hydroxylated PCBs (OH-PCBs). For example, the role of temperature in
the disposition of PCBs has been examined in juvenile rainbow
trout (Oncorhynchus mykiss) receiving dietary exposures [31].
Increasing water temperatures have been shown to decrease
the biological half-life of some of the highly persistent PCB
congeners in trout. However, increasing water temperatures
have also been shown to increase the metabolism of parent
PCBs to OH-PCBs as measured in trout plasma. Several studies
have demonstrated different mechanisms of OH-PCB toxicity,
including that OH-PCBs can act as agonists for estrogen
receptors [32] and displace thyroid hormone from plasma
transport proteins [33]. Thus, an AOP approach could be used
prospectively in this situation to identify important mechanistic

36

Environ. Toxicol. Chem. 32, 2013

toxicity pathways and teleost populations potentially at risk to

the dual stresses of increasing temperatures under GCC and
PCB contamination.
Pesticide uptake and disposition with rising temperatures

Effects of temperature on pesticide toxicity can be demonstrated by contrasting the toxicity of organophosphorus insecticides (OPs) and pyrethroids in the midge (Chironomus dilutus,
formerly Chironomus tentans). In these poikilothermic organisms, increased chemical uptake and enhanced metabolic transformation to more toxic oxon metabolites generally accompany
increased temperatures. These adverse interactions have been
demonstrated, for example, in 96-h midge lethality studies with
methyl parathion and chlorpyrifos, where acute toxicity
increased as temperatures increased from 10 to 308C due to
increased uptake and likely increased metabolic activation of
the parent OPs to their more toxic oxon forms [34]. This
metabolic activation is necessary for OP toxicity not only in
midges but in most organisms, because acetylcholinesterase, the
molecular target of OPs, is generally orders of magnitude more
sensitive to the oxon moiety. Because of increased activation
rates, GCC-induced temperature elevations will likely lead to
increased toxicity of OPs to any poikilotherms. As temperaturedependent hydrolysis rates of OPs will likely increase in
warming aquatic environments, elevated toxicity may be tempered by decreased persistence of toxic OP concentrations.
Alternatively, type 1 and some type 2 pyrethroids demonstrate decreased toxicity at elevated temperatures in poikilotherms, including the midge. Sensitivity of the midge to
permethrin and lambda-cyhalothrin has been shown to decrease
with increasing temperatures [35]. Two factors that contributed
to the inverse relationship between the toxicity of pyrethroids
and temperature included decreased neuronal sensitivity and
increased metabolism of parent compounds at elevated temperatures. Contrary to the requirement for metabolic activation of
OPs, parent pyrethroids are the toxic form of these pesticides,
while their hydrolyzed metabolites are readily excreted.
Decreased metabolic rates at lower temperatures were shown
to decrease hydrolysis and elimination rates of pyrethroids,
maintaining the toxic form of the pesticide in the neuron,
leading to greater toxicity.
Conversely, some type 2 pyrethroids have demonstrated
increasing toxicity with higher ambient temperatures, including
in cockroaches (Blattella germanica) [36], water eas (Daphnia
magna) [37], leopard frogs (Rana sp.) [38], and grass shrimp
(Palemonetes sp.) [39]. The a-cyano moiety contained on type
2 pyrethroids may be responsible for imparting greater toxicity
at higher temperatures among some organisms, although the
mechanism is not understood. Thus, elevated temperatures
under GCC could increase or decrease the toxicity of pyrethroid
insecticides depending on the species and specic pyrethroid
exposure, demonstrating the complexity of these interactions
and continued gaps in our understanding of pyrethroid toxicity
mechanisms.
Uptake and disposition of pesticides with altered salinity

Sea-level rise linked to thermal expansions, reduced snow

cover, and the accelerated melting of glaciers, ice caps, and
polar ice sheets is projected to increase the salinity of estuarine
and coastal freshwater habitats [2]. For example, regions with
diminished snow-pack runoff due to GCC are likely to experience increases in estuarine salinity. Projected temperature
increases of 2.18C by 2090 are forecasted to result in a loss
of approximately half the average April snow-pack storage for

M.J. Hooper et al.

the San Francisco Bay estuary region. A reduction of approximately 20% of historical annual spring runoff would cause
increases in salinity of up to 9 psu (9 g/L) in select regions
[40]. Estuarine areas, such as the San Francisco Bay, may be
especially susceptible to GCC and toxicant interactions due to
the diversity of species present, some of which are endangered
(e.g., delta smelt [Hypomesus transpacicus]), and the fact that
these areas are increasingly impacted by anthropogenic activities, including substantial point and nonpoint discharges of
chemicals into the system.
The relevance of increased salinity on the toxicity of chemicals has been demonstrated in coho salmon (Oncorhynchus
kisutch) acclimated to different salinity conditions and subsequently exposed to the OP phorate in 96-h acute toxicity tests.
These sh demonstrated a 30-fold increase in acute toxicity to
phorate when acclimated to 32 g/L salinity, compared with
those acclimated at <0.5 g/L salinity [41]. The present study
also demonstrated an increase in formation rates of the toxic
phorate oxon and highly toxic phorate oxon sulfoxide metabolites in liver, gill, and olfactory microsomes under the 32-g/L
salinity regime. This and other studies (with aldicarb and
fenthion, below) have posited that the increased toxicity may
be related to the differential expression or augmented activity of
avin-containing mono-oxygenases (FMOs), which are
involved in the osmoregulation and metabolism of xenobiotics
(e.g., OP activation by oxidation of peripheral thioether constituents prior to oxon formation). The enhanced activity of
FMOs has been shown to also increase toxic metabolite formation of the carbamate pesticide aldicarb, which shares a
similar thioether to phorate and acts by acetylcholinesterase
inhibition. Exposures of rainbow trout (O. mykiss) to aldicarb
and elevated salinity increased acetylcholinesterase inhibition,
toxicity of the pesticide, and microsomal production of the
aldicarb sulfoxide [42]. This altered biotransformation of aldicarb was concomitant with enhanced catalytic activity of FMOs
and the upregulation in mRNA expression of genes encoding
FMOs. In hybrid striped bass (Morone saxatilis
chrysops), a
species that expresses FMOs that are nonresponsive to salinity
induction, salinity did not affect acetylcholinesterase activity,
toxicity, or aldicarb sulfoxide formation. Coincubations of
microsomes with competitive CYP inhibitors had no impact
on sulfoxide metabolite formation, suggesting that CYPs were
not contributing to the salinity-induced sulfoxide formation.
Extension of these ndings to assessments of other anticholinesterase compounds that require thioether oxidation (e.g.,
fenthion) has demonstrated similar increases in toxicity with
increases in salinity [43,44], suggesting that this model could
apply to other compounds that are partially metabolized by
FMO pathways.
Increased acute toxicity of pesticides (lower median lethal
concentration values) resulting from increased temperature and
salinity conditions illustrate an AOP whose initiating event,
metabolic activation enhanced by climate-modied temperature
or salinity conditions, ends with increased lethality at the
organism level. Prospective scenarios might suggest that other
documented effects of pesticide toxicity in sh, such as interference with olfaction or behavior [45], may be another adverse
consequence of these pesticideclimate interactions. For example, salmonids use olfaction to detect chemical cues to provide
crucial information about food, predators, reproductive status of
mates, environmental contamination, and imprinted characteristics of natal streams. Impairment of this system can have
detrimental effects on individuals and populations [46]. Thus,
understanding the ramications of GCC on contaminant uptake

Climate change and mechanisms of chemical toxicity

and disposition can allow risk assessors to anticipate a range of

lethal and sublethal responses to contaminants.
In both ADME alteration scenarios (i.e., PCBs and pesticides), interactions occur due to CITS scenarios. The idea of
using a prospective approach is also highlighted in both ADME
examples because the underlying mechanism is fairly well
understood. It may be feasible for risk assessors to make similar
types of predictions for other interactions between GCC stressors and other toxicants.
ENDOCRINE-DISRUPTING COMPOUNDS AND
GCC INTERACTIONS

In addition to alterations in chemical uptake and disposition

by climate-associated ecosystem changes, the endocrine systems of biota are important targets of chemical toxicants.
Because hormone systems are highly integrated into the life
functions of organisms, toxicant disruptions of these systems
can lead to many specic and nonspecic responses depending
on the life stage and condition of the organism at the time of
exposure. The vertebrate endocrine system is also highly sensitive to environmental cues, such as precipitation, temperature,
and food availability, all of which are being altered by GCC.
The combined role of the endocrine system in maintaining
internal homeostasis and responding to the external environment makes it a sensitive and important target of toxicant and
GCC interactions. The following three case studies provide
examples to demonstrate some of these endocrine disruptor and
GCC interactions, with a focus on potential perturbations of the
thyroid and gonadal endocrine systems.
Amphibian metamorphosis, GCC, and the hypothalamic
pituitarythyroid system

Thyroid system functioning can be impaired by exposures

to numerous environmental contaminants, including PCBs,
polybrominated diphenyl ether (PBDE) ame retardants, PAHs,
organochlorine and OP pesticides, metals, sex steroids, and
pharmaceuticals. Exposures to thyroid-disrupting chemicals
may impair the ability of vertebrates to adequately respond
to GCC (i.e., a TICS scenario).
Exposures to thyroid-disrupting chemicals in aquatic breeding amphibians are of special concern because metamorphic
transitioning from water-based tadpoles to semiaquatic or terrestrial juveniles depends primarily on programmed secretions
of thyroid hormones. Water availability and temperature are key
variables affecting the timing of larval transitioning, with
evidence of accelerated metamorphosis in amphibian tadpoles
subjected to drying conditions and elevated water temperatures
[47,48]. This accelerated metamorphosis is considered to be an
acclimative mechanism for coping with water- or temperaturestressed environments. Exposures to thyroid disruptors at these
types of critical life stages may impact the adaptive capacity of
amphibian populations to changing environmental conditions
linked to GCC. Thus, early life stages of amphibians may be
particularly sensitive to the dual stresses of thyroid-perturbing
contaminants and GCC because their thyroid systems are
incompletely formed but nonetheless crucial to development.
Thyroid hormones are involved in many important biological processes, particularly those mediating growth, development, reproduction, and metabolism. A substantial body of
evidence has identied toxicological mechanisms by which
contaminants can disrupt thyroid regulation and thyroiddependent physiological processes. Several informative
reviews have been undertaken that may serve as a reference

Environ. Toxicol. Chem. 32, 2013

37

[4953]. Much of the research that has examined thyroid

contaminant effects on the amphibian thyroid system has
focused on laboratory measures of their potential to inhibit
metamorphosis and damage the thyroid gland [5459]. Little
is known about the extent to which thyroid disruptors are
affecting wild populations, particularly under important climate
change scenarios of elevated temperatures, water shortages, and
drought conditions. Also, there continues to be only limited
work in amphibians to elucidate toxicological mechanisms of
action. However, the thyroid system is generally highly conserved across vertebrates, so mechanistic research in other
animal models can help to inform our understanding of effects
in amphibians as they relate to potential GCC and thyroid
contaminant interactions.
Specically, some of the increasingly well-understood
molecular initiating events associated with thyroid-toxic contaminant exposures provide an opportunity to use an AOP
approach in a prospective analysis to formulate hypotheses
to determine and test whether thyroid toxicants could alter
organism resilience to GCC-linked water shortages and temperature elevations. Figure 3 provides a representative AOP that
outlines the potential interactive impacts of GCC and thyroid
disruptor exposures on amphibian metamorphosis. The AOP
depicts several molecular pathways that may converge on
reductions in levels of circulating thyroid hormones, which are
necessary to induce metamorphic transitioning in amphibians.
The biosynthesis and regulation of thyroid hormones (e.g.,
thyroxine and 3,30 ,5-triiodothyronine) are under negative feedback control by the central hypothalamicpituitarythyroid
axis. Contaminants can perturb the thyroid system at a variety
of points along the hypothalamicpituitarythyroid axis. Perchlorate, a propellant used by the military, aerospace, and
industrial sectors, is a well-documented thyroid disruptor that
impairs iodide uptake by the sodium iodide symporter of
thyroid epithelial cells [60]. Other well-described chemicals
that act on the thyroid are methimazole and 6-propyl-2thiouracil, which are pharmaceutical agents commonly used
to treat hyperthyroidism and in thyroid toxicity research as
model hypothalamicpituitarythyroid axis disruptors. These
compounds act on the thyroid by inhibiting thyroperoxidase
activity, thereby blocking iodide binding to thyroglobulin and
reducing thyroid hormone levels [61].
A variety of compounds have also been shown to alter the
transport, metabolism, and elimination of thyroid hormones.
For example, OH-PCBs and OH-PBDEs are biotransformation
products of phase I metabolism that have been shown to impair
thyroid hormone homeostasis by competitively binding to
plasma thyroid hormone transport proteins [6264]. In addition,
PCBs and PBDEs, among other chemicals, have been shown to
impair thyroid hormone homeostasis by enhancing the expression and activity of phase II thyroid hormone conjugating
enzymes, such as uridinediphospate glucuronosyl transferases
and sulfotransferases, thereby reducing thyroid hormone levels
by increasing their catabolism [6567]. Studies in sh have also
shown that PBDEs can inhibit the activity of deiodinase
enzymes, which are responsible for activating and inactivating
thyroid hormones in peripheral tissues [68]. The PBDEs and
other ame retardants, including tetrabromobisphenol A and
tetrachlorobisphenol A, as well as bisphenol A, used in plastics
may also disrupt thyroid activity by acting as antagonists to
thyroid receptors and altering the expression of receptorresponsive genes [6971].
The AOP construct in Figure 3 allows for the linkage of
several molecular initiating events associated with thyroid

38

Environ. Toxicol. Chem. 32, 2013

M.J. Hooper et al.

Thyroid system AOP

Mechanism/
toxicant

Chemical
disposi
on

Iodide uptake
inhibi
on
Perchlorate
Thyroglobulin
iodina
on
inhibi
on
Methimazole
PTU

TH transport,
metabolism,
elimina
on
altera
ons
PCBs, PBDEs
methoxychlor

Cellular
responses

Sodium iodide
symporter
Compe

ve
interference

Thyroid follicle,
epithelial cell
Reduced
thyroglobulin
iodina
on and
T3/T4 synthesis
Increase in cell
height

Thyroid
peroxidase
Compe

ve
inhibi
on
Phase I
metabolism
Toxicant
hydroxyla
on

Plasma
proteins
Compe

ve
binding

Phase II
metabolism
Transferase
induc
ons
Deiodinase
enzymes
Inhibi
on

TR antagonism
BPA, TBBPA,
TCBPA,
TMBPA, PBDEs

Thyroid
receptor
Antagonism

Accelerated
metamorphosis
Increased
droughts and
water scarcity
Elevated
water
temperatures

Acclima
on response
Hypothalamus
CRF release
Pituitary
TSH release

Thyroid
TH release

Organs and

ssues
TR-linked gene
expression
facilita
ng
metamorphosis

Organ
responses

Thyroid gland
Reduced TH
secre
on

Systemic
circula
on
Reduced TH

Peripheral cells
Increased TH
metabolism

Deiodinase
Disrup
on
PBDEs*, PTU

Climate change
eect/parameter

Toxicant-climate
interac
on AOP

Molecular
interac
ons

Peripheral cells
Decreased T3
synthesis

Organs and

ssues
Reduced TH
availability to
TH receptors
Altered
TR-linked gene
expression.
Metamorphic
processes

Organism
responses

Popula
on
responses

Amphibian early
life stages
Impaired
metamorphic
transi
oning,
deformi
es,
death
Successful
metamorphosis

Amphibian
popula
on
Declining
trajectory,
altered
dispersal and
recruitment
Popula
on
adapta
on

Fig. 3. Illustrative adverse outcome pathways (AOP) of toxicant-induced climate sensitivities among amphibians reecting potential dual interactions
between global climate change (GCC) and thyroid-disrupting chemicals (TDCs). Five mechanisms of action are depicted with unique molecular initiating events
that have been shown to intersect with reduced thyroid hormone levels and impaired metamorphosis among amphibians. These TDC AOPs share a common
outcome that could impair accelerated metamorphosis under GCC. See Figure 2 for key to interactions. BPA bisphenol A; PBDE polybrominated diphenyl
ether; PCB polychlorinated biphenyl; PTU propylthiouracil; TBBPA tetrabromobisphenol A; TCBPA tetrachlorobisphenol A; TMBPA
tetramethylbisphenol A; TH thyroid hormone; T3 triiodothyronine; T4 thyroxine; TR thyroid receptor; CRF corticotropin-releasing factor; TSH
thyroid stimulating hormone. [Color gure can be seen in the online version of this article, available at wileyonlinelibrary.com.]

contaminants to adverse outcomes at biological levels of organization that are important in risk assessments with special
consideration of expected GCC outcomes. In this particular
example, the interactions between thyroid disruption and GCC
have fairly well-dened biological responses that link several
molecular initiating events to an adverse outcome, namely,
impaired accelerated metamorphosis in amphibians that might
be subjected to GCC-linked water shortages or temperature
increases. This type of approach can be very benecial in
prospective analyses of GCCtoxicant interactions because it
can serve as the basis for identifying and testing natural
populations, with their species-specic life-history characteristics, for these types of complex interactive effects. It can also
be used to identify areas where further research is needed and

may serve as a model to identify other complex GCCthyroid

contaminant interactions that are potentially problematic.
For example, although not represented in the AOP, plasticity
in metamorphic timing has important effects on overall tness.
Amphibian tadpoles that undergo metamorphosis earlier in
development as an acclimative response to GCC may bear a
tness cost associated with this rapid metamorphosis in the form
of smaller juvenile size. This smaller size has been shown to
confer increased sensitivity to predation and reduced fecundity
at rst reproduction [7274]. Exposure to thyroid disruptors
(and other chemical pollutants) could have more deleterious
effects on these less t animals, along with other climate change
costressors, such as altered pathogen and parasite distributions
[75,76].

Climate change and mechanisms of chemical toxicity

Fish reproduction and development, GCC, and the hypothalamic

pituitarygonadal system

Gonadal hormone systems, responsive to both environmental cues and contaminant perturbations, provide examples
of how chemical and nonchemical stressors can combine to
impact reproductive performance and success, highly
relevant organismal and population-level adverse outcomes.
The hypothalamicpituitarygonadal (HPG) axis controls
virtually all aspects of reproduction and sexual development
in vertebrates. Normal function of the HPG axis is modulated by
a variety of external stimuli such as food availability, photoperiod, behavioral interactions, and, particularly in poikilotherms such as sh, temperature [77]. The natural life history
of sh species has evolved around these environmental cues,
most notably photoperiod and temperature, to optimize cycles
of reproduction and development. Some sh species can reproduce and thrive under a fairly broad range of temperatures,
while a change in temperature of even a degree or two can
completely alter reproductive timing and success in others. As a
consequence, increases in temperature associated with GCC
have affected and/or are expected to directly affect the abundance and distribution of sh through factors such as alterations
in reproductive cycles [36,7881].
Over the past decade, a substantial amount of research has
focused on environmental contaminants, including a number of
pesticides, drugs, and industrial chemicals, which have been
shown to affect reproduction and development through interactions with the HPG axis. Large-scale screening programs in
several countries, including the United States, are designed
specically to identify chemicals that affect HPG functioning
through various mechanisms and pathways [82]. Although
much of the work in this area initially focused on estrogen
receptor agonists, there has been increasing concern for and
emphasis on other pathways within the HPG axis, including
those involving the androgen receptor and synthesis of sex
steroids. A wide array of lab and eld studies with sh has
shown that reproduction and/or development can be adversely
affected by contaminants that target any number of pathways
within the HPG axis, sometimes at exceedingly low concentrations. For example, a multiyear, whole-lake study with the
drug ethinylestradiol demonstrated complete extirpation of
the extant fathead minnow population at water concentrations
of the synthetic estrogen on the order of 5 to 6 ng/L, which is
within the range reported to occur in some municipal efuents
[83].
Given that a variety of environmentally relevant chemicals
affect HPG functioning in sh and that the HPG axis is
controlled, in part, by temperature, it is highly plausible that
there would be biologically meaningful interactions between
the two types of stressors. Unfortunately, little experimental
work has been done to systematically explore this hypothesis.
Studies have documented that temperature can affect the
induction of vitellogenin (egg yolk protein) by exogenous
estrogens in several different sh species [8487]; but other
than this one pathway and endpoint, virtually nothing is known
about chemicaltemperature interactions on HPG function.
To assess the scope of potential risk associated with these
interactions on HPG functioning in sh, multiple HPG pathways and end points need to be assessed. Without this type of
baseline data, it is difcult to speculate exactly what the nature
of chemicaltemperature interactions might be in terms of
decreased tness. While it clearly is impossible to conduct
complex multistressor studies with the many (perhaps thousands)

Environ. Toxicol. Chem. 32, 2013

39

of substances of potential concern from an endocrine perspective, it is possible to generate the needed data in a focused,
resource-efcient manner.
Specically, data collection relative to chemicaltemperature
interactions can be guided by knowledge of relevant molecular
targets and associated AOPs in the sh HPG axis. A large
amount of work has been done with HPG-active chemicals in
sh, and AOPs have been described for reproductive effects of
estrogen receptor agonists and inhibitors of vitellogenesis
in females [14]. Additional AOPs for the sh HPG axis are
being developed for agonists and antagonists of the androgen
receptor, inhibitors of key CYP-based enzymes and hydroxysteroid dehydrogenases involved in steroid synthesis, and signaling mechanisms in the brain and pituitary [88]. Once a library
of high-priority AOPs (probably on the order of 1020) is
assembled, it will be possible to selectively test model chemicals representing these pathways under temperature regimes
designed to mimic expected and possible alterations occurring
in the environment with GCC. The work ideally would be
done using partial and full life-cycle tests with at least two
well-established model sh species that utilize different reproductive strategies, for example, continual versus annual spawners. Presumably, some pathways would be more likely to be
impacted by temperature interactions than others. In any case,
this approach would provide a pathway-specic knowledge
base that could be cross-referenced with the mechanismscreening data collected in conjunction with regulatory programs, to identify those HPG-active chemicals that should
receive additional scrutiny from the standpoint of potential
GCC interactions.
Hypoxia, GCC, dioxins, and dioxin-like contaminants

Many aquatic environments are subjected to widespread

hypoxia (i.e., low dissolved oxygen [DO]) and anoxia (i.e.,
absence of DO). It is an increasingly urgent global problem that
has caused species declines and major ecosystem changes.
Hypoxia has been reported across more than 400 aquatic
systems, covering thousands of square kilometers, including
expansive areas of the Baltic Sea, Gulf of Mexico, and Chesapeake Bay [8991]. The frequency, duration, and geographical
extent of hypoxia have increased over the past few decades due
to anthropogenic sources of eutrophication from nutrient pollution and fossil fuel burning coupled with wetland losses,
increased fertilizer usage, and urbanization [92].
Climate change is projected to worsen hypoxia by increasing
nutrient runoff in regions subjected to increasing and extreme
rainfall and by increasing oceanic oxygen stratication and
warming [2,93]. Conversely, the potential for stormier conditions (e.g., more hurricanes or typhoons) under GCC may
increase mixing, disrupt oxygen stratication, and reduce oxygen depletions in some benthic environments [94]. The complex
interactions between GCC, hypoxia, and contaminants are not
limited to nutrient and fertilizer runoff but are also inuenced by
interactions with other chemical contaminants, including PAHs,
dioxins, and PCBs. It is predicted that GCC will increase
environmental levels of PAHs and dioxins through biomass
burning and may alter and remobilize legacy persistent organic
pollutants such as PCBs [10,95].
Hypoxia alone has been shown to act like an endocrine
disruptor in aquatic species [96101]. Studies have also shown
that hypoxia may increase the toxicity of exposures to PAHs,
dioxins, and PCBs, leading to potential CITS [102,103]. Exposures to these chemical classes may also hinder the ability of
species to respond to increased hypoxia under climate change

40

Environ. Toxicol. Chem. 32, 2013

(TICS scenario) [104]. Interactions between hypoxia and contaminants demonstrate the complexity of direct and indirect
parameters altered by GCC that could impair the health of
aquatic organisms and populations.
While there is substantial evidence that hypoxia impairs the
reproduction and development of sh [105], the mechanisms of
toxicity on the endocrine system and HPG axis continue to be
unclear. Laboratory and eld studies have shown hypoxiainduced reductions in circulating levels of sex hormones
(testosterone, 11-ketotestosterone, estradiol) and the egg yolk
protein precursor vitellogenin concomitant with impaired
reproduction and sex differentiation in sh [97,100,101,106].
Mechanisms of action that have been demonstrated to play roles
in the hypoxia-induced reproductive impairments include
altered expression of genes and impaired activity of enzymes
responsible for steroid biosynthesis [98,100], downregulation of
the serotonergic pathway [107], and nongenomic actions of
progestins on oocyte and sperm plasma membranes [108].
In addition to hypoxia alone, GCC-linked increases of some
pollutants (e.g., PAHs, dioxins) and remobilization of others
(e.g., PCBs) coupled with worsening hypoxia may impair the
ability of organisms to respond to these dual environmental
stressors. Exposures to contaminants such as PCDDs, PCDFs,
planar PCBs, and PAHs elicit biological responses that are
triggered by binding to the aryl hydrocarbon receptor (ahR).
Functioning of the ahR pathway and its underlying mechanisms
have been well described in vertebrates and include adaptive
signaling upregulating xenobiotic metabolizing enzymes; toxic
signaling causing adverse effects from high-afnity ligands,
notably TCDD; and developmental signaling contributing to
normal development of some tissues and organs [109].
On activation, ahR proteins form heterodimers with ahR
nucleotranslocator proteins. The formation of these ahR/ahR
nucleotranslocator complexes is regulated by ligand (or xenobiotic) binding. This complex can then bind to dioxin response
elements upstream of gene coding regions, leading to altered
gene expression [109]. The ahR nucleotranslocator may also
dimerize with the a-class of hypoxia-inducible factors (HIF-1a,
HIF-2a, HIF-3a) to alter gene expression in response to low
oxygen stress, leading to a cascade of physiological responses to
low DO. Thus, because the ahR nucleotranslocator is shared
across multiple signaling pathways, it is possible that activation
of one pathway could inhibit activation of another pathway
that depends on the ahR nucleotranslocator [110]. While
mechanisms of response to hypoxia and TCDD-like compounds
are each fairly well understood, the crosstalk between these
two pathways and mechanisms by which one pathway
interferes with the other continue to be poorly understood
[102,103,105,110].
Studies in zebrash larvae and cell cultures suggest that
hypoxia may reduce ahR signaling and inhibit 2,3,7,8-TCDD
induction of CYP1A (i.e., CITS pathway) [103,110]. However,
these studies suggest that reciprocal crosstalk may not be
occurring in that dioxins have not been observed to inhibit
hypoxia signaling pathways (i.e., TICS pathway). A few studies
have also examined the crosstalk between hypoxia and PAHs.
Synergistic increases in teratogenicity have been previously
demonstrated in sh exposed to mixtures of PAH-CYP1A
inhibitors (e.g., uoranthene) and PAH-ahR agonists (e.g.,
benzo[a]pyrene). Consistent with 2,3,7,8-TCDD/hypoxia studies, PAH-ahR agonist exposures in the presence of hypoxia
reduced CYP1A activity in zebrash embryos but did not
increase teratogenicity [102]. However, zebrash coexposures
to PAH-CYP1A inhibitors uoranthene and a-napthaavone

M.J. Hooper et al.

and hypoxia were shown to cause teratogenicity by an unknown

mechanism. Another interaction that has been explored with
sh is an antagonistic interaction whereby PCB exposures make
sh less tolerant to hypoxia (i.e., TICS pathway) by impeding
the production and activity of glycolytic enzymes that are
responsible for cellular energy production when oxygen is
limited [104].
The situation presented by hypoxia serves as an example of
the complexity of interactions between changing environmental
conditions under GCC and the array of interactions of chemical
and nonchemical stressors on biota. This case demonstrates that
worsening hypoxia coupled with increasing pollution under
GCC could act at multiple levels of biological organization
and by multiple toxicological pathways, leading importantly to
impaired reproduction and development of sh. Hypoxia itself
can impair the HPG system, potentially eliciting impacts on
reproduction and development, and TCDD-like contaminants
could contribute to these impacts, albeit by very different
mechanisms. A prospective AOP would be greatly benecial
in examining these complex interactions because it could help
to identify and translate the range of interconnected mechanisms by which hypoxia and pollutants might interact to
culminate in potential impacts on reproduction and development. This type of AOP construct could then be used to identify
natural populations that might be subjected to these complex
interactions for further risk analysis. It could also help to
identify data gaps and other chemical contaminants that might
act by similar pathways. To this end, a sh vitellogenin model
has been used successfully in the eld to identify mechanisms
underlying hypoxia-induced endocrine disruption [99]. This
sort of modeling holds promise as a viable retrospective
approach to determine the role of climate-induced hypoxia
and nutrient runoff in sh HPG impairment. These types of
retrospective analyses could be used as tools to identify populations projected to be susceptible to GCC increases in rainfall,
hypoxia, and contaminant exposures.
POLAR BEARS, GCC, AND ORGANOHALOGEN
CONTAMINANTS

At the highest levels of biological organization, chemical

and GCC exposures can inuence the interactive dynamics of
individuals, populations, and communities. For example, modications of food-web dynamics by climate change can produce
community-level changes that can impact how individual
animals are exposed to contaminants. Prospective AOP analyses can help to predict and interpret potential ramications of
these complex GCC and pollutant interactions observed in the
eld.
As previously described, warming air and sea temperatures
in Arctic and subarctic regions are among the strongest
and best-documented climate change indicators [93], with
resulting changes in the timing and extent of seasonal sea ice
breakup having a profound inuence on associated ecosystems
[111,112]. Polar bears (Ursus maritimus) in the western Hudson
Bay (WHB) region of Canada occupy the extreme southern
range for this species, where GCC effects have been strongest.
Dependent on the Hudson Bay sea ice for movement, mating,
and feeding, WHB polar bears have suffered declining body
condition, birth rates, and survival rates over the past 20 years.
Measured declines have been concurrent with sea-ice breakup
occurring three weeks earlier in the summer [113,114]. These
changes appear to be inuencing concentrations and proles of
chemical contaminants in WHB polar bears as well as the

Climate change and mechanisms of chemical toxicity

potential for resulting health effects. Moreover, polar bear

decline may serve as a bioindicator of the overall declining
health of these northerly ecosystems due to the combined
impacts of GCC with other perturbations, including chemical
exposures.
Polar bears feed on seals that inhabit both pack ice and open
water. Fatty acid dietary tracers from polar bear adipose tissues
demonstrate that males feed on larger pack iceinhabiting
bearded seals (Erignathus barbatus) and smaller ringed seals
(Pusa hispida). Smaller female bears feed primarily on ringed
seals [115,116]. Since the mid-1990s, the overall proportion of
bearded seals in the WHB polar bear diet has decreased signicantly, being replaced by more ringed seals as well as harp
and harbor seals (Phoca groenlandica and Phoca vitulina,
respectively) [115].
Concurrent with this dietary shift has been a change in the
composition and concentrations of organohalogen (OHC) contaminants in polar bear adipose tissue. Concentrations of total
PBDEs and b-hexachlorocyclohexane increased, as did DDT
and DDT metabolite clearance, from 1991 through 2007 [117].
When corrected for dietary shifts during this time, noted
accumulation and clearance rates were signicantly higher.
Changes in diet and contaminants have occurred simultaneously
with earlier sea-ice breakup, though direct correlation has been
difcult to develop because of the complexity and variability of
dietary food webs, contaminant sources, and climate trends.
Investigators continue to work on understanding how GCC is
affecting the polar bear diet and the interactive mechanisms
involved in increasing contaminant bioaccumulation and clearance rates [118]. In a prospective scenario, it could be suggested
that GCC-induced community-level perturbations are changing
contaminant exposure patterns in WHB polar bears (i.e., CITS
scenario).
During ice-free periods, when polar bears are forced ashore
and prey are scarce, fasting leads to substantial body fat
mobilization and body mass loss in polar bears, with WHB
females fasting up to eight months through the denning and
early cub-rearing periods [114,119]. In a study of OHC disposition in polar bears over an onshore 60-d (mean) fasting
period, adipose, plasma, and milk concentrations of these
compounds increased signicantly with loss of body mass
and body fat. Total chlordane-like chemicals and summed PCBs
rose to near double their prefast concentrations, while DDT and
DDT metabolites decreased [120]. Increased milk concentrations of chlordanes and PCBs led to increases in body burdens
of nursing cubs of the year. In pregnant WHB female polar
bears, the actual reproductive fast averaged 192 d (n 8)
from the time the bears came ashore to emergence from their
dens with new cubs, with average body mass loss of 43% of
their prefast body weight [119]. The actual increase in systemic
and milk organochlorine concentrations that occurs through
the reproductive fast is likely much greater than the near
doubling documented over a 60-d portion of that fasting period.
As the spring ice breakup comes earlier, feeding time on the
pack ice for polar bears decreases and the effort they expend to
return to shore takes a greater toll on their fat reserves. Females
thus enter the reproductive fast with lower body fat stores, likely
leading to greater concentrations of these contaminants in both
maternal and young bears. Thus, a second stress on polar bears
from sea-ice breakup is shorter hunting time on the ice and
longer fasting periods, with both leading to greater mobilization
of adipose-sequestered OHCs, an ADME effect that leads to
substantially higher circulating and tissue body burdens of
OHCs.

Environ. Toxicol. Chem. 32, 2013

41

The seasonal increases of OHCs in fasting polar bears are

notable as they bring systemic concentrations to levels similar
to those of the more contaminated polar bears of the Svalbard
Islands (Norway) and eastern Greenland [121]. Of particular
concern are cubs of WHB polar bears, due to the increased
sensitivity of developing mammals to endocrine and immune
system effects associated with these persistent halogenated
organics. The OHC contaminants of the types and concentrations found in WHB polar bears have been correlated in polar
bears with impaired thyroid hormone regulation [122], elevated
progesterone [123] and depressed testosterone concentrations
[124], and impaired humoral and cellular immune function
[125,126]. Surrogate studies using arctic foxes and sled dogs
fed minke whale blubber rich in OHCs or control pork-fat diets
are helping to identify underlying mechanisms and cause-andeffect evidence for these correlative ndings as dosing studies
of polar bears are not feasible (reviewed in Letcher et al. [121]).
In the present case study, effects of climate in elevating OHC
concentrations (CITS) could lead to a TICS scenario due to
resulting endocrine, immune, and neurodevelopment perturbations that could potentially hinder acclimatization to GCC
stressors. The use of a prospective AOP approach allows for
prediction of potential cause-and-effect relationships resulting
from observed eld data. These predictions can be used by risk
assessors in the interpretation of existing ndings in polar bears
and in predicting the nature and magnitude of anticipated effects
in more northerly populations of polar bears, where sea-ice
retreat has not yet reached the extremes that confront the most
southern WHB populations. In this complex case study where
CITS leads to TICS, we also see the role that AOPs can play
in integrating community-level GCC perturbations [127].
Changes in food webs can lead to altered contaminant burdens
in apex predators. The impaired health effects that could
accompany these changes are expressed at the individual
organism level, though in scenarios such as that in WHB polar
bears, the accumulative effects on reproduction, recruitment,
and even survival might lead to adverse population-level effects
and potentially extirpation of some local populations.
NESTLING PASSERINES, MERCURY, AND EXTREME
CLIMATE EFFECTS

In addition to building prospective and theoretical AOP

scenarios based on empirical ndings in the elds of climate
change and ecotoxicology, risk and resource injury assessors
have recently been confronted with adverse outcomes in wild
populations without straightforward explanatory pathways.
When this occurs, working backward from adverse outcomes
through mechanistic pathways can help to formulate hypotheses
to identify causative factors (and discard unlikely scenarios).
Development of cause-and-effect relationships that explain
GCCtoxicant interactions in a specic population can provide
models and hypotheses that can be applied to other populations
faced with similar combinations of stressors.
Field studies have recently illustrated how ambient temperature and a contaminant interact as costressors on reproduction
in tree swallows (Tachycineta bicolor). Following a report that
mercury had reduced production of tree swallow nestlings
during a drought but not during the previous year of normal
weather [128], researchers established a large swallow population on mercury-contaminated and reference sites and tested
for interactions between the effects of weather and mercury on
swallow reproduction [129]. Temperature and precipitation data
from specic 5- to 10-d periods of the nesting cycle (egg

42

Environ. Toxicol. Chem. 32, 2013

production, incubation, featherless nestlings, and feathered

nestlings) were examined separately to identify toxicity mechanisms for any observed effects. Earlier investigations had
demonstrated elevated prey item and maternal and nestling
blood mercury concentrations on the contaminated sites and
weak but signicant negative relationships between reproduction measures (egg-hatching success and survival of nestlings)
and maternal blood mercury concentrations [128]. As in previous years, nesting on the mercury-contaminated site reduced
the production of young that survived to leave the nest (edglings) by approximately 20%.
During the late nestling period, a stage when nestlings are
able to thermoregulate effectively and parental behavior consists almost entirely of feeding nestlings and hunting, the
relationship between maximum daily temperature and edgling
production was positive for swallows nesting on both types of
site. This was expected because the emergence and abundance
of insects often increase with temperature [130], so the likelihood of starvation is reduced regardless of contamination
status. The more interesting nding was that during the early
nestling period, when parents devote a substantial amount of
time to managing the temperature of the nest (brooding) and less
effort feeding their blind and featherless nestlings, there was a
signicant interaction between mercury and maximum daily
temperature. Whereas higher temperatures during the early
nestling period were related to higher edgling production
on reference sites, these early temperature elevations on
mercury-contaminated sites resulted in signicantly reduced
edgling production [129].
These ndings explain the earlier observation that mercury
impacted reproduction more during hot, dry conditions. As one
of the rst examples of its kind from free-living vertebrates, it
underscores the importance of considering the interaction of
climatological and contaminant costressors. The toxicity of
unseasonable heat combined with mercury contamination is
greater than existing mercury data predict, suggesting that the
increasing frequency of extreme temperature events accompanying GCC [131] will lead to adverse effects where current
exposures do not produce detectable impacts. What is unclear is
whether the effects of this stressor combination are due to
extreme weather modifying mercury toxicity (CITS) or mercury
impacting the birds ability to acclimate to extreme elevations
in temperature (TICS). A mechanistic understanding of this
chemicalclimate interaction is necessary to fully anticipate its
repercussions in the current scenario as well as predict the
implications for other species and toxicants.
An AOP for this scenario requires a toxicity pathway for
mercury (primarily methyl mercury [MeHg] in the study birds)
and a pathway for acclimation to elevated heat conditions
(hyperthermia) in tree swallow nestlings. An AOP was constructed that provides a starting point for a retrospective analysis of causation in the combinatory toxicity of weather and
mercury in tree swallows (Fig. 4).
Work with live animals and in vitro studies provide insights
into the mechanisms of MeHg toxicity (for review, see Farina
et al. [132,133]). Once contaminated food is ingested, MeHg is
absorbed effectively (>90%) from the gut and enters tissues as a
cysteine-bound conjugate that mimics the amino acid methionine, moving freely into cells via amino acid transport proteins
on cell membranes. Within the cell, the MeHgcysteine bond is
sufciently labile to allow exchange reactions where MeHg is
transferred to other, more reactive protein thiols (R-SH) and
selenols (R-SeH), disrupting existing molecular structures and
interfering with protein function. The MeHg inactivates or

M.J. Hooper et al.

modies enzymes active in a variety of mechanisms critical

to cellular function. These include antioxidant defenses, such
as glutathione peroxidase and thioredoxin reductase, which
protect against reactive oxygen species (ROS). Interference
with glutamate reuptake into astrocytes by MeHg leads to
glutamate buildup in the synapse and overstimulation of
N-methyl-D-aspartic acid receptor calcium channels on adjacent
neurons. This and other ROS-generated membrane-disruption
mechanisms lead to ooding of calcium into sensitive neuronal
cell structures, where it disrupts mitochondria and causes
neuronal cell death. The ramications of these effects, in
addition to direct interference of MeHg with mitochondrial
oxidative phosphorylation components, are an increase in
cellular occurrence of ROS leading to lipid peroxidation,
DNA and protein oxidation, mitochondrial injury, and cell
death. In the avian nervous system, such effects may lead to
behavioral dysfunction, manifest in decreased/lethargic
foraging effort and reduced incubation times in nesting adult
birds [134]. In nestlings, motor impairment predominates, with
decreased exploratory movements and increased anomalous
movements, consistent with observed reductions in the number
and density of Purkinje cells in the cerebellum [135]. The
outcome of this mechanistic pathway could be death for nestlings should adult care or their own aberrant behavior (e.g., lack
of vocalizing for food) lead to lack of adult provisioning.
Acclimation to elevated temperatures, or hyperthermia, in
nestlings occurs primarily by means inherent to the nestling,
dissipating heat (thermolysis) with little input from adult
birds (reviewed in Dawson and Whittow [136]). Peripheral
and central neuronal and deep-body thermoreceptor inputs
are integrated in the preoptic/anterior hypothalamus. A panting
response generated in the respiratory center triggers openmouth breathing with an elevated respiratory rate, leading to
evaporative cooling. Peripheral vasodilation and cutaneous
water loss from nonkeratinized skin also further cool the
nestling. Continued adult provisioning under these conditions
is important to maintain nestling hydration as evaporative
cooling leads to body water loss. Should the nestling fail to
maintain these behaviors, adults fail to provision, or elevated
temperatures overwhelm thermolysis mechanisms, the nestling
will die.
Examining the details of this case retrospectively allows
isolation of some mechanisms as being more likely than others.
First, it is notable that the mercurytemperature interaction
occurred only during the rst week of the nestlings life, not
during egg formation or incubation or in older nestlings.
Parental care during the early nestling stage involves feeding
and brooding, either of which could be sensitive to mercury and
temperature. However, if food availability or parental foraging
ability were the target of the interaction, one would expect an
even stronger interaction in late-stage nestlings that require ever
greater amounts of food. The lack of effects in late-stage
nestlings, as well as during incubation, suggests that a decit
in parental care of the youngest nestlings was not a causative
factor in their reduced edging rates. An additional parental
behavior whose alteration might have affected nestling survival
was male provisioning of feathers during nest construction,
such that nests on mercury-contaminated sites were more
insulated, leading to mortality during hot weather. However,
the number and mass of feathers in nests did not differ between
mercury and reference sites (D. Cristol, unpublished data).
In the absence of parental effects on nestling survival, a
retrospective assessment of CITS and TICS pathways within the
AOP provides insight into potential interactive mechanisms.

Climate change and mechanisms of chemical toxicity

Environ. Toxicol. Chem. 32, 2013

43

Methyl mercury toxicity AOP

Mechanism/
toxicant

Chemical
disposition

Toxicity

Binding and
metabolism

Targets

Responses

RSH, RSeH, GSH,

MT & free
cysteine binding

Seleno- and thioprotein inactivation:

GPx, TrxR, DIO

Increased H2O2,
unstable redox
status, decreased T3

Keratin
incorporation
(e.g., feathers)

Thermoregulation

Extreme
heat events

Organism
responses

Molecular

Damage to
cells and organs

Organism effects

Synaptic glutamate
reuptake inhibition

Retrospective CITS
pathways
Climate change
effect/parameter

Cell and organ

responses

Mitochondrial protein Increased superoxide,

H2O2, OH radical, NO
binding/functional
disruption

Demethylation
Methyl
mercury

Molecular
interactions

Increased synapse
glutamate, NMDA-R
stimulation and
down-regulation,
Ca++ overload

Lipid peroxidation
DNA/protein
oxidation
Mitochondrial
injury
Neuronal death

Decreased nest
attentiveness and
nestling brooding
Altered nestling
health and
behavior

Altered thyroid
hormone function
Immunotoxicity

Retrospective TICS pathways

Acclimation response
Acclimation
control

Physiological and
behavioral responses

Skin, CNS, tissue

thermoreceptors

Panting, increased
respiratory rate,
peripheral vasodilation,
cutaneous water loss

Preoptic/anterior
hypothalamus
and respiratory
center

Metabolic responses (?)

Adult food/water
provisioning, brooding

Organism
responses

Reproductive
responses

Population
responses

Organism effects

Reproduction

Population
trajectory

Lack of body
temperature
control and death

Fledgling
mortality and
decreased
nesting success

Declining
trajectory

Body temperature
control, survival to
fledging

Nestlings fledge,
nesting success

Population
acclimation/
adaptation

Heat acclimation AOP

Adverse outcome demonstrated in field studies

Fig. 4. Adverse outcome pathways (AOPs) for investigating demonstrated [129] combined effects of extreme heat events and mercury toxicity in tree swallow
nestlings. Retrospective pathways for potential climate-induced toxicant sensitivity (CITS) and toxicant-induced climate sensitivity (TICS) mechanisms are
indicated. See Figure 2 for key to interactions. DIO iodothyronine deiodinase; GPx glutathione peroxidase; GSH reduced glutathione; H2O2 hydrogen
peroxide; MT metallothionein; NMDA-R N-methyl-D-aspartic acid receptor; NO nitric oxide; OH hydroxyl; RSH protein thiol; RSeH protein
selenol; T3 triiodothyronine; TrxR thioredoxine reductase. [Color gure can be seen in the online version of this article, available at wileyonlinelibrary.com.]

Were extreme heat events affecting MeHg toxicity (CITS), it

is likely they would impact either the disposition of MeHg or
its interaction with molecular targets (Fig. 4). Young nestling
body temperatures, not fully capable of thermolysis, rise with
ambient temperatures, which could affect the distribution,
binding, and sequestration of systemic MeHg. For example,
nestling thyroid hormone levels on mercury sites, with already
depressed 3,30 ,5-triiodothyronine concentrations [137], could
be driven down further due to increased MeHg binding of
iodothyronine deiodinase, the selenoprotein responsible for
the conversion of thyroxine to 3,30 ,5-triiodothyronine. Hyperthermic conditions, which increase ROS generation in birds
under uncontaminated conditions [138], could increase MeHginduced ROS generation and the subsequent oxidative stress in
the nestling. This effect could be additive or even synergistic,
due to interaction of multiple mechanisms of ROS generation.
Climate impacts on MeHg toxicity are thus plausible and,
based on scenarios generated from the AOP, testable to determine their validity.
The alternative pathway, where toxic effects of MeHg
interfere with nestling acclimation to hyperthermic conditions
(TICS), is also plausible as developing nestlings are particularly
sensitive to MeHg toxicity [139,140]. The limited thermolytic
mechanisms available to cavity-inhabiting nestlings proceed
through neurological pathways that could be lost due to neurotoxic effects of MeHg, impacting neuronal thermoreceptors,
central control centers, or efferent neurons that extend to control
peripheral responses. Cessation of panting, decreases in respi-

ration rate, or loss of peripheral vasodilation could quickly

lead to lethal overheating in small, immobile nestlings. Alternatively, aberrant nestling behavior during parental feeding
bouts, such as lack of or inappropriate begging activities, could
lead to ineffective nestling provisioning and decreased food
and water consumption that would also prove lethal during
periods when evaporative water loss is a primary thermolysis
mechanism. As with the retrospective CITS scenarios, the TICS
mechanisms are plausible and testable in the eld or laboratory.
A fruitful next step in unraveling the mechanism of
mercuryGCC interactions would be a mercury dosing study
varying temperature and MeHg treatments to examine the
effects of mercury and temperature on nestling bird survival
to one week of age. Testing of TICS mechanisms might prove
expeditious as thermolytic behaviors such as gaping mouth,
panting, and elevated respiratory rates, or the lack thereof due to
MeHg, would provide easily accessible evidence of hindered
acclimation mechanisms. Alternatively, increased ROS occurrence in thermally stressed and MeHg-dosed nestlings would
be evidence that temperature was accelerating the ROS generation pathways. It would not be out of the question if both
types of effects were observed, with a temporal progression of
heat-induced increases of ROS generation leading to greater
neurodegeneration and a loss of thermolytic capacity. The AOP
in Figure 4 incorporates mechanisms from across many species
but is a starting place for prospective analyses. Fine-tuning
the components by developing data for passerine species
would provide more accurate predictions for tree swallows.

44

Environ. Toxicol. Chem. 32, 2013

Understanding how species differences modify the pathways

would increase the breadth of the models applicability.
Whichever pathway or combination of pathways is responsible for climatestressor interactions in the tree swallows, the
ramications are important for conservation and species protection. If mercury impairs the developing thermoregulatory
system, leading to higher mortality of young nestlings during
unseasonable heat, and the identied mechanism is conserved
across bird species, risk managers would have a strong basis for
predicting the effects of GCC on temperate songbirds with
predicted exposure to mercury. If, instead, temperature exacerbated MeHg-induced ROS generation, neurotoxicity, or other
toxic responses, there could be wide repercussions for the
range of other compounds that work via similar mechanisms
of toxic action (e.g., other cationic metals, compounds with
electrophilic reactive metabolites). In either case, if mitigation
or habitat triage were called for, reducing environmental
mercury concentrations and/or availability would be, in the
long run, the most important approaches, with conservation
resources applied selectively to populations residing at the edge
of their physiological temperature tolerance range.
CONCLUSION

These case studies demonstrate, at a mechanistic level, how

GCC can interact with known toxic chemicals to change
anticipated exposureeffect outcomes. In the process, they
illustrate essential concepts for understanding the combined
stresses of GCC and chemical contaminants. What stands out as
an important lesson is that environmental toxicologists cannot
ignore the increasing inuences of climate change when developing effects inputs for chemical and contaminant assessments.
It would be equally unwise to forecast the effects of GCC
without considering the interaction between climatic variables
and contaminants that can alter current risk outcomes. This is
not to suggest that all chemical interactions with all species will
be altered by GCC, but rather that, in risk and injury assessment
scenarios, careful consideration should be given as to whether
inclusion of GCC as a costressor is necessary to avoid erroneous
estimates of impacts in study systems or dened populations
[141].
Recognizing the importance of potential climatechemical
interactions in assessing risk is the crucial rst step, and a path
forward using AOPs is suggested. Through AOPs, the stepwise
progression from exposure to chemicalreceptor interaction to
molecular, cellular, tissue, organ, and organismal responses can
be tracked. The inuence of changing climate variables can be
tested, extrapolated, or predicted at critical points along the
AOP, providing data on CITS. Similarly, an understanding of
biological processes necessary for acclimation to GCC effects
allows anticipation of how chemicals might perturb the acclimation process, leading to an understanding of TICS. As
toxicity mechanisms are often shared by wide chemical classes
and climate acclimation mechanisms are shared across taxonomically similar organisms, established climatechemical
AOPs provide a means by which important climatechemical
interactions can be characterized and applied across broad
chemical classes and species groups of concern.
Building on pathway approaches, the case studies demonstrate the signicance of the timing, duration, and overlap of
exposures to chemical and climate stressors. Of similar importance is the recognition that sublethal alterations due to acclimation to the dual stresses of GCC and contaminant exposures
can negatively impact an organisms tness and survival. To

M.J. Hooper et al.

answer questions of how climate and chemicals might interact

as costressors, prospective scenarios can be built based on
known or theoretical AOPs that incorporate climate modications or, alternatively, on climate acclimation or adaptation
processes that incorporate toxicological modications. Conversely, when adverse outcomes with suspected climate and
chemical interactions are observed, a retrospective analysis
can be used to identify knowledge gaps and propose and test
hypotheses that might identify the mechanistic basis for the
interaction. Once claried, the ndings from both prospective
and retrospective assessments can be used to identify and
improve our ability to predict impacts occurring in the eld.
Although the case studies addressed nonhuman impact
assessments, the methods described will work equally well in
GCCchemical interaction scenarios with humans. Increases in
human mortality from cardiovascular system and respiratory
systemrelated complications during heat waves are well established, suggesting one might work retrospectively through the
physiological processes involved to identify the knowledge
gaps and propose hypotheses and experiments that may explain
the role of chemicals in morbidity and mortality due to combined temperature and contaminant exposures. Although extensive research along these lines has not been carried out, heat
waves will clearly be a more frequent event as the result of
GCC, and assessing risk of human deaths in major cities is going
to be an important part of the planning and risk-assessment
processes [142]. Increased formation of secondary photochemical products such as ground-level ozone, which also has a
signicant association with increased morbidity and mortality
[143], a rise in the number of wildres, and increasing desertication of many regions in the world will further add to the
burden of increasing atmospheric particulates, heightened cardiopulmonary complications, and compromised global human
health. Understanding the mechanism for these deaths will
require identication of the independent and interactive modes
of action of temperature, ozone, and particulate matter. Once
their respective roles are elucidated through both retrospective
and prospective mechanistic investigations, the relative benets
of mitigative measures (e.g., reducing particulate matter and
ozone precursors) can be assessed.
What is clear from the examples provided here is that a better
understanding of how toxicological mechanisms interact with
climate-induced stressors will provide a solid platform for
improved effect assessments for both humans and wildlife.
In chemical risk assessments for human health, retrospective
AOP approaches can provide the biological plausibility that will
inform predictions of changed patterns of disease as a result of
GCC. Epidemiologists can use empirical data from existing and
past associations between disease and climate to make projections about the human health implications of GCC, tying them
to toxicological mechanisms through AOP scenarios. For environmental managers, AOP constructs and toxicological mechanisms allow prediction of GCCcontaminant interactions,
which can facilitate refocusing and prioritization of regulatory
efforts, species protection plans, research agendas, and conservation planning.
AcknowledgementContributors who supported the Pellston workshop and
publications are gratefully acknowledged and documented in the introduction to this series (Stahl et al. [144], this issue). K. Solomon, J.E. Hinck, and
two anonymous reviewers improved an early draft of the present report.
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