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Master: Uncertainty in Exposure and Health-Risk Assessment: An Integrated Approach
Master: Uncertainty in Exposure and Health-Risk Assessment: An Integrated Approach
UCRL- 102225
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Thomas E. McKone
and
Kenneth T. Bogen
May 1990
MASTER vh
DISCLAIMER
D IS C L A IM E R
UCRL—102225
DE90 012988
Thomas E. McKone
and
Kenneth T. Bogen
INTRODUCTION
One can represent the average individual risk within a population exposed to
an environmental contaminant as resulting from a source term; the exposure
function, which converts the source into a lifetime equivalent contact per
individual; the fraction of contaminant delivered to the organism after contact; and
the toxic potency associated with the delivered dose. In actual practice, the process of
estimating exposure and risk can be more complex and include temporal and/or
spatial relations and functional dependencies among the source, exposure, dose, and
the incidence of detriment. If we view risk as the simple product of exposure and
potency, then uncertainty in risk can be evaluated by assessing separately the
uncertainty in each term. However, as we move to the use of physiologically based
pharmacokinetic models and biologically based dose-response models where health
detriment is not always a linear function of exposure, the impact of exposure
uncertainties will become harder to quantify and more difficult to dismiss. Using a
case study for contamination of ground water with tetrachloroethylene (PCE), we
characterize here the uncertainty in human exposure models and the combined
uncertainty in exposure and dose-response models. In characterizing uncertainty in
exposure models, we address three key issues: (1) uncertainty in predicting the
relation between sources of contaminants and concentrations in the accessible
environment; (2) uncertainty in quantifying pathway exposure factors that relate
environmental concentrations to levels of exposure; and (3) the important
contributions to the combined uncertainty in environmental dispersion and
pathway exposure factors.
The goal of this paper is to consider a strategy for evaluating and reducing
sources of uncertainty in predictive exposure and health-risk assessments. We focus
on the volatile organic chemical tetrachloroethylene in California water systems
derived from ground water. We divide our analysis into five steps. First, we
consider the magnitude and variability of PCE concentrations available in large
public water supplies in California. Second, we characterize pathway exposure
factors (PEFs) for ground water exposures and estimate uncertainty for each PEE.
Third, we consider models describing uptake and metabolism to estimate the
relation between exposure and metabolized dose. Fourth, we consider the
carcinogenic potency of the metabolized PCE dose. Finally, we combine the results
to estimate the overall magnitude and uncertainty of individual risk within the
exposed population.
WATER-SUPPLY CONCENTRATIONS
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public-water supply systems with at least one well in which PCE contamination had
been detected. These data have a number of limitations including (a) incomplete
sampling data (even though all large water systems in California were sampled,
only a limited number of wells in each system were sampled), (b) lack of
information on the fraction of the_t&t3l system -supply provided by any single well,
(c) limited data on how concentrations vary with time, and (d) no information on
the relation between concentrations in individual wells and concentrations in the
water supply lines for individual households.
CR: C; EE x ED ^
:di = x —x---------- x C, = PEF(k—d) x Ck
BW a AT (1)
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C; EF x ED
PEF(k-»i) = CR, x —L x ———
-BW-
Ck AT (2)
where [CRj/BW] is the contact rate per unit body weight such as kg(soil)/kg-d,
L(milk)/kg-d, or m3(air)/kg-d; Cj/Ck is the ratio of concentration in the "contact"
medium i (i.ev air, tap water, milk, soil, etc.) to the concentration in environmental
medium k (air, water, soil), units depend on the two media; EF is the exposure
frequency, days per year; ED is the exposure duration, years; AT is the averaging
time, days; and PEF(k->i) is the pathway exposure factor relating the concentration
Ck in medium k to the chronic daily intake, mg/kg-d, during the period ED.
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We calculate the mean and standard deviation of the PEF for ingestion of
ground water using intake per unit body -weight, Iw/BW in L/kg-d, averaged rr/er a
lifetime.
For this pathway the exposure route is ingestion, the source medium and the
contact medium are ground water, the contact rate is the water intake per unit body
weight in L/kg-d, the exposure frequency is 365 d/y, the exposure duration is 70 y,
and the averaging time is 25,550 d.
We used data compiled by the ICRP4 and the EPA5 to calculate, as a function
of age, fluid intake on a per-unit-body weight basis. The standard deviation in this
ratio is estimated by calculating the variance in this ratio under the assumption that
fluid intake scales with body weight to the two-thirds power.
(5)
where g2(iw/bw) the variance in the ratio of fluid intake to body weight; BW is
the body weight, kg; cj2iw is the variance in the fluid intake; (J2byv t^ie variance in
body weight; and 0(iw/bw) is the covariance between breathing rate and body
weight. We estimate the distribution of lifetime average fluid intake per unit body
weight to be a lognormal distribution with an arithmetic mean and arithmetic
standard deviation of 0.034 and 0.013 L/kg-d as summarized in Table I.
For this pathway the exposure route is inhalation, the source medium is
water, the contact medium is indoor air, the contact rate is the breathing rate per
unit body weight, the exposure frequency is 365 d/y, the exposure duration is 70 y,
and the averaging time is 25,550 d. Efforts to assess human exposure to
contaminated tap water have revealed that significant exposures to volatile organic
compounds (VOCs) can occur from pathways other than ingestion. A review by
McKone6 indicates that exposure to volatile chemicals in tap water by inhalation
may be as large or larger than exposure from fluid ingestion. The contaminants
available in the indoor air are mobilized by showers, baths, toilets, dishwashers,
washing machines, and cooking. McKone6 has developed a model that describes the
daily concentration histories of volatile compounds within various compartments
of the indoor air environment as a result of home water use.
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Table I. Types of distributions and distribution moments used for the input
parameters.
Shower duration,
0.13 .085
r-H
oq
Lognormal
ETS in h/d
Arithmetic
Minimum Maximum
mean
Exposure time in the house, 14
Uniform 8 20
ETh in h/h
Skin permeability,
Uniform 0.004 0.01 0.007
PC in m/h
*
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Table I. Type of distributions and distribution moments used for the input
parameters (continued).
Arithmetic
Parameter description Distribution type Minimum Maximum
mean
Fraction of skin exposed during Uniform 0.4 0.9 0.65
showering and bathing, fsa
The results of this model provide a basis for calculating the pathway exposure factor
that can be used to estimate the inhalation exposure attributable to the contaminant
concentration Cw (in mg/L) in tap water. This model divides the indoor-air volume
into three compartments—the shower/bath stall, the bathroom, and the household
volume. Concentrations within these compartments are dependent on chemical
mass transfers from water to air, compartment volumes, and air-exchange rates.
Using measured mass-transfer efficiencies from water to air for radon, McKone5 6 has
estimated the typical or "reference" average concentrations of a chemical having the
mass transfer efficiency of radon. For chemicals other than radon, McKone6 has
shown that the transfer efficiency is given by
,-2/3
2.0 x 106(m2/s)
^x “ ^Rn x T
r zs ^ RT
___
-
fN
H x D2/3
D
(5)
l
where (j)x is the mass transfer efficiency of contaminant x from water to air; (j)Rn is
the mass transfer efficiency of radon from water to air; is the contaminant
diffusion coefficient in water, m2/s; Da is the contaminant diffusion coefficient in
air, m2/s; R is ihe universal gas constant, torr-L/mol-k; T is the temperature, in k J. few 1^4 iL^AwL A.9 A .C
kelvins; and H is the Henry's constant in torr-L/mol. (j)]^ is 0.70 for showers and
0.54 for all household water uses including showers.6
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where Wsh0wer the water use per individual in the shower, L/h; W^ouse the
water use in L/h for all household activities and averaged over 24 h; and VRshower,
VRfoath/ and VRhouse are the average ventilation rates for air in the shower,
bathroom, and total house compartments respectively, m3/h.
where [BR/BW] is the ratio breathing rate to body weight, m3/kg-d, averaged over a
lifetime; and ETS, ETb, and ETh are the exposure time in, respectively, the shower,
the bathroom, and the house—the amount of time, in h/d, that an individual
spends in each compartment.
We calculate the breathing rate per unit body weight using data from the
ICRP4 and the procedure described above for fluid intake per unit body weight. The
result is a lognormal distribution with an arithmetic mean value and arithmetic
standard deviation of 0.39 and 0.5 m3/kg-d, respectively.
James and Knuiman9 analyzed data on domestic water use from a sample of
3,000 households in Perth, Australia. Their analysis reveals that the mean duration
of a shower in this population is approximately 8 min with a geometric standard
deviation (GSD) of roughly 1.8 and the mean shower flow rate is approximately 8
L/min with a GSD of roughly 1.4. Based on this data, we model the variability of
shower exposure time with a lognormal distribution having an arithmetic mean
and standard deviation, respectively, of 0.13 h and 0.085 h and the variability of
shower water use with a lognormal distribution having an arithmetic mean and
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standard deviation respectively of 0.13 L/h and 0.047 L/h. We assume that total
water use can be represented by a lognormal distribution with a GSD of 1.4 and
arithmetic mean of 42 L/h and that the amount of time an individual spends in the
bathroom can be represented by a lognormal distribution with an arithmetic mean
of 033 h and a GSD of L8. We model +he amount of dime spend by individual in a
house with a uniform distribution ranging from 8 to 20 h. These distributions are
summarized in Table I.
We estimate that the transfer efficiency of PCE from tap water to shower air
can be represented by a triangular distribution with a range of 0.1 to 0.9 and a
likeliest value of 0.4 and that the transfer efficiency from water to household air for
all water uses can be represented by a triangular distribution with a range of 0.1 to 0.9
and a likeliest value of 0.3. Ventilation rates in the shower, bathroom and house
are based on the assumption that the volumes of these compartments are
respectively 2, 10, and 600 m3 and that the number of air changes per hour range
from 2 to 10 in the shower, 1 to 10 in the bathroom, and 0.5 to 2 in the house.6 These
distributions are summarized in Table I.
For this pathway the exposure route is dermal contact, both the source
medium and the contact medium are water, the contact rate is the amount of PCE
that passes through the skin surface (stratum cerneum) per unit body weight per
hour, the exposure time is the number of hours per day spent in bathing or shower,
the exposure frequency is 365 d/y, the exposure duration is 70 y, and the averaging
time is 25,550 d.
The model we use for dermal uptake from tap water is based on a paper by
Brown et al.9, who assumed that (a) dermal uptake of contaminants occurs mainly
by passive diffusion through the stratum corneum, (b) resistance to diffusive flux
through layers other than the stratum corneum is negligible, and (c) steady-state
diffusive flux is proportional to the concentration difference between water on the
skin surface and internal body water. Our dermal-uptake PEF is based on the
additional assumptions that children spend approximately the same amount of
time bathing or showering per week as adults and that the amount of time adults
spend in showering or bathing is the same as the showering time, ETS, reported
above. We calculate the PEF for dermal uptake of contaminants using the following
expression,
where SA/BW is total skin surface area per unit body weight averaged over a
lifetime, m2/kg; fsa is the fraction of the total skin surface that is in contact with
water during bathing and swimming, m2; PC is the chemical-specific dermal
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permeability constant, m/h; ETS is the exposure time, h/d; and CF is a conversion
constant, 10~3 L/m3.
Information on the relation between body weight and surface area has been
published by the ICRP4 and the EPA5! The ICRP recommends the following
formula to relate surface area (SA) in m2 to body weight (BW) in kg,
c A _ 4 BW + 7
BW + 90 (ID
We estimate the variability in surface area per unit body weight by by combining
these two formulations using a lognormal distribution of lifetime average body
weight with arithmetic mean and standard deviation equal to, respectively 58 and 14
kg. The resulting distribution of surface area to body weight is a lognormal
distribution with an arithmetic mean and standard deviation of 0.027 and 0.0025
m2/kg. Based on the range of permeability constants reported for volatile
compounds by Brown et al.9, we represent the permeability parameter, PC, with a
uniform distribution ranging from 0.004 to 0.01 m/h. The fraction of skin surface in
contact with water during showering and bathing is represented by a uniform
distribution ranging from 0.4 to 0.9. These distributions are summarized in Table I.
*
-l
f mr lim mr 1 + Q, ■U-L
Qn->0 K
(13)
t
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where f *rnr is the limiting fraction of inhaled VOC metabolized at extremely small
doses; Qa is the alveolar ventilation rate, 354 L/h; Ch is ihe blood flow to the liver
compartment, 93 L/h; Pb is the blood/air partition coefficient, 10 L blood/L air; Qn is
the concentration in inhaled air, mg/L air; and K is the low-dose metabolic clearance
rate, ' ’ ' •• - "
K = Vmax/Km; (14)
Vmax is the maximum metabolic rate, mg/h and has a best estimate value of 4.1
mg/h based on Ikeda et al. 12 and a best estimate value of 12 mg/h based on Ohtsuki
et al.14; and Km is the Michaelis constant, mg/L; and has a best estimate value of 0.19
mg/L based on Ikeda et al.13 and a best estimate value of 6.1 mg/L based on Ohtsuki
et al.14. This equation also pertains to the metabolism of any volatile organic
compound absorbed dermally, because dermally-acquired VOC entering the
systemic circulation is subject to pulmonary excretion in the same manner as a
respired dose.15 Bogen15 developed an analogous equation to predict the fraction of
very low doses of an orally applied VOC, such as PCE, that is metabolized (f%0)-
-1 -l
f 1™= limfmo = 1 +—I +
R—>0 K|Qa Q,]
(15)
where R is the rate of ingestive infusion, mg/h. Based on the uncertainty in Km and
Vmax values, we represent the uncertainty in the quantities, fmr* and fmo* with
uniform distributions. fmr* ranges from 0.038 to 0.46 and fm0* ranges from 0.053 to
0.63. These distributions are summarized in Table I.
POTENCY
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The average individual risk within a population exposed to PCE in this case
study results from: a source term; the exposure function, which converts the source
into a lifetime equivalent contact per individual; the fraction of contaminant
delivered to the organism after contact; and the toxic potency associated with the
delivered dose. Based on current regulatory assumptions, risk is proportional to
average population dose at low levels of exposure. According to this model, the
lifetime increased probability of cancer following exposure to a carcinogen at a
lifetime, time-weighted average dose rate, D, is assumed to be approximately equal
to the product of qi x D, for a very small D, where qi is a low-dose slope of the dose-
response curve (the "potency") derived from a set of tumor-incidence data.
Following this model the information and models described in the preceding
sections can be combined into an overall model of risk.
We calculate the uncertainty in this estimated risk per individual for the population
exposed to PCE in ground water based on the concentration data, exposure models,
dose models, and potency estimates described above. Using the Monte Carlo-
spreadsheet program Crystal Ball,19 we calculate the composite uncertainty in risk
based on the uncertainty for each input parameter, as defined above and
summarized in Table I. Figure 3 shows the resulting cumulative distribution of risk
based on 10,000 simulations. This distribution has an arithmetic mean of 1.0 x 10‘6
and a geometric standard deviation of 7.1. The 95% upper bound value of risk from
this cumulative distribution is 3.5 x 10~6. In contrast, the risk one would calculate by
using the arithmetic mean value of each input is 8.0 x 10'7 and the risk one would
calculate using the 95% upper bound value of each input is 1.3 x 10'3. Roughly 65%
of the variance in the cumulative distribution of risk shown in Figure 3 is
attributable to variance in potency, 20% is attributable to variance in concentration,
10% is attributable to variance in the parameters of the exposure model, and 5% is
attributable to variance in the parameters used to convert exposure to metabolized
dose.
13
1 >
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V
Cumulative Distribution for 10,000 trials
Arithmetic 95 % upper
mean bound
1.00
482348235323485353235323532348235323532353235323532353902323
XI
as
xi
o
0.0
0.0 1.50e-6 3.00e-6 4.50e-6 6.00e-6
ACKNOWLEDGEMENTS
This work was performed under the auspices of the U.S. Department of Energy
through Lawrence Livermore National Laboratory under Contract W-7405-Eng-48
with funding provided by the Office of Research and Development of the U.S.
Environmental Protection Agency.
REFERENCES
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7. W.J. Fisk, R.K. Spencer, D.T. Grimsrud, F.J. Offermann, B. Pedersen, and R.
Sextro, Indoor Air Quality Control Techniques, Radon, Formaldehyde,
Combustion Products, Pollution Technology Review No. 44, Noyes Data
corporation. Park Ridge, New Jersey, 1987.
8. I.R. James and M.W. Knuiman, "An Application of Bayes Methodology to the
Analysis of Diary Records from a Water Use Study, I. Am. Stat. Assoc. 82: 705-
711 (1987).
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