Science of the Total Environment 690 (2019) 853–866

Contents lists available at ScienceDirect

Science of the Total Environment

journal homepage: www.elsevier.com/locate/scitotenv

Review

1,4-Dioxane as an emerging water contaminant: State of the science and

evaluation of research needs
Krystal J. Godri Pollitt a,⁎, Jae-Hong Kim b, Jordan Peccia b, Menachem Elimelech b, Yawei Zhang a,c,
Georgia Charkoftaki a, Brenna Hodges b, Ines Zucker b, Huang Huang a, Nicole C. Deziel a, Kara Murphy d,
Momoko Ishii a, Caroline H. Johnson a, Andrea Boissevain e, Elaine O'Keefe f, Paul T. Anastas a,g, David Orlicky h,
David C. Thompson i, Vasilis Vasiliou a,⁎
a
Department of Environmental Health Sciences, School of Public Health, Yale University, New Haven, CT 06510, United States
b
Department of Chemical & Environmental Engineering, School of Engineering & Applied Science, Yale University, New Haven, CT 06520, United States
c
Department of Surgery, School of Medicine, Yale University, New Haven, CT 06520, United States
d
Northeast States for Coordinated Air Use Management (NESCAUM), Boston, MA 02111, United States
e
Stratford Health Department, Stratford, CT 06615, United States
f
Office of Public Health Practice, School of Public Health, Yale University, New Haven, CT 06510, United States
g
Center for Green Chemistry and Green Engineering, Department of Chemistry, Yale School of Forestry & Environmental Studies, New Haven, CT 06511, United States
h
Department of Pathology, University of Colorado School of Medicine, Aurora, CO 80045, United States
i
Department of Clinical Pharmacy, University of Colorado School of Pharmacy, Aurora, CO 80045, United States

H I G H L I G H T S G R A P H I C A L A B S T R A C T

• 1,4-Dioxane is an emerging environ-

mental contaminant and a probable car-
cinogen.
• The de minimis cancer risk level is High levels

exceeded at 7% of U.S. drinking water

sites.
• The physicochemical properties chal-
lenge detection and remediation of 1,4-
dioxane.
• This review presents data needed to set
an enforceable drinking water standard.

a r t i c l e i n f o a b s t r a c t

Article history: 1,4-Dioxane has historically been used to stabilize chlorinated solvents and more recently has been found as a
Received 21 May 2019 contaminant of numerous consumer and food products. Once discharged into the environment, its physical
Received in revised form 26 June 2019 and chemical characteristics facilitate migration in groundwater, resulting in widespread contamination of drink-
Accepted 26 June 2019
ing water supplies. Over one-fifth of U.S. public drinking water supplies contain detectable levels of 1,4-dioxane.
Available online 28 June 2019
Remediation efforts using common adsorption and membrane filtration techniques have been ineffective,

Abbreviations: 1,1-DCA, 1,1-dichloroethane; 1,1,1-TCA, 1,1,1-trichloroethane; ATSDR, Agency for Toxic Substances and Disease Registry; EPA, Environmental Protection Agency; GC,
gas chromatography; HEAA, β-hydroxyethoxyacetic acid; MS, mass spectrometry; TCE, trichloroethylene; UCMR, unregulated contaminant monitoring rule; U.S., United States.
⁎ Corresponding authors.
E-mail addresses: krystal.pollitt@yale.edu (K.J. Godri Pollitt), vasilis.vasiliou@yale.edu (V. Vasiliou).

https://doi.org/10.1016/j.scitotenv.2019.06.443
0048-9697/© 2019 Elsevier B.V. All rights reserved.
854 K.J. Godri Pollitt et al. / Science of the Total Environment 690 (2019) 853–866

highlighting the need for alternative removal approaches. While the data evaluating human exposure and health
Editor: Damia Barcelo effects are limited, animal studies have shown chronic exposure to cause carcinogenic responses in the liver
across multiple species and routes of exposure. Based on this experimental evidence, the U.S. Environmental Pro-
Keywords: tection Agency has listed 1,4-dioxane as a high priority chemical and classified it as a probable human carcinogen.
1,4-dioxane
Despite these health concerns, there are no federal or state maximum contaminant levels for 1,4-dioxane. Effec-
Drinking water
Health
tive public health policy for this emerging contaminant requires additional information about human health ef-
Exposure fects, chemical interactions, environmental fate, analytical detection, and treatment technologies. This review
Sensors highlights the current state of knowledge, key uncertainties, and data needs for future research on 1,4-dioxane.
Remediation © 2019 Elsevier B.V. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 854
2. Environmental behavior and persistence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 855
2.1. Environmental occurrence. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 855
2.2. Co-contaminants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 855
2.3. Environmental fate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 855
3. Routes of exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 856
3.1. Drinking water . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 856
3.2. Food . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 856
3.3. Consumer products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 856
3.4. Bathing and showering . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 856
4. Toxicology and carcinogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 857
4.1. Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 857
4.2. Metabolism and elimination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 857
4.3. Carcinogenic effects. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 858
4.4. Mechanisms of carcinogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 858
4.5. Cancer potency factor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 859
5. Exposure assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 859
5.1. Environmental samples . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 859
5.2. Biological samples . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 860
6. Health effects in humans. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 861
7. Remediation methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 861
7.1. Abiotic advanced oxidation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 861
7.2. Bioremediation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 862
8. Implications for further studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 863
9. Suggestions for community engagement and preparedness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 863
Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 864
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 864

1. Introduction and Disease Registry (ATSDR) listed 1,4-dioxane as one of the

1,4-Dioxane (C4H8O2; CAS No. 123–91-1) is a synthetic chemical
that was historically used as a stabilizer in chlorinated solvents in in-
dustrial processes, such as 1,1,1-trichloroethane (1,1,1-TCA). More
recently, it has been used as a solvent in the production of a variety
of organic chemicals found in paints, lacquers, dyes, antifreeze, de-
odorants, shampoos, and cosmetics (ATSDR 2012; EPA, 2006). 1,4-
Dioxane has also been used as a food additive and in the formulation
of pesticides and food packaging adhesives (ATSDR 2012; DHHS
2014). In the United States (U.S.), environmental releases of 1,4-di-
oxane are regulated as hazardous waste only when this chemical is
used as an industrial solvent. When used in other applications (i.e.,
additive, pesticide, adhesive, etc.), its disposal is not regulated
(EPA, 2011; EPA, 2017b). Such limited regulation leads to consider-
able environmental release, e.g., approximately 617,000 pounds in
2017 from solvent use alone (EPA, 2017a; EPA, 2018b). The high mo-
bility and persistence of 1,4-dioxane enables it to distribute widely
in the environment.
Significant improvements have been made in recent decades in
controlling microbial and chemical threats to water supplies. Fed-
eral agencies in the U.S. have recognized the threats to drinking
water posed by emerging contaminants, such as 1,4-dioxane, at
Superfund sites. For example, the Agency for Toxic Substances
Superfund priority substances (214th among 275 compounds)
based upon its potential toxic effects and propensity to contami-
nate drinking water (ATSDR 2017). The U.S. Environmental Protec-
tion Agency's (EPA) unregulated contaminant monitoring rule
(UCMR) also prioritized 1,4-dioxane for inclusion in the
2013–2015 test round. In UCMR, “contaminant of emerging con-
cern” is designated to compounds of which (i) the risk to human
health and the environment is not fully understood, and (ii) drink-
ing water standards have not been developed. These emerging con-
taminants represent key research needs especially when there is
evidence of widespread exposure and potentially serious adverse
effects. While substantial effort has been placed by the U.S. EPA
on certain emerging drinking water contaminants (e.g.,
perfluorinated alkyl substances), relatively little regulatory atten-
tion has been given to 1,4-dioxane. As a result, drinking water guid-
ance values established in recent years by jurisdictions range
widely from 0.35 to 77 μg/L due to uncertainties in the potability
of water affected by this contaminant. This situation is further com-
plicated by the difficulty of removing 1,4-dioxane from drinking
water by conventional treatment technologies.
Given these considerations, this review highlights the current state
of knowledge, key uncertainties and data needs for future research on
1,4-dioxane.
 K.J. Godri Pollitt et al. / Science of the Total Environment 690 (2019) 853–866
2. Environmental behavior and persistence
The chemical and physical properties that facilitate the mobility of
this contaminant through groundwater to drinking water supplies will
be discussed.
2.1. Environmental occurrence
The occurrence of 1,4-dioxane in the environment has been associ-
ated with contaminated groundwater in industrial sites (Adamson
et al. 2016; Lippincott et al. 2015; Postigo and Barcelo 2015). In the
U.S., 1,4-Dioxane is listed as number 214 on the ATSDR's Substance Pri-
ority List and was found in According to U.S. EPA's UCMR-3 testing, 1,4-
dioxane was found to be the second most prevalent prior contaminant
in public water supplies, detected at 21% of the 4864 tested sites across
the U.S. (Fig. 1A) (Adamson et al. 2015; EPA, 2015). Exceedances of the
federal health risk guideline level for 1,4-dioxane (based upon the can-
cer de minimis 1 in a million-reference value of 0.35 μg/L) were found at
6.9% of these tested sites (See Section 4.5: Cancer Potency Factor). Most
of these sites were clustered in specific geographic areas, including the
north Atlantic coast, the upper Midwest, and California (Adamson
et al. 2017). Long Island NY is one example of a region impacted by ele-
vated 1,4-dioxane concentration; approximately 66% of its public water
supplies exceed the federal guideline level (Fig. 1B). This contaminant
has also been increasingly detected at a growing number of locations in-
ternationally, including Japan (Abe 1999; Tanabe et al. 2006), Korea (An
et al. 2014), Canada (Health Canada 2018), the United Kingdom, and
Germany (Karges et al. 2018; Stepien et al. 2014; Stepien and
Püttmann 2013).
2.2. Co-contaminants
1,4-Dioxane is commonly found in affected groundwater as a mix-
ture with other chlorinated solvents, including 1,1,1-TCA, 1,1-dichloro-
ethane (1,1-DCA), and trichloroethylene (TCE), all of which are also
listed in the ATSDR's Substance Priority List. Together with 1,4-dioxane,
these contaminants have been detected at 1699 current or former U.S.
EPA Superfund National Priority List sites. While 1,4-dioxane was de-
tected at only 31 of these sites, testing for this contaminant only became
commonplace in the past 15 years. As such, its likely occurrence at some
waste sites might have not been documented (ATSDR 2016) (ATSDR
2006) (ATSDR 2015). Based on the U.S. Air Force Environmental Resto-
ration Program Information Management System, Anderson et al.
(2012) reported that 1,4-dioxane was present in 17.4% of the ground-
water monitoring wells; TCE and/or 1,1,1-TCA were detected in 93.7%
of all samples containing 1,4-dioxane, confirming the notion that 1,4-
Fig. 1. 1,4-Dioxane concentrations in public water supplies (surface and groundwater) by zip code across the U.S. (A) and Long Island, NY (B) (adapted from U.S. EPA, 2015). MRL: Minimum
reportable level.
855
dioxane is seldom found independent of chlorinated solvent contami-
nants. A high correlation between the occurrence of 1,4-dioxane and
TCE was also found in studies performed in other countries such as
Germany (Karges et al. 2018). These findings highlight the need to fur-
ther study the biological effects of mixtures of 1,4-dioxane and chlori-
nated solvents, and suggest that the dominant source of 1,4 dioxane in
the environment is from its use with chlorinated solvents.
2.3. Environmental fate
1,4-Dioxane can be released into the air, water or soil. It is in general
not a concern in the atmosphere, since it is non-volatile with very low
Henry's Law constant (4.8 × 10−6 atm·m3/mol at 25 °C) (O'Neil 2013;
Verschueren 2008). Half-life is also relatively short at 35 h due to gas-
phase photo-oxidation (Mohr 2001). In water, 1,4-dioxane can occur
at high concentration due to high solubility (100 mg/mL) (NTP 1992).
Low octanol-water partitioning coefficient (log Kow = −0.27) (ATSDR
2012) and weak adsorption into mineral phases and organic matter
(Jackson and Dwarakanath 1999; Lesage et al. 1990; Priddle and
Jackson 1991) allow 1,4-dioxane to efficiently leach into water systems
and transport through even subsurface environment (Zhang et al.
1990); limited mobility has only been observed in regions with clay
soils. Coupled with its chemical inertness, 1,4-dioxane is extremely per-
sistent in groundwater with half-life of 2–5 years, while moderately
persistent in surface water with half-life of 56 days (Adamson et al.
2015; EPA, 2018a). Consequently, point-source releases of 1,4-dioxane
can cause plumes which have the potential to contaminate both near-
field and distal water-supply wells. In California, for example, where
N2000 sites contain elevated concentrations of 1,4-dioxane, N50% of
plumes exceeded 270 m in length and N10% were longer than 1000 m
(Adamson et al. 2014).\
A shorter lifetime of 1,4-dioxane in surface water compared to sub-
surface water is likely related to more prevalent microbial degradation
in the former environment. Through monooxygenase-metabolic or co-
metabolic pathways, it can be progressively transformed to β-
hydroxyethoxyacetic acid (HEAA), ethylene glycol, glycolate, and oxa-
late (Huang et al. 2014; Mahendra et al. 2007; Zhang et al. 2017). Min-
eralization of these intermediates to carbon dioxide and water is
achieved by select bacterial cultures (Grostern et al. 2012; Lan et al.
2013; Mahendra et al. 2007). Aerobic metabolism of 1,4-dioxane has
been demonstrated by several bacterial and fungal strains, including
Pseudonocardia dioxanivorans CB1190 (Mahendra and Alvarez-Cohen
2005; Parales et al. 1994), Mycobacterium sp. PH-06 (Kim et al. 2009),
Rhodococcus 219 (Bernhardt and Diekmann 1991), and Cordyceps
sinensis (Nakamiya et al. 2005). Through this metabolic transformation
process, bacteria and fungi use 1,4-dioxane as a sole energy and carbon
856 K.J. Godri Pollitt et al. / Science of the Total Environment 690 (2019) 853–866

source. Co-metabolism of 1,4-dioxane occurs in numerous bacterial Table 1

strains when grown on a carbon substrate, typically a C2 to C5 alkane Drinking water guidelines and criteria for 1,4-dioxane (An et al. 2014; EPA US, 2017b; EPA
US, 2018a, b; Health Canada 2018; Mulisch et al. 2003; WHO 2005; Yamamoto et al. 2018).
(Mahendra and Alvarez-Cohen 2006; Vainberg et al. 2006). These mi-
croorganisms include Mycobacterium austroafricanum JOB5 (Lan et al. Jurisdiction Target Type of target Year target
2013), Pseudonocardia sp. strain ENV478 (Vainberg et al. 2006), concentration was
(μg/L) introduced
Rhodococcus ruber ENV425 (Lippincott et al. 2015) and Pseudonocardia
K1 (Mahendra and Alvarez-Cohen 2006). Application of biodegradation Alaska 77 Groundwater cleanup level 2016
California 1.0 Public health protective 2011
as a potential 1,4-dioxdane remediation strategy will be further
concentration
discussed in Section 7.2: Bioremediation. Connecticut 3.0 Action level 2013
Reactive transport models have been instrumental in evaluating the Indiana 4.6 Groundwater screening level 2016
fate and transport of contaminants in subsurface. These computational Maine 4.0 Guideline 2016
models predict advective-dispersive transport and reactions that trans- Massachusetts 0.3 Guideline 2004
Michigan 7.2 Drinking water criterion 2017
form and immobilize contaminants over large temporal and spatial do- Minnesota 1.0 Health risk limit 2013
mains (Anderson et al. 2015; Benjakul 2010). Despite frequent and New Jersey 0.4 Groundwater quality criterion 2015
successful use in simulating the fate of other subsurface contaminants New York 1.0 Draft minimum criterion level 2018
including halogenated solvents, it has not yet been used for 1,4-dioxane North Carolina 3.0 Drinking water criterion 2015
Texas 9.1 Protective concentration level 2016
in groundwater due to the dearth of data required to accurately quantify
U.S. 0.35 U.S EPA, screening level for tap 2017
mass transfer and biotic/abiotic transformation in complex environ- watera
mental matrix. For example, the impact of co-contaminants and their Germany 0.1 Federal environmental agency, 2003
degradation byproducts on the potential inhibition of 1,4-dioxane re- suggested guideline
moval (Deng et al. 2018) needs to be carefully evaluated under the var- Canada 50 Health Canada, draft drinking 2018
water guideline
ious physicochemical conditions likely to be encountered in subsurface
Republic of 50 Ministry of the environment, 2014
environment. Careful validation of the model against existing field data Korea provisional standard
on 1,4-dioxane migration also needs to be performed. Development of Japan 50 Water pollution control law, 2009
these transport models will facilitate identification of drinking-water drinking water standard
World Health 50 Guideline 2005
resources vulnerable to 1,4-dioxane releases, predication of exposure
Organization
routes, and proper allocation of remedial actions.
a
U.S. EPA has not set an enforceable Minimum Criterion Level.

3. Routes of exposure
Exposure to 1,4-dioxane occurs through ingestion of contaminated
water and food, dermal contact or inhalation of vapors (ATSDR 2012;
DHHS 2014; EPA, 2010). These environmental exposure pathways to
1,4-dioxane will be discussed.
3.1. Drinking water
Ingestion of 1,4-dioxane through drinking water is the dominant
pathway of exposure (Abe 1999; Anderson et al. 2012; Chiang et al.
2008; Karges et al. 2018; Stepien et al. 2014; Sun et al. 2016). As
discussed in Section 2.1: Environmental Occurrence, approximately 7%
of public drinking water supplies in the U.S. exceed the federal health
risk guideline level of 0.35 μg/L (EPA, 2013). According to a recent anal-
ysis by a non-government organization, when extrapolated across the
U.S., these drinking water levels would expose millions of public
water consumers to elevated cancer risk from 1,4-dioxane contamina-
tion (Environmental Working Group (EWG) 2017). The World Health
Organization as well as federal agencies in Japan, Korea, and Canada
have all recommended a drinking water guidance level of 50 μg/L (An
et al. 2014; EPA, 2018a; Health Canada 2018; WHO 2005; WHO 2011;
Yamamoto et al. 2018). In Germany, 1,4-dioxane is not specifically reg-
ulated but it is classified as a non-regulated toxic substance by the Ger-
man Federal Environmental Agency which has suggested a guideline
value of 0.1 μg/L (Mulisch et al. 2003). In contrast, there is currently
no federal maximum contaminant level for 1,4-dioxane in the U.S.
This has resulted in different criteria and guidelines across states that
range from 0.3 μg/L in Massachusetts to 77 μg/L in Alaska (Table 1).
The wide range of acceptable concentrations of 1,4-dioxane across juris-
dictions is partially attributable to differing exposure assumptions and
cancer risk targets (See Section 4.5: Cancer Potency Factor).
3.2. Food
1,4-Dioxane has been found in various food products (Health
Canada 2018; Nishimura et al. 2004). Sources of 1,4-dioxane contami-
nation include adhesive material used on food packaging, pesticides
used to treat food crops, and manufactured food additives (e.g., polysor-
bate 60, 65, and 80, and polyethylene glycol) (ATSDR 2012). According
to the food-exposure study by Health Canada and Environment Canada
(2010), formula-fed infants (b0.6 months of age) were reported to ex-
perience the highest exposure to this contaminant (1.1 μg/kg body
weight/day) followed by children aged 1 through 4 years (0.3 μg/kg
body weight day). In the U.S., 1,4-dioxane content in food additives is
regulated to not exceed 10 mg per kg of additive
(PharmacopeialConvention, 2008).
3.3. Consumer products
Personal care products containing ethoxylated surfactants are also a
potential source of 1,4-dioxane (Health Canada 2018). Elevated concen-
trations have been reported for various cosmetic products (279 mg/kg)
and children's shampoo (85 mg/kg) in the U.S. (Black et al. 2001). As-
sessments of consumer products available in Japan and Taiwan revealed
high levels of 1,4-dioxane in shampoos (45.5 mg/kg), body washes
(15.7 mg/kg), hand soaps (7.5 mg/kg), and hair conditioners
(0.14 mg/kg) (Fuh et al. 2005; Makino et al. 2006; Tahara et al. 2013;
Tanabe and Kawata 2008). In contrast, concentrations in laundry deter-
gents were found to be minimal (b5 mg/kg) (Fuh et al. 2005; Makino
et al. 2006; Tanabe and Kawata 2008). It is interesting to note that expo-
sure to 1,4-dioxane has been estimated to be greater in women (1.2
μg/kg body weight/day) than men or children. The elevated exposure
was primarily attributed to inhalation of the volatilized contaminant
from personal care products and, to a lesser extent, from dermal absorp-
tion via topical application (Bronaugh 1982; ECB 2002; Health Canada
and Environment Canada 2010; NICNAS 1998). The exposure through
the use of body wash, shampoo, and moisturizers, albeit relatively low
at 0.04 μg/kg body weight/day, were also reported for infants (Health
Canada and Environment Canada 2010).
3.4. Bathing and showering
Volatile contaminants in drinking water such as halogenated disin-
fection byproducts contribute to inhalation and dermal exposure during
 K.J. Godri Pollitt et al. / Science of the Total Environment 690 (2019) 853–866 857

bathing and showering (Krishnan and Carrier 2008). However, these
exposure routes have been estimated to be negligible compared to
other routes, although data are quite limited (Health Canada 2018).
4. Toxicology and carcinogenesis
Organ systems primarily affected by 1,4-dioxane include the liver
and kidneys. Adverse nasal and ocular effects have also been re-
ported (DeRosa et al. 1996; Dourson et al. 2014; Fujiwara et al.
2008; Kano et al. 2009; Kasai et al. 2009; Kasai et al. 2008; Stickney
et al. 2003). This section discusses studies evaluating 1,4-dioxane-
induced toxicity, as well as the cancer and non-cancerous effects of
this contaminant.
4.1. Toxicity
When administered chronically to rats and mice via drinking water,
1,4-dioxane was shown to induce dose-dependent liver toxicity, mani-
festing as degeneration of hepatic cells and development of pre-
neoplastic lesions (Table 2) (EPA, 2013c; Fishbein 1981; Goldsworthy
et al. 1991; Kano et al. 2009; Stott et al. 1981). Other hepatic effects of
chronic 1,4-dioxane exposure via drinking water include increased
liver to body weight, centrilobular swelling, necrosis, increased DNA
synthesis, chromosomal damage, and enzyme leakage in rats and mice
(Kano et al. 2009; Roy et al. 2005; Stott et al. 1981). Chronic exposure
to 1,4-dioxane through drinking water consumption has also been re-
ported to impact the kidney, causing degeneration of cortical tubule
cells, tubular necrosis, and glomerulonephritis (EPA, 2013c).
4.2. Metabolism and elimination
Defining the mechanism of 1,4-dioxane toxicity requires a compre-
hensive understanding of its metabolic pathways. While few studies
have described 1,4-dioxane metabolism in humans, experiments in
rats have demonstrated that it is rapidly absorbed and metabolized to
HEAA and, subsequently, to diglycolic acid (Besenhofer et al. 2010;
Landry et al. 2011). 1,4-dioxane metabolism is also likely to result in
production of HEAA and diglycolic acids. The metabolism to HEAA is
postulated to involve multiple pathways occurring in the liver, kidney,
and nasal mucosa (Fig. 2) (Woo et al. 1977). Cytochrome P450s (specif-
ically CYP2E1) appear to be involved in two of these pathways (Nannelli
et al. 2005b). The third hypothesized pathway proposes that 1,4-diox-
ane is first metabolized to diethylene glycol, followed by conversion to
2-hydroxyethoxyacetaldehyde which is rapidly metabolized to HEAA
(Centers for Disease Control and Prevention 2017; Schier et al. 2013).
Bioremediation studies have shown that monooxygenase-expressing
microorganisms can similarly metabolize 1,4-dioxane into glyoxylate
via the production of 2-hydroxyethoxyacetaldehyde, HEAA, and 1,4-di-
oxane-2-one (Grostern et al. 2012) (See Section 2.3: Environmental
Fate).
Exposure studies suggest that the average half-life of 1,4-dioxane in
human body is relatively short at approximately 1 h (Braun 1977; Braun
and Young 1977) (Eckert et al. 2013; Göen et al. 2016; Young et al.
1976) (Table 3). For example, a chamber exposure study found that in-
halation exposure to 50 ppm (v) of 1,4-dioxane caused elevated 1,4-di-
oxane concentrations in plasma immediately following exposure but
levels rapidly decreased to below detectable limits by six hours after
the end of exposure (Young et al. 1977). Reflecting the rate of 1,4-diox-
ane metabolism, the half-life of HEAA was much longer at 2.7 h; its

Table 2
1,4-Dioxane-Induced Liver Toxicity (Adapted from U.S. EPA 2013).

Study Designa Doseb (mg/kg/d) Cytotoxicityc Proliferation/hyperplasiac Liver tumorsd

Kociba et al. (1974) Rats 0 − − 2/106

Male and females 14 − − 0/110
104-week exposure 121 + + 1/106
1307 + + 12/66
NCI (1978) Rats 0 − − 2/31
Males 240 − − 2/32
110-week exposure 530 − − 1/33
NCI (1978) Rats 0 − − 0/31
Females 350 − − 10/33
110-week exposure 640 − − 11/32
NCI (1978) Mice 0 − − 8/49
Males 720 − − 19/50
90-week exposure 830 − − 28/47
NCI (1978) Mice 0 − − 0/50
Females 380 − − 21/48
90-week exposure 860 − − 35/37
Kano et al. (2009) Rats 0 − − 3/50
Males 11 − − 4/50
104-week exposure 55 − − 7/50
274 + − 39/50
Kano et al. (2009) Rats 0 − − 3/50
Females 18 − − 1/50
104-week exposure 83 − − 6/50
429 − − 48/50
Kano et al. (2009) Mice 0 − − 23/50
Males 49 − − 31/50
104-week exposure 191 − − 37/50
677 + − 40/50
Kano et al. (2009) Mice 0 − − 5/50
Females 66 − − 35/50
104-week exposure 278 − − 41/50
964 + − 46/50
a
Design includes the species under investigation, animal genders used and exposure duration.
b
Animals were exposed to 1,4-dioxane in drinking water.
c
“+”: increased cytotoxicity; “-”: no evidence of cytotoxicity.
d
Numerator: incidence of liver tumor; Denominator: effect number of animals.
858 K.J. Godri Pollitt et al. / Science of the Total Environment 690 (2019) 853–866

Fig. 2. Postulated metabolic pathways of 1,4-dioxane in humans.

(Adapted from Woo et al. 1977)

concentrations lagged behind 1,4-dioxane concentrations by an hour
and persisted over 18 h after the exposure (Sweeney et al. 2008;
Young et al. 1977). During an eight-hour inhalation exposure, 1,4-diox-
ane and HEAA concentrations reached steady state levels in blood
within the first few hours of exposure, and were detected in urine for
up to four hours and 24 h post-exposure, respectively (Göen et al.
2016) (Table 3). Urinary concentrations of 1,4-dioxane measured across
the eight-hour exposure period corresponded to approximately 0.3% of
the theoretically inhaled total 1,4-dioxane amount, while HEAA ex-
creted in urine represented 53% of the estimated exposure.
4.3. Carcinogenic effects
To date, in vivo studies have documented 1,4-dioxane-induced
tumor formation in the liver and nasal cavity following chronic expo-
sure through inhalation or ingestion (Table 2) (Dourson et al. 2017;
Wilbur et al. 2012) (ATSDR 2012) (Kano et al. 2009; Kasai et al. 2009;
Kociba et al. 1974). The formation of tumors in the liver has been further
demonstrated to be dose-dependent, with enhanced effects in female
mice compared to males over a two-year period (Kano et al. 2009). In
contrast, in vitro studies have failed to demonstrate any genotoxic ef-
fects induced by 1,4-dioxane (EPA, 2013). It is unclear whether 1,4-di-
oxane or its metabolites are responsible for the formation of
hepatocellular tumors. While the primary metabolite found in urine,
HEAA, has not been reported to be highly toxic or carcinogenic, other
metabolites, including diethylene glycol and diglycolic acid (Fig. 2),
have been shown to exhibit toxicity in the liver and kidney (Conrad
et al. 2016; Landry et al. 2015; Landry et al. 2011; Schier et al. 2013).
Furthermore, the metabolism of 1,4-dioxane has been shown to induce
several isoforms of CYP450 in various tissues following acute oral ad-
ministration by gavage or drinking water (Nannelli et al. 2005a). Thus,
it is plausible the toxic metabolites produced, such as diethylene glycol
and diglycolic acid in combination with the induction of the CYP iso-
forms (i.e. CYP2E1) in the liver may have contributed to the hepatic tu-
morigenesis responses observed.
It is noteworthy that all the aforementioned co-contaminants of 1,4-
dioxane, 1,1,1-TCA, 1,1-DCA, and TCE, have been shown to cause carci-
nogenic responses in the liver and kidneys of animals via the formation
of reactive metabolites (ATSDR 2006). To the best of our knowledge, no
studies have examined the effects of mixtures involving 1,4-dioxane
and its chlorinated solvent co-contaminants. Additive toxic effects on
the liver and kidney are plausible for binary and higher-order combina-
tions of these chlorinated compounds with 1,4-dioxane, as has been re-
ported for the chlorinated compounds themselves in interaction studies
(Goldsworthy and Popp 1987; Inoue et al. 1989).
4.4. Mechanisms of carcinogenesis
Despite the evidence of a carcinogenic effect, the mechanism by
which 1,4-dioxane causes cancer is currently unclear (EPA, 2013). The
data summarized in Table 2 do not support a cytotoxicity-based mech-
anism as six out of ten studies showed no cytotoxic effect. All studies,
however, demonstrated the presence of liver tumors. In addition, tu-
mors have been found at exposure doses that were without overt cyto-
toxicity in the liver (Kano et al. 2009). Interestingly, studies have shown
that 1,4-dioxane appears to be a tumor promoter rather than initiator
(Dourson et al. 2014; EPA, 2013; Kitchin and Brown 1990; Lundberg
et al. 1987). The data showed that 1,4-dioxane promoted the

Table 3
Summary of Human 1,4-Dioxane Toxicokinetic and Biomonitoring Studies.

Study Exposure concentration, route, Study populationa Sample Measurement time, post- exposure Average concentration
duration type (hrs)b (mg/L)

1,4-Dioxane HEAA

Chamber exposure 50 ppm Healthy Adult volunteers Urine 0 4.3 422

Young et al. (1977) Inhalation N=4 4 0.22 473
Sweeney et al. (2008) 6h 18 b 0.07 3.3
0 13 5.0
Plasma 4 1.5 2.0
18 b 0.07 b 0.5
Chamber exposure 20 ppm Healthy Adult volunteers Urine −2.5 0.85 160
Eckert et al. (2013) Inhalation N = 18 1.5 Not reported 204
Göen et al. (2016) 8h −4.0 0.98 Not measured
Whole blood
0 1.1 Not measured
Occupational exposure 1.6 ppm Adult Dioxane plant workers Urine 0 0.31 49.7
Young et al. (1976) Inhalation N=5
7.5 h
NHANES, 2013–2014 Not measured General Adult population Whole blood Spot samples b 0.0015 Not measured
CDC (2017) N = 3125
a
N indicates the number of participants in each study.
b
Negative number indicate samples that were collected during the exposure period.
 K.J. Godri Pollitt et al. / Science of the Total Environment 690 (2019) 853–866
carcinogenic potential of diethylnitrosamine in rats (Lundberg et al.
1987), and significant mortality was observed when it was adminis-
tered for 60 weeks as a promoter (4 male and 5 female mice survived,
n = 30/sex) (King et al. 1973).
A mechanistic transcriptomic analysis conducted in rats exposed to
1,4-dioxane in drinking water (440 mg/kg-day) for four weeks suggested
that 1,4-dioxane exposure elicited a unique pattern of altered gene ex-
pression in rat liver. These marker genes had previously been used to seg-
regate genotoxic (3,3-dimethylbenzidine, diethylnitrosamine) from non-
genotoxic (diethylhexylphthalate) carcinogen expression profiles
(Furihata et al. 2018). More specifically, gene expression profiles treated
with 1,4-dioxane were different from those with typical genotoxic
hepatocarcinogen for five genes (Bax, Btg2, Cdkn1a, Lrp1, and Plk2) and
substantially different from treatment with a typical non-genotoxic
hepatocarcinogen for nine genes (Aen, Bax, Btg2, Ccnf, Ccng1, Cdkn1a,
Mbd1, Phlda3, and Tubb4b). A more recent in vivo study concluded that
1,4-dioxane was clastogenic (i.e., induced chromosomal breakages) in
the liver but not genotoxic in the bone marrow (Itoh and Hattori 2019).
Indirect genotoxic mechanisms related to inhibition of DNA repair is
one of several plausible mechanisms to explain the divergent
genotoxicity responses observed by in vitro and in vivo studies investigat-
ing 1,4-dioxane.
Based on this evidence, it is reasonable to conclude that the mecha-
nism by which 1,4-dioxane promotes cancer is not easily explained by
classic schemes. Further studies are needed to understand the cellular
mechanism of 1,4-dioxane-induced carcinogenesis using a systems bi-
ology approach employing advanced transcriptomic and metabolomic
techniques.
4.5. Cancer potency factor
The exposure dose-dependent formation of liver tumors by 1,4-di-
oxane reported by Kano et al. (2009) was used as a basis for dose-
response modeling and human extrapolation by the U.S. EPA's Integrate
Risk Information System to derive a cancer potency factor of 0.1
mg/kg/day (EPA, 2013). This cancer potency factor was subsequently
used to develop the federal health risk guideline of 0.35 μg/L for 1,4-di-
oxane in drinking water based on a cancer de minimis one-in-a-million-
reference value.
The Kano et al. (2009) study enabled calculation of the cancer po-
tency factor because it tested a broad range of doses in male and female
rats and mice. However, there was a large gap between the lowest dose
in the most sensitive test group (66 mg/kg/day; female mice), the calcu-
lated human equivalent benchmark concentration (7 mg/kg/day, lower
limit) (EPA, 2013) and the environmental exposure levels relevant for
consideration of drinking water criteria (0.35 to 10 μg/L). Extrapolating
responses from animal to humans across multiple orders of magnitude
is typical in cancer risk assessment; however, it requires low-dose
modeling assumptions to be made to predict the risk at the much
lower doses to which humans are likely to be exposed. Given the lack
of definitive mechanistic information, the U.S. EPA has assumed a linear
low-dose approach from the calculated human equivalent benchmark
concentration. This approach has been disputed based on evidence
that hepatotoxicity and regenerative hyperplasia co-occurred in some
1,4-dioxane dose-response studies, suggesting a plausible basis for a
cytotoxicity-based threshold response (Dourson et al. 2014, 2017).
However, as stated above and shown in Table 2, this was not always
the case, since liver tumorigenesis was observed in absence of
cytotoxicity.
Additional mechanistic studies are needed to understand how 1,4-
dioxane may contribute to liver carcinogenesis in humans at doses
below the levels tested by Kano and coworkers and that are more rep-
resentative of actual low, environmentally-relevant levels of exposure.
This information is critical to allow quantitative risk assessments for
1,4-dioxane that can form the basis of deriving a more accurate cancer
859
potency factor and ultimately setting a regulatory standard for drinking
water.
5. Exposure assessment
Quantifying exposure to 1,4-dioxane presents analytical challenges
due to its high affinity for water, lack of readily detectable functionality,
and low concentration in environmental and biological samples. Nu-
merous analytical techniques have been suggested for 1,4-dioxane de-
tection over a wide concentration range in a broad spectrum of
aqueous matrices. Analytical approaches for measuring 1,4-dioxane
usually include a preparation stage (e.g., pre-concentration or extrac-
tion) to improve sensitivity, which is then followed by separation
using gas chromatography (GC) and detection by mass spectrometry
(MS) or flame ionization (Fig. 3). These methods for exposure assess-
ment are discussed below.
5.1. Environmental samples
Several pre-concentration techniques have been developed over the
past four decades to concentrate 1,4-dioxane from water samples, in-
cluding purge-and-trap, headspace, and phase extraction. These
methods have been reported to achieve detection limits ≈ 10 μg/L
(Table 4) (EPA, 1984; EPA, 1996a; EPA, 1996b; EPA, 1996c; EPA,
1996d; Friant and Suffet 1979). Given the miscibility of 1,4-dioxane in
water, its low volatility from water, and low partition coefficient, vari-
ous modifications of these preparation techniques have been suggested
to attain the sensitivity required for drinking water monitoring (1 μg/L)
(Epstein et al. 1987; Park et al. 2005). For example, modified purge-and-
trap procedures with extended purge time and temperature as well as
increased addition of salt improve detection limits, i.e., down to 0.15
μg/L (Sun et al. 2016). Frozen microextraction and continuous liquid-
liquid extraction of water samples further improve detection sensitivity
to 0.20 μg/L (Draper et al. 2000).
The heightened regulatory attention to 1,4-dioxane prompted the
development of advanced analytical methods for detection of trace
quantities (b0.1 μg/L). Using solid phase extraction of 1,4-dioxane as a
pre-concentration approach for environmental samples minimizes in-
terferences and lowers detection limits to 0.05 μg/L (Carrera et al.
2017; Isaacson et al. 2006; Song and Zhang 1997). A decade ago, the
U.S. EPA released Method 522 for determination of 1,4-dioxane in
drinking water by solid phase extraction using coconut charcoal or syn-
thetic carbon cartridges and dichloromethane elution prior to GC–MS
analysis with selected ion monitoring (EPA, 2008). This resulted in a de-
tection limit between 0.020 and 0.026 μg/L in drinking water, suitable to
detect 1,4-dioxane below the one-in-a-million cancer risk level
established by the U.S. EPA (0.35 μg/L).
While the laboratory-based methods discussed above accurately
characterize trace levels of 1,4-dioxane in environmental samples,
such analytical measurements present challenges when monitoring dy-
namic systems, such as public water supplies. Portable sensors that pro-
vide real-time information about the temporal variability of 1,4-dioxane
concentrations in the field are lacking but would be of high value to
water systems operators. Development of sensors for 1,4-dioxane for
deployment across public water distribution systems involves several
aspects, such as a recognition event wherein 1,4-dioxane is specifically
and selectively detected through interaction with the sensor receptors,
and a corresponding signal response to report on the interaction, e.g.,
chemical, optical, or electrical response. The sensing components
should then be translated into practical devices able to perform onsite
under environmental conditions. Finally, connection of the sensing de-
vice to a wireless sensor network would provide an additional advan-
tage for real-time monitoring of 1,4-dioxane. Ideally, sensitivity to 1,4-
dioxane would be achieved through the design of specific sensing ele-
ments that recognize 1,4-dioxane as a single target. In that case, a recog-
nition event might occur through selective binding of substances or
860 K.J. Godri Pollitt et al. / Science of the Total Environment 690 (2019) 853–866

Fig. 3. Analytical methods commonly used for measuring 1,4-dioxane in environmental and biological samples.

chemical reaction. Several studies have described various sensor tech-
nologies for remote monitoring of 1,4-dioxane in aqueous samples.
Kumar et al. (2015) developed a silver nanoparticle-based
solvatochromic sensor that selectively quantifies 1,4-dioxane in various
solvents with a 1 mg/L detection limit. Sensors based on infrared and
photoacoustic spectroscopy have also been investigated but exhibit
poor 1,4-dioxane sensitivity (20 mg/L detection limit) (De Melas et al.
2003; Holthoff et al. 2015). Luminescent porous organic polymers
have also been created that quantify 1,4-dioxane in glycol medium
(Heuvelsland 1988; Ma et al. 2016; Zhou et al. 2015). The approaches
developed thus far offer low selectivity and detection limits insufficient
to detect U.S. EPA-based action levels of 1,4-dioxane. Sensors that use
DNA aptamers, nanobodies, or antibodies have shown promise for
their high selectivity, and their affinity for target molecules (commonly
in the 0.1 to 10 nM range) (Hamaguchi et al. 2001; Liss et al. 2002).
When these biomolecules have been coupled to electrochemical dis-
placement sensors, exceptionally low detection levels (pM to aM
range) have been realized (Hansen et al. 2006; Zhang et al. 2018).
Development of these highly sensitive sensors for real-time monitoring
of 1,4-dioxane in the field would enable detection of dynamic contami-
nation events and thereby facilitate rapid notification of the public of
exceedances in public water supplies.
5.2. Biological samples
Biomonitoring is a popular approach for personal exposure assess-
ment of a contaminant in a biological sample. Human biomonitoring
studies use GC–MS for separation and detection and follow the same
methods used for detection of 1,4-dioxane in water samples
(Section 5.1: Environmental Samples). However, extraction techniques
used for biological samples (e.g., urine, plasma, whole blood) differ from
those used for water samples. Headspace and liquid-liquid extraction
protocols have been reported for 1,4-dioxane with detections limits of
100 and 137 μg/L, respectively (Table 4) (Eckert et al. 2013; Göen
et al. 2016; Sweeney et al. 2008). An additional method using direct in-
jection of urine and plasma sample reported a detection limit of 70 μg/L

Table 4
Summary of Analytical Techniques and Water Methods for Measurement of 1,4-Dioxane in Water and Biological Fluids.

Study Limit of detection (μg/L) Sample matrix Sample volume (mL) Extraction and analysis techniquea

Friant and Suffet (1979) 740 Water 5 Headspace GC–MS

EPA US (1996a, b, c, d) 12 Water 5–25 Liquid-liquid extraction; GC–MS
Methods 5031, 5032
EPA US (1996a, b, c, d) 12 Water 5–25 Liquid-liquid extraction; GC–MS
Methods 8260B, 8015B
U.S. EPA (1984) 10 Water 5 Purge-and-trap; GC–MS
Method 1624
Park et al. (2005) 6 Water 200 Liquid-liquid extraction; GC–MS
Epstein et al. (1987) 1 Water 4000 Liquid-liquid extraction; GC-FID
Isaacson et al. (2006) 0.31 Water 80 Solid-phase extraction; GC–MS
Draper et al. (2000) 0.20 Water 1000 Liquid-liquid extraction; GC–MS
Sun et al. (2016) 0.15 Water 5 Purge-and-trap; GC–MS
Song and Zhang (1997) 0.05 Water 1 Solid-phase extraction; GC–MS
Carrera et al. (2017)
U.S. EPA (2008) 0.02 Water 100 Solid-phase extraction; GC–MS
Method 522
Sweeney et al. (2008) 137 Blood 0.1 Liquid-liquid extraction; GC–MS
Göen et al. (2016) 100 Urine, blood 2 Headspace GC–MS
Braun (1977) 70 Urine, plasma 0.5 Direct injection; GC–MS
Braun and Young (1977)
Chambers (2017) 0.5 Blood 3 Headspace solid-phase microextraction, GC–MS
a
GC: gas chromatography; MS: mass spectrometry; FID: flame ionization detector.
 K.J. Godri Pollitt et al. / Science of the Total Environment 690 (2019) 853–866
for 1,4-dioxane (Braun 1977; Braun and Young 1977). While these
methods were able to detect 1,4-dioxane in blood and urine following
moderate to high exposure levels (1.6–50 ppm), their sensitivity was
reduced compared to most techniques used for monitoring environ-
mental water samples (0.02–12 μg/L) (Table 4). More recently, an ex-
traction technique using headspace solid-phase microextraction
developed at the U.S. Centers for Disease Control and Prevention
(CDC) achieved the most sensitive levels of detection than other bio-
monitoring approaches for 1,4-dioxane detection (0.5 μg/L) (Table 4)
(Chambers 2017). This method was used to test whole blood samples
from the U.S. general population (NHANES 2013–2014). All 3125 sam-
ples analyzed were found to be below the level of detection (Centers
for Disease Control and Prevention 2017). It is clear that evaluation of
the general population to low dose exposure to 1,4-dioxane requires
improved analytical methods with increased sensitivity for 1,4-dioxane
detection.
As previously discussed, 1,4-dioxane is rapidly metabolized via cyto-
chrome P450 monooxygenases to 1,4-dioxane-2-one and HEAA (See
Section 4.2: Metabolism and Elimination). Human chamber studies
have demonstrated that HEAA can be used as a short-term surrogate
marker of moderate-to-high inhalation exposure to 1,4-dioxane
(Table 3). While HEAA has not been evaluated as a biomarker of envi-
ronmental exposure to 1,4-dioxane, the sensitivity of analytical tech-
niques to detect low levels of HEAA supports the feasibility of
measuring this compound in the general population. However, an im-
portant caveat of using HEAA for such exposure assessment is the
non-specificity of this metabolite to 1,4-dioxane. For example, HEAA is
also the major metabolite produced from diethylene glycol, diethylene
glycol ethers, and diethylene glycol monoethyl ether, all of which are
used in antifreeze preparations, petroleum solvent extraction, produc-
tion of polyurethanes and unsaturated polyester resins, and dehydra-
tion of natural gas (Göen et al. 2016; Larranaga et al. 2016; Schier
et al. 2013). Nevertheless, environmental exposure of the general pop-
ulation to these chemicals is limited (Schriks et al. 2010; Stefania et al.
2009).
As an alternative to measuring 1,4-dioxane directly or focusing
solely on the major metabolite of this contaminant, MS-based metabo-
lomics may serve as a possible screening tool for risk assessment. This
approach could be used to characterize an endogenous signature of me-
tabolite biomarkers for the assessment of 1,4-dioxane exposure. In addi-
tion, the metabolomic signature of 1,4-dioxane could be used as a basis
to investigate the potential toxic effects associated with biomarker indi-
ces of exposure. This can be performed through evaluation of biochem-
ical pathways and networks. (Rattray et al. 2018).
6. Health effects in humans
1,4-Dioxane has been classified as a probable human carcinogen
based on evidence from experimental animal studies but there is a pau-
city of data related to the impact of 1,4-dioxane exposure on human
health. A small study in 2006 evaluated responses induced by controlled
1,4-dioxane exposure. This chamber study included twelve healthy vol-
unteer participants and concluded that exposure to 20 ppm 1,4-dioxane
for 2 h did not increase the frequency of symptoms such as blinking,
nasal swelling, inflammation, or difficulty with pulmonary function
(Ernstgård et al. 2006).
All other human studies have exclusively focused on elevated occu-
pational exposures in small cohorts (N 〈200) with most evaluating
cancer-related mortality. Buffler et al. (1978) conducted a retrospective
cohort study to estimate the association between occupational expo-
sure to 1,4-dioxane and cancer mortality among 165 workers at a
major chemical plant in Texas. No estimate was given by authors of
workers' exposure levels to the 1,4-dioxane. Between April 1, 1954
and June 30, 1975, 12 deaths occurred in these plant workers, of
which three were cancer-related. Although the number of observed
deaths was higher than the expected Texas age-sex-race (N = 4.9)
861
and cause-specific (N = 1.7) deaths, the difference was not statistically
significant. Kramer et al. (1978) recruited 151 matched pairs of exposed
and control workers from two adjacent textile plants in Michigan be-
tween 1969 and 1975; one plant used 1,1,1-TCA as a cleaning solvent
which contained 4% 1,4-dioxane. This study did not find any alterations
in cardiovascular or hepatic parameters to be associated with occupa-
tional exposure to 1,1,1-TCA. Thiess et al. (1976) conducted a cohort
study in Germany between 1964 and 1974 that included 74 workers
who were exposed to 1,4-dioxane. The number of overall deaths (N
= 12) and cancer-related deaths (N = 2, one lamellar epithelial carci-
noma and one myelofibrotic leukemia) were not significantly increased
over the expected number of cancer deaths in age- and gender-match
patients in the general population (N = 14.5). Stickney et al. (2003)
reviewed an unpublished study conducted in 1976 which reported
four cancer cases (a colon cancer, a pulmonary cancer, a lymphosar-
coma, and a glioblastoma) among 80 workers who were exposed to
1,4-dioxane. The observed number of cancer cases was similar to the ex-
pected number of cancer deaths in the general population. While this
small number of available epidemiologic studies do not support an asso-
ciation between 1,4-dioxane and cancer, only limited conclusions can
be drawn from these studies because their sample sizes were too
small to allow detection of a low-level elevated cancer risk. In addition,
the reported cancers had sites of origin that were not in line with those
seen in animal models (which mainly manifested in the liver or nasal
cavity; See Section 4.4: Carcinogenic Effects) (Stickney et al. 2003).
Available exposure assessment methods have limited the feasibility
of epidemiological studies to evaluate 1,4-dioxane across general popu-
lations (See Section 5: Exposure Assessment). 1,4-Dioxane concentra-
tions can be measured in public drinking water supplies to infer
exposure in large populations; however, a single residential estimate
of 1,4-dioxane in water is subject to exposure misclassification depend-
ing on an individual's consumption of water sourced from locations
other than home, e.g., from work or bottled water. Exposure misclassifi-
cation can be reduced by using biological samples to assess 1,4-dioxane
exposure. Unfortunately, the low sensitivity of current analytical tech-
niques for biomonitoring 1,4-dioxane inhibits exposure assessment in
the general population. Only through the development of new, more
sensitive detection methods will meaningful epidemiological studies
be possible in humans.
7. Remediation methods
The unique physical and chemical characteristics of 1,4-dioxane
present challenges in remediation from contaminated groundwater
(Stepien et al. 2014). 1,4-dioxane favors partitioning into the aqueous
phase where it is completely miscible, rendering common physical sep-
aration techniques, such as air stripping or adsorption by activated car-
bon, unsuitable. Removal by membrane filtration is also ineffective;
even reverse osmosis fails to reach higher than 70% rejection due to its
small size and neutrality (Kegel et al. 2010; Linares et al. 2011). These
physical removal processes, even if they are effective, simply transfer
1,4-dioxane from one phase to another, wherein it is more concentrated
and requires subsequent treatment. Abiotic and biotic oxidation that
mineralizes or otherwise partially degrades 1,4-dioxane to fewer toxic
products are desired. These remediation strategies of contaminated
groundwater are discussed in this section.
7.1. Abiotic advanced oxidation
1,4-Dioxane degradation by conventional oxidants such as chlorine
is not effective (Klečka and Gonsior 1986; Li et al. 2018) and can lead
to the formation of the chlorinated byproducts that are more toxic
than the parent 1,4-dioxane (Li et al. 2018; Woo et al. 1980). Alterna-
tively, past studies have demonstrated mineralization of 1,4-dioxane
by reactive radicals such as hydroxyl (•OH) and sulfate radicals
(SO4•−) in advanced oxidation processes (Fig. 4) (Campos-Martin
862 K.J. Godri Pollitt et al. / Science of the Total Environment 690 (2019) 853–866

Fig. 4. Pathways of abiotic advanced oxidation processes (adapted from Zhang et al. 2017). Compounds shown in a dotted box are biodegradable intermediates.

et al. 2006; Wacławek et al. 2017). However, practical implantation re-
quires effective pretreatment that removes other water constituents
such as natural organic matter which can reduce the efficiency of 1,4-di-
oxane degradation by scavenging radicals. Engineering advanced oxida-
tion is also complicated by several challenges, including the need for
continual dosing of precursor chemicals and provision of high energy
(e.g., heat or ultraviolet (UV) irradiation), since short-lived radicals
need to be generated in situ by “activating” stable precursor oxidants
such as ozone (O3), hydrogen peroxide (H2O2), and persulfate (HSO− 5 tions, such as electrochemical treatment with membrane filtration or
and S2O2− 8 ) (Barndõk et al. 2014; Coleman et al. 2007; Feng et al.
2017; Lee et al. 2015; Son et al. 2009; Zhong et al. 2015). The lack of a
facile method to quantify trace levels of 1,4-dioxane also makes it diffi-
cult for advanced oxidation process to be responsive to spatial and tem-
poral variations in water quality (See Section 5.1: Environmental
Samples).
Alternative oxidative treatments continue to emerge but with both
longstanding and novel technical barriers to overcome. Direct oxidation
of 1,4-dioxane at the anode of an electrochemical cell has been shown to
proceed under conditions of low conductivity which may be relevant to
groundwater. However, a lack of selectivity (which can lead to the for-
mation of toxic halogenated byproducts in the presence of chloride)
and the high cost of typical boron-doped diamond electrodes (com-
monly used in such electrochemical cells) remain unresolved obstacles
(Choi et al. 2010; Jasmann et al. 2016). Photocatalytic advanced oxida-
tion processes in a slurry reactor coupled with membrane filtration
are also appealing options due to effectiveness in completely degrading
1,4-dioxane. However, the high energy consumption to provide light
(often UV) and pressure for membrane filtration requires careful cost
analysis (Hwangbo et al. 2019). The integration of diverse unit opera-
ozonation, have yielded promising results that warrant further investi-
gation (Kishimoto et al. 2008; Mameda et al. 2017).
7.2. Bioremediation
Biological degradation of 1,4-dioxane has been explored as an al-
ternative approach to remediate contaminated water. As described
in Section 2.3: Environmental Fate, select bacterial and fungal strains
are capable of degrading 1,4-dioxane through metabolic and co-
metabolic pathways under aerobic conditions (Gedalanga et al.
2014; Lan et al. 2013; Mahendra and Alvarez-Cohen 2006; Zhang
et al. 2017). Field testing at contaminated sites has shown the
 K.J. Godri Pollitt et al. / Science of the Total Environment 690 (2019) 853–866
promise of bioremediation under specific conditions (e.g., the pres-
ence of nutrients and dissolved oxygen), while the inhibitory effects
of certain metals and chlorinated solvents are limiting factors (Shen
et al. 2008; Zhang et al. 2017). Further enhancement of 1,4-dioxane
removal efficiency has been achieved through a bioaugmented ap-
proach wherein 1,4-dioxane-degrading bacterial strains are grown
on granular activated carbon adsorbents (Myers et al. 2018). Field in-
vestigations evaluating the feasibility and utility of these
bioaugmented adsorbents for surface groundwater remediation are
still necessary. While biological degradation can be a viable option
for site remediation, slow degradation kinetics is likely to limit its
application for potable water treatment (Li et al. 2010).
8. Implications for further studies
1,4-Dioxane contamination in groundwater illustrates key scientific
and policy challenges that can occur with emerging contaminants. A
current lack of scientific consensus on low dose health effects of 1,4-di-
oxane has inhibited the establishment of enforceable federal standards
on safe drinking water targets. Consequently, major gaps remain in
water testing, exposure assessment, and effective treatment. Millions
of drinking water consumers in the U.S. are estimated to be ingesting
1,4-dioxane at levels that confer an elevated cancer risk. While current
research provides an indication of the health risks and informs policy
options, there are major scientific gaps that need to be filled to improve
health protection from this contaminant.
1. Research to establish drinking water targets. The variations in
state guidance values for 1,4-dioxane in water demonstrates the
lack of consensus on the methodology to derive a health-based tar-
get. The major discrepancy in these guidance values is rooted in the
poor understanding of the 1,4-dioxane cancer mechanism and how
to apply the high dose animal data to risk associated with chronic ex-
posure to low, environmentally-relevant levels. Early theories that
1,4-dioxane was a completely non-genotoxic agent, causing liver
cancer only at high cytotoxic doses, appear to have less credibility
today in light of the evidence for in vivo genotoxicity and carcinoge-
nicity at moderate, non-cytotoxic doses (Gi et al. 2018; Kano et al.
2009). Given the lack of in vitro mutagenicity of 1,4-dioxane (or its
metabolites), alternative hypotheses need to be examined. Thus, re-
search has focused on how 1,4-dioxane produces genetic damage
in vivo but not in vitro (Morita and Hayashi 1998). Inhibition of
DNA repair is a plausible hypothesis given that one difference be-
tween in vivo and in vitro systems is the greater likelihood of back-
ground DNA damage in need of repair in vivo. Inhibition of DNA
repair could have promotional and co-carcinogenic effects rather
than initiating activity which fits with the experimental evidence re-
lating to 1,4-dioxane. Future studies should examine this and other
mechanisms for genotoxic effects that do not involve direct interac-
tion with DNA, such as topoisomerase II inhibition. Sensitive
transcriptomic, metabolomic and stem cell studies are needed to un-
derstand 1,4-dioxane-induced early effects in the liver that can lead
to genotoxicity and carcinogenesis.
2. Research to understand 1,4-dioxane exposure and effects in
human populations. Sufficiently powered epidemiology studies in-
vestigating the general population have yet to be conducted. Such
studies would be enhanced by the development of sensitive bio-
markers of exposure and effect. These could examine the relative
contribution of exposures to 1,4-dioxane in food and consumer prod-
ucts as well as contaminated water supplies. Transcriptomic and
metabolomic indicators of perturbation uncovered in animal testing
could potentially be used in epidemiology studies. Such studies are
urgently needed to better understand human exposure and the pub-
lic health implications of 1,4-dioxane exposure.
3. Research to develop rapid, in situ detection of 1,4-dioxane. Detec-
tion of 1,4-dioxane on-site and in real-time is critical given the
863
spatially dispersed nature of private wells, the potential for changing
water supply characteristics, such as groundwater levels and plume
movement. Research to improve detection capabilities will involve
the development of highly selective binding and sensing compo-
nents and will require field testing under various scenarios.
4. Research to improve 1,4-dioxane treatment. Advanced oxidation
processes are the promising option for centralized large-scale treat-
ment of drinking water which is distributed to consumers through
a network of water distribution pipes. However, application for a
decentralized treatment such as smaller public supplies and point-
of-use household treatment is challenging. Considering the prevalent
contamination in groundwater that serves as a source for drinking
water in many contaminated sites, advancing advanced oxidation
process technologies for smaller, modular applications are needed.
Immediate research needs include (i) making smaller advanced oxi-
dation process systems cost efficient, (ii) better control of reaction
oxidation byproducts, and (iii) effectively integrating with other
treatment options to enhance the efficiency of advanced oxidation
process (e.g., pretreatment to remove organic matter that reduce
the treatment efficiency).
5. Research to investigate co-occurring exposures. Past epidemio-
logic study results may have been confounded by exposure of
human subjects to other solvents (and/or other risk factors) since
few studies isolated exposure to common co-occurring 1,4-dioxane
contaminants, such as TCE or 1,1,1-TCA. Therefore, it is important
to consider co-contaminants when studying 1,4-dioxane.
Successful completion of these research activities will address the
key questions still outstanding for 1,4-dioxane as an environmental
contaminant, and enable improvements in community engagement
and public health protection
9. Suggestions for community engagement and preparedness
Engagement with communities about 1,4-dioxane in the water sup-
ply will uncover a multitude of concerns. Likely areas of concern include
proximity of 1,4-dioxane sources to drinking water supplies, responsi-
ble parties, health effects, regulatory levels in water, vulnerable popula-
tions, availability and sufficiency of current treatment systems, and
recommendations for medical screening and for lowering health risks
in the future. Addressing these concerns requires the participation of
numerous stakeholders and agencies involved in environmental inves-
tigation, risk assessment, and site remediation processes, and who com-
monly span local, state, and federal levels.
Identifying and responding to community concerns about 1,4-diox-
ane in an open and transparent way is essential for meaningful engage-
ment and broad participation as remedial options are evaluated and site
decisions are made. Technical information regarding the potential
health risks associated with 1,4-dioxane exposure (e.g., liver cancer)
must be distilled into clear messages that can be understood by all com-
munity members. It is also essential to inform the public that (i) health
risks are multifactorial processes, and (ii) 1,4-dioxane exposure is only
one of potentially many environmental risk factors associated with po-
tential adverse health outcomes. Community members should be made
aware that there are modifiable lifestyle factors that can affect these
health risks, and that are within their control. Action at the individual
stakeholder level can complement the short- and long-term solutions
developed by responsible parties and governmental agencies to the
contamination issue.
Situations involving emerging drinking water contaminants, such as
1,4-dioxane, require intensive and sustained community engagement,
with opportunities for stakeholders to participate in the continuum of
effort from investigation through remediation. Providing unfettered ac-
cess to site-related and health information, and various platforms to un-
derstand the health risks, uncertainties and options for moving towards
solutions allows impacted communities to actively participate in the
864 K.J. Godri Pollitt et al. / Science of the Total Environment 690 (2019) 853–866
process and following precautionary principles. Further, it is important
for researchers to recognize the key role that community members
can play in advocating for the interests of those most impacted, holding
local, state and federal agencies accountable, and supporting the devel-
opment and adoption of science-based remedies.
Funding
This research did not receive any specific grant from funding agen-
cies in the public, commercial, or not-for-profit sectors.
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