Transcript 1,4-Dioxane: Contamination in Water and an Assessment of Regulations Andrew Evans, Ryan Silvers and Antonio F.

1,4-Dioxane: Contamination in Water and an Assessment of
Regulations
Andrew Evans, Ryan Silvers and Antonio F. Machado
Dept. of Environmental and Occupational Health, California State University, Northridge
Abstract
Fate and Transport
Levels in Environment & Drinking Water
1,4-Dioxane is a synthetic industrial chemical that is
completely miscible in water. Due to this miscibility, it
easily leaches from soil into groundwater where it is
highly mobile and resistant to biodegradation. Its
transport into drinking water supplies is of utmost
concern as it has been classified by the EPA as
“Likely to be carcinogenic in humans.” In this literature
review, we evaluated the current body of scientific
research to investigate whether Federal and State
drinking water regulations for 1,4-Dioxane
appropriately reflect the current understanding of the
risks associated with human exposure.
Introduction
1,4-Dioxane is commonly referred to as just Dioxane
because its isomers are rare. It is a cyclic diether with
polar properties. Dioxane is a manufactured chemical
that does not occur naturally in the environment. It has
been utilized since the early 1950s.
It is used in the industrial production of consumer
products like soap, polyester, plastics, as a stabilizer
for chlorinated solvents, and as a solvent in the
production of paper, electronics, pharmaceuticals,
paint stripers, dyes, and degreasers.¹
If drinking water is contaminated with 1,4-Dioxane atypical filtration methods are often necessary since it
is difficult to separate out of water.
When Dioxane does accumulate to dangerously high
levels in the body, it has been known to cause liver
and kidney necrosis and it induces nasal and hepatic
tumors in rats.
However, according to the Ames test and the primary
hepatocyte DNA repair assay, Dioxane is not
mutagenic.
Chemical Structures
β-hydroxyethoxyacetic
acid
(Primary Metabolite)
1,4-Dioxane
Production and Use
-1,4-Dioxane is manufactured commercially by the
acid catalyzed dehydration and ring closure of
diethylene glycol.²
-1,4-Dioxane is used as a solvent for chemical
processing, and as a reagent in the formation of
plastics, rubber, insecticides, and herbicides. It can be
found as an impurity in cosmetics, household and
industrial detergents, and pharmaceuticals as a byproduct in ethoxylated emulsifiers.²
-1,4-Dioxane may be found in commercial products
containing one of the following ingredients.²
PEG
Polyethylene
Polyoxyethylene
Polyethylene
glycol
-eth
-oxynol
Remediation
Standard wastewater treatment methods and
conventional activated sludge methods have proven
ineffective. Air-stripping and granular activated
charcoal do not remove 1,4-Dioxane from water.³
It is important to note, that some bacterial strains have
a high ability to degrade 1,4-Dioxane as a sole carbon
and energy source.
The chemical properties of Dioxane cause it have high mobility
and persistence because it’s very polar and has no functional
groups that would react with nearby molecules, that’s why it
doesn't biodegrade.
For example, with a Henry’s law constant under 5, volatilization of
Dioxane from water is relatively slow. The low Octanol to water
coefficient (-0.27) leads to enhanced mobility in soil and leaching
into groundwater.⁵
These results demonstrate that neither bank filtration nor activated
carbon effectively capture and significantly remove 1,4-Dioxane
from the water. However, the removal of 1,4-Dioxane is
achievable through certain processes. For example, advanced
oxidation processes (AOP) like Ozone.⁵
The California Department of Public Health (CDPH) has
a drinking water notification level (NL) of 1.0 micrograms per liter (μg/L).³
166 of 168 concentrations that exceeded the NL of 1 μg/L were in Los
Angeles and Orange county public groundwater sources.³ It is not
uncommon for rural residents and farmers in Los Angeles to tap the
groundwater table for drinking water and irrigating crops. Since 1,4-dioxane
can bioaccumulate in plant matter, there is a potential for consumers who eat
crops irrigated with contaminated water to ingest 1,4-dioxane.
It is estimated that over a million pounds of Dioxane were released to the
environment in the mid 90’s. The presence of 1,4-Dioxane in the
environment is thought to be related to the disposal of chemical solvents
containing Dioxane and from disposal of Dioxane itself. Since 1,4-Dioxane is
highly mobile in soils subsequent leaching of the chemicals from
landfills has resulted in contamination of groundwater.³
Due to its persistence and minimal biodegradability, industries that
discharge Dioxane in solvents should utilize a stripping technique
to decrease the amount of Dioxane in their effluent.⁵
1,4‐Dioxane is expected to have bioavailability since it binds very
weakly to organic matter. 1,4‐Dioxane is expected to evaporate
from dry soil but little to no evaporation from wet soil and saturated
river banks will occur.⁶
Metabolism
Landfill
C4H8O2
Water well
1,4 dioxane leachate
Groundwater
Carcinogenicity
-In terms of water contamination, the principle route of exposure to
-Several chronic oral toxicity studies in rodents have resulted in tumor
1,4-Dioxane is oral absorption. No human data exists evaluating the
efficiency of oral absorption. However, absorption following ingestion
in animal models is rapid and virtually complete.⁷
formation in the kidneys, liver, and nasal mucosa. However, a mechanism
of action for how 1,4-Dioxane induces tumors is still under investigation.
-No data exists evaluating metabolism in humans. However, 1,4Dioxane is widely distributed and rapidly metabolized in animals.
Studies in rats have shown that metabolism is performed efficiently by
Cytochrome P450 enzymes (CYP2B1/2 and CYP2E1). Furthermore,
this metabolism is inducible by
phenobarbitol administration,
fasting, and high doses of
1,4-Dioxane itself.⁸
-β-hydroxyethoxyacetic acid
(HEAA) is the primary
metabolite, which is rapidly
excreted in urine.⁸
-1,4-Dioxane is not genotoxic or mutagenic as it does not cause point
mutations, DNA repair, or tumor initiation. However, it appears to promote
tumors and stimulate DNA synthesis.¹¹
-Induction of 1,4-Dioxane metabolism by administration of phenobarbital
or fasting failed to increase liver toxicity. Therefore, toxicity and tumor
formation most likely result from 1,4-Dioxane itself
rather than HEAA or an unknown metabolite.⁸
-Despite extensive metabolism, a saturation
threshold exists which is toxicologically
relevant.1,4-Dioxane doses yielding plasma
concentrations below 30-100 µg/ml in animals are
rapidly and efficiently detoxified by Cytochrome
P450 enzymes with little to no toxicological effects.
This is evidenced by multiple chronic low dose
animal studies resulting in no observed toxicity. At
plasma concentrations higher than 100 µg/ml, the
metabolizing capacity is exceeded with proportional
increases in toxicological manifestations.¹¹ ¹² ¹³
-No data exists evaluating
elimination of 1,4-Dioxane in
humans following oral
absorption. However, exposure
to an inhalation time weighted
average (TWA) of 1.6 ppm 1,4-Dioxane for 7.5 hours in human
volunteers resulted in HEAA and 1,4-Dioxane concentrations in urine
at a ratio of 118:1. A follow up study showed an elimination half-life of
59 minutes in adult males exposed to 50 ppm 1,4-Dioxane for 6 hours.
These findings suggest that 1,4-Dioxane is rapidly metabolized and
eliminated in humans.⁹ ¹º
-Dourson et al. (2014) developed a mechanism of
action to explain 1,4-Dioxane liver tumor production
which involves induced cytotoxicity followed by regenerative cell
proliferation and stimulation of endogenously mutated DNA to form
tumors. The specific key events of this mode of action are: (1) Saturation
of metabolism and accumulation of the parent compound, (2) Cell
hypertrophy and necrosis, (3) DNA synthesis, (4) Regenerative cell
proliferation, and (5) Promotion of endogenously-initiated tumors.¹¹
Non-Cancer Health Effects
Analysis of Regulations/Conclusions
-Liver and kidney toxicity are the primary non-cancer health effects
observed in subchronic and chronic oral exposure studies in animals.
Liver toxicity included hepatocellular degeneration, necrosis, and preneoplastic changes. Kidney toxicity included degeneration of the
cortical tubule cells, necrosis with hemorrhage, and
glomerulonephritis. The EPA derived a reference dose (RfD) of .03
mg/kg/day based on liver and kidney toxicity in rats exposed to 1,4Dioxane in drinking water for 2 years.¹² ¹³ ¹⁴
-No federal maximum contaminant level (MCL) exists for 1,4-dioxane in
drinking water, however, an MCL is not necessary for the determination of
clean up and action levels.¹⁴ Massachusetts, Connecticut, and Florida all
have action levels of 3 µg/L. California has a drinking water notification
level of 1 μg/L, and a source removal standard of 35 μg/L.
-In chronic inhalation studies conducted in rats, nasal and liver toxicity
were the primary non-cancer health effects. Nasal toxicity included
degeneration of nasal tissue and pre-neoplastic cell proliferation,
while liver toxicity included necrosis of the centrilobular region and
pre-neoplastic changes as well. The EPA derived a reference
concentration (RfC) of .03 mg/m³ based on co-critical effects of
olfactory epithelium atrophy and respiratory metaplasia in rats
exposed for 2 years via inhalation.¹ ¹⁴
-Based on an EPA RfD of .03 mg/kg/day¹⁴, an average body weight of
70kg, an average drinking water intake of 2L per day, and a relative
source contribution of 20% from drinking water¹¹, we calculated a
Maximum Contaminant Level Goal (MCLG) of 210 μg/L 1,4-Dioxane. This
MCLG sufficiently protects against cancer and non-cancer toxicity in
humans based on the current body of scientific research.
-Human environmental exposures to 1,4-Dioxane occurring via water
contamination are unlikely to approach doses that saturate metabolizing
enzymes and which produce the observed liver and nasal toxicity and
tumors in rodent studies. Therefore, the current state notification and
action levels previously mentioned are sufficiently effective from a public
health standpoint. However, the potential for higher public exposures exist
due to industrial and commercial groundwater contamination. Therefore,
continuous sampling and analysis of drinking water remains warranted.
-The developmental effects of 1,4-Dioxane on pregnant rats were
investigated by Giavini et al. Only the highest dose (1,000 mg/kg/day)
had an effect, reducing maternal weight gain by 10% and reducing
In one study, four different strains were able to tolerate fetal birth weight by 5%. No change was observed over controls in the
a range of pH concentrations, incubation temperatures, number of implantations, live fetuses, resorptions, or malformations.¹⁵
-Future toxicological studies should investigate more subtle non-cancer
and NaCl concentration.⁴ This is significant because it
-Neurological effects of acute high-dose exposure in animals included endpoints, such as gene expression and immunological effects, to identify
suggests that all four strains could degrade 1,4potential long term epigenetic changes due to 1,4-Dioxane exposure.
staggered gait, narcosis, paralysis, coma, and death.¹⁴
Dioxane under relatively wide ranging conditions,
implying that the strains are adaptable and may be
References
used for industrial wastewater treatment.
(1) Kasai T, Kano H, Umeda Y, Sasaki T, Ikawa N, Nishizawa T, et al. 2009. Two-year inhalation study of carcinogenicity and chronic toxicity of 1,4-dioxane in male rats. Inhalation Toxicology 21:889-897.(
In addition to biologics, some types of chemical
treatment are highly effective in removing 1,4-Dioxane
from water. Advanced oxidation processes, which use
peroxide and UV-light or ozone, have been shown to
destroy 1,4-Dioxane.³
(2) ATSDR (Agency for Toxic Substances and Disease Registry). (2012) Toxicological profile for 1,4-Dioxane. Atlanta, GA: U.S. Department of Health and Human Services, Public Health Service.
(3) GAMA Program, Division of Water Quality. "1,4-Dioxane." Cold Spring Harbor Protocols 2006.11 (2006): Pdb.caut345. Waterboards.ca.gov. State Water Resources Control Board, 13 May 2014. Web. 05 Dec. 2014.
(4) Sei, Kazunari, Keiko Miyagaki, Takashi Kakinoki, Kunihiro Fukugasako, Daisuke Inoue, and Michihiko Ike. "Isolation and Characterization of Bacterial Strains That Have High Ability to Degrade 1,4-dioxane as a Sole Carbon and
Energy Source." Biodegradation 24.5 (2013): 665-74. Web. 06 Nov. 2014.
(5) Stepien, Daria K; Diehl b, Peter; Helm, Johanna; Alina Thoms,Puttmann, Wilhelm; Fate of 1,4-dioxane in the aquatic environment:From sewage to drinking water Water Research 4 8 ( 2 0 1 4 ) 4 0 6 - 4 1 9
(6) Sorenson, Heather. "1,4-Dioxane and the Application of Phytoremediation at North Carolina Hazardous Waste Groundwater Contaminated Sites." North Carolina State University (2013): 1-45. Web. 11 Nov. 2014.
(7) Young, JD; Braun, WH; Gehring, PJ. (1978a). The dose-dependent fate of 1,4-Dioxane in rats. J Environ Pathol Toxicol 2: 263-282.
(8) Nannelli A, De Rubertis A, Longo V, Gervasi PG. 2005. Effects of dioxane on cytochrome p450 enzymes in liver, kidney, lung and nasal mucosa of rat. Arch Toxicol 79:74-82.
(9) Young, JD; Braun, WH; Gehring, PJ; Horvath, BS; Daniel, RL. (1976). 1,4-Dioxane and beta-hydroxyethoxyacetic acid excretion in urine of humans exposed to dioxane vapors. Toxicol Appl Pharmacol 38: 643-646.
(10) Young, JD; Braun, WH; Rampy, LW; Chenoweth, MB; Blau, GE. (1977). Pharmacokinetics of 1,4-Dioxane in humans. J Toxicol Environ Health 3: 507-520.
(11) Dourson M, Reichard J, Nance P, Burleigh-Flayer H, Parker A, Vincent M, et al. 2014. Mode of action analysis for liver tumors from oral 1,4-dioxane exposures and evidence-based dose response assessment. Regulatory
Toxicology and Pharmacology 68:387-401.
(12) Kociba, RJ; McCollister, SB; Park, C; Torkelson, TR; Gehring, PJ. (1974). Results of a 2 year ingestion study of 1,4-Dioxane in rats. Toxicol Appl Pharmacol 30: 275-286.
(13) Kano H, Umeda Y, Saito M, Senoh H, Ohbayashi H, Aiso S, et al. 2008. Thirteen-week oral toxicity of 1,4-dioxane in rats and mice. The Journal of Toxicological Sciences 33:141-153.
(14) U.S. EPA. IRIS Toxicological Review of 1,4-Dioxane. U.S. Environmental Protection Agency, Washington, DC, EPA/635/R11/003A, 2013.
(15) Giavini, E; Vismara, C; Broccia, ML. (1985). Teratogenesis study of dioxane in rats. Toxicol Lett 26: 85-88.