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Liter-Equivalence Extrapolation for Four Trihalomethanes (THMs):
What Drink Would It Take to Get the Same Internal Dose?
C.R. Eklund, E.M. Kenyon, R.A. Pegram, J.E. Simmons U. S. EPA, ORD, RTP, NC 27711
Background
Disinfection byproducts (DBPs) are formed when oxidizing
disinfectants react with inorganic and organic matter in water.
EPA regulates 4 trihalomethane (THM) DBPs in drinking water:
chloroform (TCM), bromodichloromethane (BDCM), dibromo-
chloromethane (DBCM), and bromoform (TBM) as a group.
Environmental exposure studies and physiologically based
pharmacokinetic (PBPK) model analyses demonstrate that,
compared to oral exposure, dermal and inhalation exposure to
water containing BDCM results in more BDCM being delivered to
the systemic circulation and thus available for biotransformation in
extra hepatic tissues.
Recent epidemiology findings indicate an association between
exposure to disinfected tap water and bladder cancer.
Mechanistic data suggest target tissue metabolism via the
glutathione pathway is likely to be important for some types of
BDCM-induced toxicity, including carcinogenicity. Thus, systemic
circulating dose is an important determinant of potential adverse
effects in extra-hepatic target tissues such as the urinary bladder.
Objective & Approach
Use liter equivalency analysis to evaluate the impact of route of
exposure: oral vs. inhalation and dermal (via bathing or showering)
on two measures of internal dose - area under the curve in venous
blood (AUCv) and amount metabolized in liver. We simulated
showering for 10 minutes or bathing for 20 with water containing 8.2,
12.2, 13.5, and 8.7 pg/LforTCM, BDCM, DBCM and TBM,
respectively. These are measured drinking water concentrations from
a system with predominantly brominated species of THMs (Gulf
coast TX, Lynberg et al., 2001).
What is Liter Equivalency?
The concentration (jjg/L) of each THM required to be
consumed orally in one liter of water to achieve the same
values for specific internal dose measures when showering
or bathing under particular exposure scenarios.
U.S. Environmental Protection Agency
Office of Research and Development
THM PBPK Model
¦hdf
Lung
Skin
Kidney
RPTG
SPTG
Fat
Liver
Gl Tract *
K' i	f
metabolism
Blue arrows are routes of exposure.
Kf refers to glutathione metabolism
pathway, active for brominated, but not
chlorinated, THMs. Vmax and Km refer to
oxidative (CYP) metabolic pathway.
RPTG and SPTG are rapidly and slowly
perfused tissue groups, respectively.
Model Parameters
Model structure, assumptions and
physiological parameters are the same as
the published BDCM model (Kenyon et al.,
2016), repeated for each of the THMs.
Partition coefficients and metabolism
parameters are matched for species source
(rodent vs. human) to avoid mis-
interpretation when comparing THMs.
Blood:air partition coefficients were derived
from humans and were divided by rodent
tissue:air partition coefficients to calculate
tissue: blood partition coefficients.
Metabolism parameters for the oxidative
pathway were derived from rodent studies.
Liter Equivalency - Showering & Bathing
Shower - AUCv
Shower - Amount Metabolized in Liver
0
05
>
3
O"
HI
50.0
45.0
40.0
35.0
30.0
25.0
20.0
15.0
10.0
5.0
0.0
V 1.5
BDCM DBCM TBM
¦ Dermal ¦ Inhalation
Bath - AUCv
I
TCM
BDCM DBCM TBM	TCM
¦ Dermal ¦ Inhalation
Bath - Amount Metabolized in Liver
g>i2o
15 20
> 3
BDCM DBCM TBM
¦ Dermal ¦ Inhalation
I
TCM
BDCM DBCM	TBM
¦ Dermal ¦ Inhalation
I
TCM
Liter Equivalency Analysis - ingested water concentration (assuming 1 liter of water consumed) required to produce the same value for the
dose metrics, area under curve in venous blood (AUCv) and amount metabolized in liver for 4 THMs resulting from a 10 minute shower or
20 minute bath with water containing 8.2, 12.2, 13.5, and 8.7 pg/L for TCM, BDCM, DBCM and TBM, respectively. The individual
contributions of inhalation and dermal routes of exposure are represented as stacked bars.
Progress for a Stronger Future
Chris Eklund
Summary and Future Work
This analysis suggests a large contribution for dermal and inhalation exposure
routes during showering or bathing to internal dose of all THMs reaching the
systemic circulation (AUCv).
Dermal uptake was relatively greater compared to inhalation uptake for both AUCv
and amount metabolized in liver following showering and bathing (TCM < BDCM <
DBCM < TBM), reflecting decreasing volatility across chemicals which results in
lower air concentrations.
The contribution of inhalation exposure was relatively greater during showering
compared to bathing because of greater volatilization during showering compared
to bathing.
Consideration of multiple routes of exposure when evaluating risks from water-
borne THMs provides for a comprehensive basis to assess human health risk.
Future work will focus on
•	Target tissue biotransformation (bladder) to eventually evaluate metabolic
interactions
•	Impact of variability in physiological parameters on measures of internal
dose
•	Monte Carlo analysis (using input water concentrations) to assess impact
of variability in water concentrations on measures of internal dose
Disclaimer: This work is part of EPA's Strategic Research Action Plan, Safe and Sustainable
Water Resources (SSWR) 6.01 D. The views expressed in this poster are those of the authors
and do not necessarily represent the views or the policies of the U.S. Environmental
Protection Agency. Any mention of trade names, manufacturers or products does not imply an
endorsement by the United States Government or the U.S. Environmental Protection Agency.


The Methodology |



TCM BDCM DBCM TBM
8.2 12.2 13.5 8.7 |jg /L



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1. Run model for 10-minute shower
Vb or 20 minute bath.
Dermal, Inhalation Exposures
2. Determine dose menrics 3.
• AUC for venous blood _
* • Amount metabolized in liver. ""
"Bootstrap" the model to determine Liter Equivalent ('!
needed to reach these dose metrics. gt~]
Oral exoosure y
concentration required in 1 liter of water.
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