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Cite This: Environ. Sci. Technol. Lett. 2019, 6, 638−649 pubs.acs.org/journal/estlcu

Organophosphate Ester Flame Retardants: Are They a Regrettable

Substitution for Polybrominated Diphenyl Ethers?
Arlene Blum,†,‡ Mamta Behl,§ Linda S. Birnbaum,∥ Miriam L. Diamond,⊥ Allison Phillips,●
Veena Singla,# Nisha S. Sipes,§ Heather M. Stapleton,@ and Marta Venier*,∇
†
Green Science Policy Institute, Berkeley, California 94709, United States
‡
Department of Chemistry, University of California, Berkeley, Berkeley, California 94705, United States
§
National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709,
United States
See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

∥
National Cancer Institute at National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709,
Downloaded via CALEPA AIR RESOURCES BOARD on January 6, 2020 at 17:36:39 (UTC).

United States
⊥
Department of Earth Sciences, University of Toronto, Toronto, Ontario, Canada M5S 3B1
●
Risk Assessment and Natural Resource Sciences Inc., Arcadis, Raleigh, North Carolina 27607, United States
#
Program on Reproductive Health and the Environment, Department of Obstetrics, Gynecology and Reproductive Sciences,
University of California, San Francisco, San Francisco, California 94143, United States
@
Nicholas School of the Environment, Duke University, Durham, North Carolina 27708, United States
∇
O’Neill School of Public and Environmental Affairs, Indiana University, Bloomington, Indiana 47401, United States
*
S Supporting Information

ABSTRACT: As the use of polybrominated diphenyl ethers (PBDEs), and

the entire class of organohalogen flame retardants, is declining, the use of
organophosphate ester flame retardants (OPFRs) is increasing. In this
paper, we ask whether OPFRs are a better choice than PBDEs. To address
this question, we compared OPFRs with PBDEs for a wide range of
properties. Exposure to OPFRs is ubiquitous in people and in outdoor and
indoor environments, and OPFRs are now often found at higher levels
compared to PBDE peak exposure levels. Furthermore, data from toxicity
testing, epidemiological studies, and risk assessments all suggest that there
are health concerns at current exposure levels for both halogenated and
nonhalogenated OPFRs. Obtaining the scientific evidence needed for regulation of OPFRs can take many years. Given the large
number of OPFRs in use, manufacturers can move toward healthier and safer products by developing innovative ways to reduce
the risk of fire for electronics enclosures, upholstered furniture, building materials, and other consumer products without adding
flame retardant chemicals.

■ INTRODUCTION
Flame retardants are added to consumer products and building
materials to reduce the risk of fire. Their use is driven by
flammability standards, usually based on small-scale fire testing,
which may not accurately predict real life fire behavior.1,2
Beginning in the 1970s, polybrominated diphenyl ethers
(PBDEs) were added to consumer products, including
furniture, children’s products, and electronics. After extensive
research showed that PBDEs were persistent, bioaccumulative,
and toxic, in 2004 the European Commission and California
banned the use of Penta- and OctaBDE, two commercial
mixtures primarily used in North America. Also, in 2004, the
U.S. Environmental Protection Agency (US EPA) negotiated a
phase-out of new production of these two PBDE commercial
mixtures with U.S. manufacturers. Subsequently in 2009, the
US EPA negotiated the phase-out of DecaBDE production, the
PBDE with the largest production volume. Penta- and
OctaBDE were added to the Stockholm Convention in 2009,
prompting more than 150 signatories to legislate their phase-
out (see Figure 1 and Table S1 for more details about the
regulatory timeline). DecaBDE was added to the Stockholm
Convention in 2017 and similarly phased out of use in most
countries.
Unfortunately, old furniture, electronics, vehicles, and other
products containing PBDEs continue to be used and reused in
spite of the phase-outs and bans that prevent their use in newly
manufactured products. The resultant long-term exposure to
PBDEs, especially in low-income communities, is another
Received: September 17, 2019
Revised: October 7, 2019
Accepted: October 8, 2019
Published: October 22, 2019

© 2019 American Chemical Society 638 DOI: 10.1021/acs.estlett.9b00582

Environ. Sci. Technol. Lett. 2019, 6, 638−649
Environmental Science & Technology Letters
Figure 1. Timeline of major regulatory milestones for PBDEs and
OPFRs. Policy enactment dates are listed; implementation/com-
pliance dates are often later (see Table S1 for detailed information).
reason to avoid alternative flame retardants that could be
similarly harmful.
As the use of PBDEs and the class of organohalogen flame
retardants (flame retardants containing carbon and halogen
elements, most often bromine or chlorine) is declining due to
regulatory action and manufacturers’ voluntary actions, the use
of organophosphate ester flame retardants (OPFRs) is
increasing. For example, DecaBDE production in the United
States dropped from 50 million pounds (23000 tonnes) in
2012 to <25000 pounds (11 tonnes) in 2015.3 During the
same time frame, the U.S. production volume of various
OPFRs has remained constant or increased.3
OPFRs are organic esters of phosphoric acid-containing
either alkyl chains or aryl groups, and they may be halogenated
or nonhalogenated (see Figure S1). In addition to their use as
flame retardants, OPFRs are used as plasticizers in consumer
products and construction materials.4,5 OPFRs are also
oxidation products of phosphites, which are commonly used
antioxidants in plastic products.6,7 Commercial flame retardant
formulations that contain mainly OPFRs have replaced
639
Review
PentaBDE in residential furniture.8,9 OPFRs have also been
used as substitutes for Octa- and DecaBDE in electronics, with
resorcinol bis(diphenylphosphate) (RDP or PBDPP) and
triphenyl phosphate (TPHP) measured in televisions at
milligram per gram levels.10−12 Table 1 lists the OPFRs
discussed in this paper.
Extensive scientific research now suggests that the entire
class of organohalogen flame retardants may have hazardous
properties, and some authoritative bodies are now addressing
this problem with a chemical class approach (see Table S1).13
In 2017, the U.S. Consumer Product Safety Commission
(CPSC) accepted a petition to ban furniture, children’s
products, electronic enclosures, and mattresses containing
any member of the class of organohalogen flame retardants. In
May 2019, at the request of the CPSC, the National Academies
of Sciences (NAS) released a report titled “Scoping Report for
Conducting a Hazard Assessment of Organohalogen Flame
Retardants as a Class”.14 This report states that “the number of
chemicals in use today demands a new approach to risk
assessment, and the class approach is a scientifically viable
option”. The authors of the report concluded that “the best
approach is to define subclasses as broadly as is feasible for the
analysis”. Although the challenges to a class approach might
appear daunting, the alternativeindividual assessments of
hundreds of chemicalsis unrealistic. The report supports the
idea that the class approach can prevent the problem of
“regrettable substitution” of a replacement lacking adequate
toxicity information for a phased out known hazardous
substance. Regrettable substitution occurs because of the
difficulty of changing industrial processes and a lack of
toxicological information, causing manufacturers to replace a
phased-out chemical with a “drop in” substitute chemical that
has a similar structure, function, and potential for harm. The
NAS report also highlights the point that the cumulative
exposures and risks are ignored when chemicals are assessed
individually. In 2018, the European Commission (EU)
proposed to prohibit the entire class of organohalogen
chemicals in electronic display enclosures and stands,15
effective April 1, 2021. The manufacturers of televisions and
other electronics will need to find an alternative solution to
meet flammability codes, and it is likely that industry will look
to nonhalogenated OPFRs.
In this paper, we ask whether OPFRs, as a class, have a
reduced potential for harm compared to PBDEs or if they are
an example of regrettable substitution. To address this
question, we compared OPFRs and PBDEs with regard to
their environmental fate, measured levels indoors, exposure
levels among the general population, and evidence of adverse
health effects. Our comparison was performed by reviewing the
literature, although the review was not comprehensive. We
conclude by discussing current policy changes and oppor-
tunities to innovate for less hazardous materials and products
with reduced potential for harm compared to that of flame
retardants.
■
ENVIRONMENTAL BEHAVIOR
The idea that OPFRs are less harmful than PBDEs was largely
based on the presumption that OPFRs are less environmentally
persistent and hence have a lower potential for widespread
environmental distribution and exposure. However, mounting
evidence calls this presumption into question.
PBDEs have been classified as persistent organic pollutants
(POPs) under the Stockholm Convention due to their
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Environmental Science & Technology Letters Review

Table 1. List of Major OPFRs Cited in the Text Along with CAS Numbers (adapted from refs 17 and 106), Molecular Formula,
Molecular Weight (g/mol), LogKOW, Log KOA, TSCA, DSL
molecular molecular weight
OPFR full name CAS Registry No. formula (g/mol) LogKOWa LogKOAa TSCAb DSLc
TEP triethyl phosphate 78-40-0 C6H15O4P 182.16 0.9 5.5 yes (imported) yes
(450−4500 tonnes)
TNBP tri-n-butyl phosphate 126-73-8 C12H27O4P 266.32 3.8 7.7 yes (450−4500 tonnes) yes
TCEP tris(2-chloroethyl) phosphate 115-96-8 C6H12Cl3O4P 285.48 1.6 7.6 yes (imported) (11−45 yes
tonnes)
TCIPP+ tris(2-chloro-1-methylethyl) 13674-84-5 C9H18Cl3O4P yes (23000−45000 yes
phosphate tonnes)
TPP tripentyl phosphate 2528-38-3 C15H33O4P 308.40 no no
TDMPP tris(3,5-dimethylphenyl) 9006-37-5 C24H27O4P 410.44 8 13.5
phosphate
TDCIPP tris(1,3-dichloro-2-propyl) 13674-87-8 C9H15Cl6O4P 430.90 3.7 10.6 yes
phosphate
TPHP triphenyl phosphate 115-86-6 C18H15O4P 326.28 4.7 10.5 yes (450−4500 tonnes) yes
EHDPP 2-ethylhexyl diphenyl 1241-94-7 C20H27O4P 362.40 6.3 11.3 yes (imported) yes
phosphate (450−4500 tonnes)
TBOEP tris(2-butoxyethyl) phosphate 78-51-3 C18H39O7P 398.47 3.0 12.3
DOPP dioctyl phenyl phosphonate 1754-47-8 C22H39O3P 382.52
TmCP tri-m-cresyl phosphate 563-04-2 C21H21O4P 368.36 6.3 12.0
TpCP tri-p-cresyl phosphate (tri-p- 78-32-0 C21H21O4P 368.37 6.3 12.0
tolyl phosphate)
ToCP tri-o-cresyl phosphate (tri-o- 78-30-8 C21H21O4P yes yes
tolyl phosphate)
TPPP tris(2-isopropyl phenyl) 64532-95-2 C27H33O4P 452.52 9.1 14.0
phosphate
TDBPP tris(2,3-dibromopropyl) 126-72-7 C9H15Br6O4P 697.61 4.2 14.1 yes no
phosphate
TTBPP tris(4-tert-butylphenyl) 78-33-1 C30H39O4P 494.62 10.4 15.0 yes (withheld) yes
phosphate
IPP isopropylated phenyl 68937-41-7 (mix of C21H18O4P− 368.28−452.28 NR NR yes
phosphate isomers) C27H30O4P
IDDP isodecyl diphenyl phosphate 29761-21-5 C22H31O4P 390.45 7.3 12.0
a
Toxic Substances Control Act Chemical Substance Inventory (TSCA Inventory). https://www.epa.gov/tsca-inventory/how-access-tsca-inventory
(accessed May 2018). bUS EPA; CDR database, 2016. https://www.epa.gov/chemical-data-reporting (accessed May 2018).17 Withheld means that
the production volume was withheld (values in parentheses are estimated production volumes for 2015). cDSL indicates inclusion or not on the
Canadian domestic substance list.

persistence, ability to undergo long-range transport, bioaccu-
mulation potential, and toxicity to both humans and wildlife.16
PBDEs have been documented in air, water, and terrestrial and
aquatic biota at a global scale (see Tables S1−S4). They are
nonpolar compounds with generally low volatility and vapor
pressures (see Figure S2). PBDEs can degrade, albeit slowly, in
environmental matrices through photodegradation and micro-
bial debromination, which can create more bioavailable and
toxic congeners.
OPFRs are expected to be less persistent in the environment
than PBDEs.17 Data on their persistence are scant, and the
physical and chemical properties of OPFRs are difficult to
measure or estimate, which makes prediction of their
environmental behavior more uncertain than that of PBDEs.
Although their higher vapor pressures lead to the expectation
of higher air concentrations compared to those of PBDEs (see
Figure S2), they are also expected to have shorter half-lives in
air and thus reduced atmospheric long-range transport
potential.18 Compared with PBDEs, OPFRs and especially
chlorinated OPFRs are more soluble and can persist in water,
which gives them the ability to undergo long-range transport
via waterborne routes.19,20 Thus, rather than being POPs, as is
the case with PBDEs, chlorinated OPFRs appear to be
persistent mobile organic compounds (PMOCs), which is
equally concerning.18,21
640
Although OPFRs were not expected to accumulate in the
environment on the basis of their physical and chemical
properties, multiple measurements show that the concen-
trations of many OPFRs have reached values that are orders of
magnitude higher in air and water in numerous environments
ranging from urban areas to remote Arctic and Antarctic
locations, compared to those of PBDEs when they were at
peak use (see Figure 2 and Tables S2 and S3). OPFRs are
readily scavenged from air by precipitation and then trans-
ported to surface waters because of their higher solubility and
weak tendency for sequestration in soil and other carbon-rich
matrices compared to PBDEs. This efficient scavenging of
OPFRs by rain, coupled with high emission rates, results in
some urban surface water concentrations being similar to those
from treated final wastewater treatment plant effluent (see
Table S1).18 In Great Lakes water, for example, concentrations
of OPFRs were in the range of 10−100 ng/L while ∑BDE
(defined as the sum of total measured BDE congeners, which
can vary from study to study) values were significantly lower,
with a range of 0.05−0.25 ng/L (see Table S2 for specific
data). Despite their high aqueous solubility, OPFRs also
accumulate in sediment by virtue of high emissions and their
ability to be transported to aquatic systems. For example,
∑14OPFR values were ∼0.5−50 ng/g of dry weight (g dw) in
the Great Lakes sampled in 2010−2013,22 comparable to
concentrations of 0.5−6.7 and <4 to >240 ng/g dw for
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Environmental Science & Technology Letters
Figure 2. Bar chart representing selected median concentrations of
total OPFRs and total PBDEs in (A) outdoor air (picograms per
cubic meter), (B) water (nanograms per liter), and (C) indoor dust
(nanograms per gram). Each bar represents data from a different
study (see Tables S2−S5 for details about the studies included and for
a more comprehensive list of locations).
∑9BDE and BDE-209, respectively, measured at their peak
usage.23
Finally, numerous measurements confirm not only the
presence but also the relative abundance of OPFRs in remote
locations, which cannot be explained by local releases. For
example, total OPFRs have reached a median concentration of
237 pg/m3 in Canadian Arctic air19,24−26 while ∑BDE air
concentrations, at the time of peak use, were orders of
magnitude lower. OPFRs have also accumulated in Arctic
sediments at concentrations 10−100 times greater than those
of PBDEs, which, as noted above, is unexpected because
OPFRs are less likely to deposit due to of their high water
solubility.27
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Overall, environmental measurements clearly show that
OPFRs demonstrate long-range transport and accumulation in
the environment that rival those of PBDEs, despite expect-
ations to the contrary. In addition, whereas concerns with
PBDEs were due to them being POPs, OPFRs fit into a
different class of concern, that of PMOCs.
■ INDOOR BEHAVIOR AND HUMAN EXPOSURE
Concentrations of PBDEs and OPFRs in indoor air, in house
dust, and on hand wipes provide critical information about the
exposure potential because inhalation, hand-to-mouth contact,
and dermal absorption are all important routes of human
exposure to flame retardants. Below, we provide evidence of
relatively high levels of exposure to OPFRs compared to
PBDEs, originating from elevated levels in indoor air, house
dust, and food.
The widespread use of PBDEs since the late 1970s resulted
in near-ubiquitous human exposure, with ∑BDE in breast milk
and serum levels (both lipid-adjusted) peaking in the early to
mid-2000s.28,29 However, the increasing use of OPFRs
following the phase-out of PBDEs has also led to greater
human exposure, and urinary OPFR biomarker levels have
been steadily climbing since the early 2000s.30 Interestingly,
OPFRs have been found in dust at substantial levels for at least
two decades. For instance, ∑OPFR levels are similar to
∑PBDE levels in house dust standard reference material
(SRM 2585; ∼5000 ng/g), which was prepared from hundreds
of vacuum cleaner bags collected in several U.S. states in the
mid-1990s.9,31−33 This comparison suggests that exposure to
OPFRs was similar to exposure to PBDEs in the 1990s but
now appears to have increased since the phase-out of PBDEs.
The growing prevalence of OPFRs and decreasing amounts
of decaBDE in indoor house dust correlate with their changing
production levels in the United States. Common OPFRs such
as tricresyl phosphate (TCP), tri-n-butyl phosphate (TNBP),
and 2-ethylhexyl diphenyl phosphate (EDHPP) each have had
production volumes of ≤10 million pounds (4500 tonnes)
yearly since 2012,34 compared to 10−50 million pounds
(4500−23000 tonnes) of DecaBDE in 2012, dropping to
<25000 pounds (11 tonnes) in 2015.35
Although the percentage by weight application of PBDEs
and OPFRs to polyurethane foam is roughly identical (∼3−
7%), OPFRs are also heavily used in electronics. As a result,
OPFRs have been detected at much higher levels in indoor air
(Table S4).8,36 While this is partly accounted for by OPFRs
being used as both flame retardants and plasticizers, it is also
likely reflective of the higher vapor pressure of OPFRs
compared to that of PBDEs, leading to increased off-gassing
of OPFRs from treated products into indoor air (Figure S2).
Studies from North America and Europe conducted in the
early to mid-2000s, when PBDE use and exposure were at their
height, reported average ∑BDE indoor air concentrations in
the range of 100−600 pg/m3.37−39 By contrast, recent studies
report levels of OPFRs in the nanogram per cubic meter range,
at least an order of magnitude higher than for PBDEs (Table
S4). Much like those of PBDEs, OPFR air concentrations have
been found to fluctuate seasonally. They also vary depending
on the microenvironment, with cars and offices often having
higher concentrations compared to living spaces, reflecting
high usage and emissions.39−41
Because OPFRs have vapor pressures that are higher than
those of PBDEs, it might be assumed that OPFR dust
concentrations would be lower than PBDE dust concen-
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Environmental Science & Technology Letters
trations. However, despite regional differences in flame
retardant dust concentrations, recently reported ∑OPFR
geometric mean and median dust levels are either equivalent
to (if considering the measured sum of PBDE congeners in
commercial mixtures) or higher than ∑PBDE geometric mean
and median dust levels from the early to mid-2000s (Figure 2).
Reported ∑OPFR geometric mean and median dust
concentrations range from low micrograms per gram to low
milligrams per gram (Table S5).3,16,33,41−46 Several recent
studies have estimated the daily exposure to OPFRs and
PBDEs (e.g., nanograms per kilogram per day) via levels
measured in indoor dust, and the results demonstrate that
exposure to OPFRs is higher.47,48
Although data are limited for PBDEs, OPFRs have been
found on hand wipes at levels higher than those of PBDEs,
suggesting that the magnitude of exposure via hand-to-mouth
and dermal transfer pathways is potentially greater for OPFRs
than for PBDEs (Table S3). As for PBDEs, OPFR exposure
may also result from dietary or diet-associated intake.49,50 The
use of EHDPP, TPHP, and TNBP in food packaging material
is approved by the U.S. Food and Drug Administration, and
their migration from plasticized film wrappers into food has
been documented.51 The presence of OPFRs has also been
reported in butter, bread bags, fish, and drinking water.52−54
Likewise, a recent study detected tris(2-chloroisopropyl)
phosphate (TCIPP) and TNBP in >70% of 87 food samples
and five tap water samples collected in Australia.55 On the
basis of the levels found in food, the estimated daily dietary
intake was 4.1 ng/kg of body weight (kg bw) for tris(2-
chloroethyl) phosphate (TCEP), 25 ng/kg bw for TCIPP, and
6.7 ng/kg bw for TNBP. In Sweden, Poma et al. detected
EHDPP in composite food samples from multiple food
categories and estimated a daily intake of ∑OPFRs [TCEP,
TPHP, EHDPP, tris(1,3-dichloro-2-propyl) phosphate or
TDCIPP, and TCIPP] in the range of 6−49 ng/kg bw.56
The total dietary intake of ∑7OPFRs in fish from the
Philippines was 22 ng (kg bw)−1 day−1.57 In a U.S. market
basket study from 1988, the dietary intake for TPHP was
calculated as 0.3−4.4 ng (kg bw)−1 day−1.58 For comparison,
the estimate of the daily intake of ∑13BDE congeners for U.S.
adults was 0.9 ng/kg bw and that for ∑18BDE congeners for
Canadian adults was 0.7 ng/kg bw during the 2000s.59,60
Because of differences in metabolism between the two
chemical classes, the comparison of PBDE and OPFR internal
dose levels is challenging. PBDEs are bioaccumulative and have
long half-lives (weeks to years) in the human body, while
OPFRs are rapidly metabolized with relatively short half-lives
(hours to days).61,62 PBDEs have been measured in human
serum as biomarkers of exposure, while diester metabolites
have been measured in human urine as indicators of OPFR
exposure. Serum PBDE levels have been documented in the
picomolar to low nanomolar range (on a wet weight basis),
with BDE-47 generally detected most frequently and at the
highest concentration of all BDE congeners (although it should
be noted that BDE-209 and higher-molecular weight
congeners were often not included in past serum anal-
yses).63−65 Urinary OPFR metabolite levels have been
reported in the low to mid nanomolar range, with diphenyl
phosphate (DPHP, metabolite of multiple OPFRs), 1-hydroxy-
2-propyl bis(1-chloro-2-propyl) phosphate (BCIPHIP, metab-
olite of TCIPP), and bis(1,3-dichloro-2-propyl) phosphate
(BDCIPP, metabolite of TDCIPP) frequently detected at
higher levels compared to other urinary metabolites,66,67
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although regional differences exist.68 While it is difficult to
compare serum PBDE levels to urinary OPFR metabolite
levels, detection frequencies among biospecimens are similar.
BDE-47 was detected in 97% of serum samples (n = 2062)
tested in the 2003−2004 National Health and Nutrition
Examination Survey (NHANES), and recent urine analyses
have detected BDCIPP, BCIPHIPP, and DPHP in >95% of
tested samples.40,55,63,68−71 From these data, it is evident that
OPFR exposure is pervasive in the human population and that
vulnerable subpopulations like infants and children may be
more highly exposed.66,71−74
Continuing OPFR biomonitoring efforts will help define
trends regarding human exposure to OPFRs. To summarize,
OPFRs and their metabolites can be detected at relatively high
levels and frequencies in indoor air, dust, food items, and
human biospecimens. Given that OPFR exposures may still be
increasing, it is clear that the current potential for indoor
exposure to OPFRs is substantially greater than it was for
PBDEs in the early to mid-2000s, when PBDE use was at its
height.
■ TOXICITY AND HEALTH EFFECTS
Another important aspect of this comparison between PBDEs
and OPFRs is understanding how the toxicity profiles of these
classes of compounds compare with each other. As a class, 97
OPFR flame retardants were shown to have potential toxicity
based on the Quick Chemical Assessment Tool (QCAT).75
The US EPA categorized some of the alternative flame
retardants as high-priority compounds that critically need more
toxicological studies or for which regulatory measures could be
envisaged.75
Although the use of OPFRs is on the rise, their toxicological
hazard has not yet been well-characterized, and indeed, a more
complete understanding of the toxicity of PBDEs has emerged
only after their regulation. This section summarizes recent
toxicity data and describes a linkage between toxicity data
noted in in vitro and in vivo studies with human exposure,
ultimately identifying data gaps that need to be addressed. In
addition to OPFRs and PBDEs, we also compared the toxicity
profile of tetrabromobisphenol A (TBBPA) because it is the
most highly produced brominated flame retardant in the
world.76 Its production has remained fairly stable over the
years, likely a reflection of its primary use as a reactive flame
retardant (as opposed to PBDE additive use). The EU noted
“no health effects of concern” for TBBPA for adults or infants
based on adequate margins of safety.77 However, evidence in
the literature suggests effects on reproductive and nervous
system development, including brain and thyroid function.76,78
OPFRs, PBDEs, and TBBPA appear to have comparable
developmental and neurodevelopmental toxicity potential in a
variety of in vitro assays that represent processes critical to
neurodevelopment such as neuronal proliferation, neurite
outgrowth, synaptogenesis, and network formation.75,79 They
have also been shown to affect reproduction, development, and
motor activity in a multitude of alternative animal models such
as zebrafish, Caenorhabditis elegans, and Planaria.79−87
Furthermore, similar to that of PBDEs, exposure to OPFR
and TBBPA appears to elicit behavioral alterations that persist
into adulthood, long after cessation of developmental
exposure.88,89
To relate toxicity data from in vitro and alternative animal
models, as well as traditional in vivo animal studies to human
exposure, we used a high-throughput toxicokinetic model
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Environmental Science & Technology Letters
(HTTK)90,91 to convert the data, thereby allowing compar-
isons across the various exposure scenarios (Figure 3). The
Figure 3. Flame retardant plasma concentrations measured or
estimated from ingestion using data from house dust, breast milk,
and/or handwipe samples (colored bars and circles) are compared to
the most potent in vitro concentration per chemical (black dots) and
in vivo point of departure (POD; triangles). The filled triangles
represent rat plasma concentrations based on in vivo POD values
(when available), and the empty triangles represent the minimum risk
levels (MRLs). The colored bars represent the range of concen-
trations, and the circles represent the mean, median, or maximum
median (see the Supporting Information for further details about
these calculations).
main purpose of this analysis is twofold. The first is to compare
in vitro and in vivo PODs (points of departure) to inform
readers about how novel rapid testing strategies relate to
traditional rodent studies in their toxicological outcomes, so
that they may be used as complementary approaches. The
second is to compare the minimum risk levels (MRLs, i.e.,
PODs values including safety factors, which are equivalent to
RfDs or reference doses) to measured human exposures.
First, plasma concentrations were simulated in the model
using data from house dust, breast milk, or hand wipes samples
(Figure 3 and Table S7). Important input parameters for the
model were the estimated oral exposures based on child
feeding (for breast milk), ingestion due to hand-to-mouth
actions (for dust), and chemical-specific parameters, such as
the fraction of the chemical bound to plasma, intrinsic
metabolic clearance, pKa, LogP (lipophilicity), and molecular
weight. A detailed description of these values and calculations
can be found in Tables S7−S9. The internal exposure values
calculated with the HTTK model were then compared to POD
values from developmentally or neurodevelopmentally asso-
ciated in vitro assays and/or in vivo alternative animal (i.e.,
zebrafish) assays to understand how in vitro PODs relate to
human exposure. A POD is defined as a dose−response point
that marks the starting point for low-dose extrapolation; that is,
the POD is the exposure level at which an effect is seen.
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The in vitro POD to human plasma concentration
comparison found that the in vitro POD for TPHP, BDE-47,
TDCIPP, and TBBPA lies within the range of estimated
plasma concentrations from human exposure, as indicated by
an overlap of the colored bars with the black filled circles
(Figure 3). For other compounds such as trimethyl phenyl
phosphate (TMPP), isodecyl diphenyl phosphate (IDDP),
EHDPP, isopropylated phenyl phosphates (IPP), tert-butylated
phenyl diphenyl phosphate (BPDP), and TCEP, the biological
activity in vitro occurred at concentrations higher than those
estimated from human exposure data. However, it should be
noted that, even though the in vitro POD appears to be higher
for these latter compounds, there are limited exposure data for
these OPFRs. This is important because, while we do not know
the potential health effects of these OPFRs, they have patterns
of in vitro activity at comparable concentrations similar to that
of the phased-out flame retardant (e.g., BDE-47) and TBBPA.
Where available (TMPP, TDCIPP, and TCEP), we then
compared the HTTK-modeled plasma concentrations to the
POD values obtained from in vivo rat studies that are currently
used to set the minimum risk levels (MRLs, empty triangles).
According to ATSDR, an MRL is an estimate of the daily
human exposure to a hazardous substance that is likely to be
without appreciable risk of adverse health effects over a
specified duration of exposure.92 This comparison showed that
for some compounds such as TDCIPP, the in vivo rodent POD
lies within the range of human exposure, while for others such
as TCEP, toxicity in animal studies is noted at a higher
concentration compared with human exposure. Differences in
sensitivities between the findings in rodents to that in human-
derived cell-based models or toxicokinetic, toxicodynamic and/
or exposure characteristics should be taken into account. For
some of the less well-studied OPFRs such as IPP, BPDP,
EHDPP, and IDDP, even though it may appear that there is a
wide margin of exposure between current serum concen-
trations in humans and predicted toxicological effects, it should
be noted that there are relatively sparse exposure data available.
Furthermore, due to recent CPSC and EU regulations (Table
S1), the use of the nonhalogenated OPFRs is projected to be
on the rise.
While this general strategy provides insights into those
OPFRs for which concern could be greatest, it has several
caveats. For example, it does not consider sensitive populations
or even genetic variability within a population, which could
significantly change the interpretation.93 This approach is also
limited by several model constraints; e.g., the in vivo POD used
to set MRLs for some compounds such as BDE-47 and TBBPA
could not be plotted because in silico model parameter
estimates were unavailable. Additionally, as only developmen-
tally or neurodevelopmentally associated in vitro assays were
used to evaluate the in vitro potency of these compounds, other
assays surveying a broader biological space could indicate
additional biological disruption.
Nonetheless, these findings indicate that the in vitro activity
for some of the OPFRs (i.e., TDCIPP and TPHP) is
comparable to that of the phased-out BDEs (e.g., BDE-47)
and lies within the range of human exposure (TPHP).
Importantly, animal data are sparse for many of these
OPFRs, but for compounds where data do exist, the in vitro
activity appears to be at levels comparable to the in vivo PODs
for some compounds (e.g., TDCIPP). Hence, it is imperative
to consider novel strategies for integrating data to provide
rapid and timely relevant information for human health
DOI: 10.1021/acs.estlett.9b00582
Environ. Sci. Technol. Lett. 2019, 6, 638−649
 Table 2. Overview of Data for Specific OPFRs, Including CAS Registry Numbers, Major Uses, U.S. Production Volumes for 2015, a Summary of Biomonitoring Data, Major
Regulatory Actions, and Risk Assessment/Epidemiological Dataa
chemical/CAS Registry No. uses U.S. production volume (2015) biomonitoring regulatory actions associations in epidemiological studies and risk assessment
TPHP/115-86-6 industrial; commercial; consumer: foam 1−10 million lb increasing exposure;30 ubiquitous expo- CA SCP,b reproductive adverse reproductive outcomes;107 prenatal exposures
seating and bedding, plastic and rubber sure in NHANES: 92%, higher ex- and neurological tox- associated with decreased IQ and working memory in
products, and nail polish posures in women and higher ex- icity; WA CSPAc children;108 in combination with other OPFRs, increase
posures in 6−11-year-old children71 in behavioral problems96
FDA Indirect Additives used in Food
Contact Substances
TDCIPP/13674-87-8 industrial; commercial; consumer: foam 10−50 million lb increasing exposure;30 ubiquitous expo- CA Prop 65, carcino- in combination with other OPFRs, prenatal exposures
seating and bedding sure in NHANES: ≥92% exposure in gen; CA SCP, carcin- associated with decreased IQ and working memory in
women71 ogen; WA CSPA children;108 cancer risks of concern for infants;97 cancer
risks of concern for children99
IPP/68937-41-7 (mix of industrial; commercial; consumer: foam 1−10 million lb CA SCP, reproductive
isomers) seating and bedding, and plastic and and neurological tox-
rubber products icity; WA CSPA
EHDPP/1241-94-7 industrial; commercial; consumer: foam 1−10 million lb WA CSPA; MDHd
seating and bedding, and plastic and chemical of high con-
rubber products cern
FDA Indirect Additives used in Food
Environmental Science & Technology Letters

Contact Substances
IDDP/29761-21-5 industrial; commercial; consumer: foam withheld CA SCP, reproductive
seating and bedding, and plastic and and neurological tox-
rubber products icity; MDH chemical
of high concern
TMPP (TCP)/1330-78-5 industrial; commercial; consumer: plastic 1−10 million lb CA SCP, reproductive

644
and rubber products, lubricants and and neurological tox-
greases, and other unspecified uses icity; WA CSPA
TCEP/115-96-8 industrial, unspecified 25000−100000 lb ubiquitous exposure in NHANES: CA Prop 65, carcino- in combination with other OPFRs, increase in behavior
≥89% exposures in 6−11-year-old gen; EU toxic to re- problems;96 risks of concern for cancer and reproductive
children71 production; CA SCP effects for infants97
carcinogen; WA
CSPA
RDP (PBDPP)/57583-54-7 industrial; commercial; consumer: plastic 1−10 million lb CA SCP
and rubber products and other un-
specified uses
TCIPP/13674-84-5 industrial; commercial; consumer: foam 50−100 million lb widespread exposure in NHANES: CA SCP, carcinogen; in combination with other OPFRs, increase in behavior
insulation, building/construction ma- ≥61% exposures in 6−11-year-old WA CSPA problems;96 paternal levels associated with decreased
terials, foam seating and bedding children and higher exposures in fertilization;95 risks of concern for cancer and reproduc-
products, and electronic products women71 tive effects for infants97
TNBP/126-73-8 industrial; commercial; consumer: adhe- 1−10 million lb ubiquitous exposure in NHANES: EU CMRe; MDH
sives/sealants and inks/toners ≥81% exposures in women71 chemical of high con-
cern; WA CSPA
FDA Indirect Additives used in Food
Contact Substances
a
Data from US EPA’s Chemical Data Reporting, NIH PubChem, and the Chemical Hazard Data Commons. bCA SCP indicates CA Safer Consumer Products Program Candidate Chemical List. cWA
CSPA indicates WA Children’s Safe Products Act Chemicals of High Concern for Children. dMDH indicates Toxic Free Kids Act Chemicals of High Concern or Priority Chemicals. eEU CMR indicates
EU Carcinogen, Mutagen or Reproductive Toxicant.
Review

Environ. Sci. Technol. Lett. 2019, 6, 638−649

DOI: 10.1021/acs.estlett.9b00582
Environmental Science & Technology Letters
protection, especially for sensitive populations, to complement
time and cost intensive animal studies.
■
EPIDEMIOLOGICAL EVIDENCE
Epidemiological evidence points to concern about PBDEs and,
more recently, OPFRs. PBDEs are well-established neuro-
developmental toxicants (see Table 2). In a meta-analysis, Lam
and co-workers concluded that there was sufficient evidence
supporting an association between developmental PBDE
exposure and reduced IQ.94 A similar conclusion was also
reached by the extensive review of the literature conducted by
the National Academies of Sciences, Engineering and
Medicine, although their work was restricted to BDE-47.93
Evidence from epidemiological studies is now indicating that
OPFRs could also be causing adverse effects at ambient
exposures. For example, Carignan et al. reported that urinary
concentrations of DPHP, a metabolite of several OPFRs, as
well as a stand-alone flame retardant, were significantly
associated with adverse reproductive outcomes (e.g., failed
fertilization and implantation) in 211 U.S. women undergoing
in vitro fertilization.30 Carignan et al. also found that paternal
urinary concentrations of BDCIPP were associated with
reduced rates of fertilization.95 Castorina et al. reported
evidence of the developmental toxicity of OPFRs, finding that
∑OPFR metabolites measured in pregnant women, and
particularly DPHP, were significantly associated with decreased
IQ and working memory of their 7-year-old children in the
CHAMACOS birth cohort in California.95 Lipscomb et al.
found a significant dose-dependent relationship between the
exposure of 92 U.S. children (3−5 years of age) to ∑OPFRs
(TCIPP, TCEP, and TPHP) measured using silicone
wristbands and teacher ratings of less responsible behavior
and more externalizing behavior problems.96
Limited risk assessments of OPFRs have been conducted in
the past 10 years. The exposure of infants to TCEP, TDCIPP,
and TCIPP present in children’s products and residential
upholstered furniture was associated with an increased risk of
cancer97 and reproductive effects for TCEP and TCIPP.72,98
This finding is further supported by a study investigating
TDCIPP exposure in U.S. infants.72 Bradman et al. identified
cancer risks exceeding California health risk-based guidelines
for TDCIPP in early childhood education environments.99
Canada issued a draft risk assessment proposing that TCIPP be
considered toxic on the basis of human exposure to foam-
containing upholstered furniture, but TDCIPP was not
considered to pose a threat to human health at current
exposures.100 Authoritative government bodies have evaluated
current data and listed several OPFRs as chemicals of concern
or known to have specific health hazards (see Table 1 and
Table S4).
Overall, data from traditional toxicity testing, new approach
methods, epidemiological studies, and risk assessments all
indicate health concerns for both halogenated and non-
halogenated OPFRs.
■
POLICY APPROACHES TO OPFRS
As concerns about OPFR exposure and toxicity have emerged,
regulators in the United States, EU, and other jurisdictions
have responded with policies that gather data, inform
consumers, limit flame retardants of concern, and/or change
flammability standards to reduce the need for flame retardants.
Such responses have been aimed especially at vulnerable
645
Review
populations (e.g., children) and uses in common consumer
products that result in widespread exposures (see Figure 1,
Table 2, and Table S1). In the United States, the federal law
covering most industrial, commercial, and consumer product
chemicals, the 1976 Toxic Substances Control Act (TSCA),
was acknowledged to be ineffective.101 Faced with a lack of
regulation for decades, individual U.S. states have stepped in to
issue their own regulations. As shown in Figure 1, initial
policies for individual OPFR chemicals focused more on data
gathering (for example, the Washington Children’s Safe
Product Act requiring reporting of chemicals use to the
state) or labeling (for example, California Proposition 65
requiring warnings).
The past decade has seen a shift toward changing
flammability standards so that flame retardants are not needed
in consumer products when they do not provide a significant
fire safety benefit. In 2016, the TSCA was updated; although
there were potential improvements in the law, it remains to be
seen if public health protections from toxic chemicals will be
improved.102,103 Canada, through its Chemical Management
Plan, has regulated PBDEs and TCEP.99 OPFRs and other
flame retardants in Canada are being assessed with a
recommendation for declaring TCIPP potentially harmful to
human health,100 but these assessments remain constrained to
a chemical-by-chemical basis rather than taking a more
comprehensive approach to managing OPFRs and other
flame retardants as a class.
The trends in Figure 1 and Table S1 indicate that policy
makers are increasingly concerned with the use of hazardous
chemicals in consumer products, especially those that result in
exposures to children. An emerging trend is to require
informed substitution (e.g., 2015 Minnesota House Bill
1100-MN 2015) or to avoid regrettable substitution (e.g.,
2016 Washington, DC, Carcinogenic Flame Retardant
Prohibition Amendment Act104), by creating health criteria
for replacement chemicals.
■
LOOKING FORWARD
Here we have shown that, as with PBDEs in the past, OPFRs
are now being used in large volumes, are sufficiently persistent
to be detected globally, present health hazards, and may cause
harm to humans, especially children, at current exposure levels.
Given the large number of OPFRs on the market, obtaining
the level of evidence a government often requires to regulate
each compound would prove to be expensive and lengthy.
However, manufacturers and purchasers can make informed
choices now to eliminate use of potentially harmful chemicals.
As PBDEs and other organohalogen flame retardants are
phased out, instead of replacing them with OPFRs with a
similar potential for harm, we suggest pursuing creative “out-
of-the-box” strategies such as improved product design to
minimize flammability and using alternative materials that are
inherently flame resistant. For example, one manufacturer
reduced flame retardants in TV cases by removing the power
supply from inside the TV. An external power source was used
(like in a laptop power cord), thus eliminating the need for
flame retardants in the plastic case around the TV.105
Furthermore, only using flame retardants when they provide
a proven benefit can reduce health risks without impacting fire
safety.
This paper has shown that the replacement of PBDEs with
OPFRs is likely a regrettable substitution. The time has come
for manufacturers, with the help of the scientific community, to
DOI: 10.1021/acs.estlett.9b00582
Environ. Sci. Technol. Lett. 2019, 6, 638−649
Environmental Science & Technology Letters
stop moving from the use of one family of harmful chemicals
to the next and to instead find innovative ways to reduce both
fire hazard and the use of hazardous chemicals.
■
ASSOCIATED CONTENT
*
S Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.es-
tlett.9b00582.
Plasma bioequivalents using high-throughput toxicoki-
netic (HTTK) modeling, Tables S1−S9, Figures S1 and
S2, and additional references (PDF)
■
AUTHOR INFORMATION
Corresponding Author
*E-mail: mvenier@indiana.edu.
ORCID
Miriam L. Diamond: 0000-0001-6296-6431
Nisha S. Sipes: 0000-0003-4203-6426
Heather M. Stapleton: 0000-0002-9995-6517
Marta Venier: 0000-0002-2089-8992
Author Contributions
All of the authors contributed equally to this work.
Notes
The authors declare no competing financial interest.
■ ACKNOWLEDGMENTS
The authors thank Anna Soehl for coordinating this effort,
Shaorui Wang for help with compiling data and references, and
Swati Rayasam for help with Figure S1.
■
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649 DOI: 10.1021/acs.estlett.9b00582

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