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Toxicology xxx (2012) xxxxxx
Toxicology
journal homepage: www.elsevier.com/locate/toxicol
School of Engineering, Okanagan Campus, The University of British Columbia, 3333 University Way, Kelowna, BC V1V 1V7, Canada
Contaminated Sites, Environmental Health Program Regions and Programs Branch Health Canada, Suite # 674, 220-4 Avenue SE, Calgary, AB T2G 4X3, Canada
a r t i c l e
i n f o
Article history:
Received 23 April 2012
Received in revised form 9 November 2012
Accepted 24 November 2012
Available online xxx
Keywords:
Data fusion
Human health risk assessment
Contaminated sites
DempsterShafer theory
Petroleum hydrocarbons
a b s t r a c t
The exposure and toxicological data used in human health risk assessment are obtained from diverse and
heterogeneous sources. Complex mixtures found on contaminated sites can pose a signicant challenge to
effectively assess the toxicity potential of the combined chemical exposure and to manage the associated
risks. A data fusion framework has been proposed to integrate data from disparate sources to estimate
potential risk for various public health issues. To demonstrate the effectiveness of the proposed data
fusion framework, an illustrative example for a hydrocarbon mixture is presented.
The Joint Directors of Laboratories Data Fusion architecture was selected as the data fusion architecture and DempsterShafer Theory (DST) was chosen as the technique for data fusion. For neurotoxicity
response analysis, neurotoxic metabolites toxicological data were fused with predictive toxicological
data and then probability-boxes (p-boxes) were developed to represent the toxicity of each compound.
The neurotoxic response was given a rating of low, medium or high. These responses were then
weighted by the percent composition in the illustrative F1 hydrocarbon mixture. The resulting p-boxes
were fused according to DSTs mixture rule of combination. The fused p-boxes were fused again with
toxicity data for n-hexane.
The case study for F1 hydrocarbons illustrates how data fusion can help in the assessment of the health
effects for complex mixtures with limited available data.
2012 Elsevier Ireland Ltd. All rights reserved.
1. Introduction
Human health risk assessment (HHRA) is an important component of the management of risk related to contaminated sites;
however, the exposure and toxicological data used in HHRA are
obtained from diverse and often heterogeneous sources. Uncertainty arises from incomplete, vague or ambiguous data, while
variability is found in the inherent differences between individuals
in a population. Toxicity data may be obtained for different species,
different exposure routes, different organization levels (gene, cell,
organ, system, individual, and population) and different toxicological end points. Exposure data are variable by nature, but uncertainty
is also inevitable it is impossible to completely characterize a site
Disclaimer: This paper uses material from a report that was prepared under contract to Health Canada (Prairies Region), Contaminated Sites, Environmental Health
Program. However, the views and opinions, if any, expressed in this paper and the
report does not necessarily reect the opinion of Health Canada nor is it Health
Canada guidance.
Corresponding author. Tel.: +1 250 486 2936.
E-mail addresses: radyck@interchange.ubc.ca (R. Dyck), shaqul.islam@ubc.ca
(M.S. Islam), amin.zargar@ubc.ca (A. Zargar), asish.mohapatra@hc-sc.gc.ca
(A. Mohapatra), rehan.sadiq@ubc.ca (R. Sadiq).
1
Tel.: +1 403 221 3284.
for all chemical and physical parameters given limited and incomplete data. Complex mixtures found on contaminated sites can pose
a signicant challenge to effectively assess the toxicity potential
of the combined chemical exposure and to manage the associated
risks. Because of the variable nature of complex mixtures, there
are not always sufcient or consistent data about the environmental fate, persistence, bioavailability and toxicity across the range of
constituents in the mixture.
The toxicity of chemical mixtures is generally assessed with
respect to the mixture as a whole, or by somehow combining the
toxicities of the individual components of the mixture. Often, there
is incomplete information for mixtures or their components, or
conicting information about the toxicity of the components. When
considering exposure to chemical mixtures, there are a number of
complicating factors to be considered
variability in the number of constituents and percent weight of
each constituent compound in the mixture,
variability in contaminant transport due to different chemical
properties (e.g., solubility and volatility),
variability in the ability of a receptor to take up the compounds
(kinetic parameters including absorption, metabolism, distribution, and excretion),
0300-483X/$ see front matter 2012 Elsevier Ireland Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tox.2012.11.010
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Fig. 1. Proposed data fusion based human health risk assessment framework (Sadiq et al., 2011). The 11 steps within the framework are grouped as problem formulation,
low level fusion, feature level fusion, and decision level fusion.
variability in the toxic response to the compounds (including target organ or tissues, mode of action, temporal variation in effects,
and toxicodynamic properties),
interactions which cause effects either higher or lower than those
achieved by either dose or response additivity. The term additivity is used when the effect of the combination of chemicals
can be estimated directly from the sum of the scaled exposure
levels (dose addition) or the responses (response addition) of the
individual chemicals (US EPA, 2000).
In order to integrate datasets from numerous sources, specialized data fusion techniques (Fig. 1) can be incorporated into the
HHRA framework earlier suggested by National Academy of Sciences (NAS, 2009).
Data fusion is a process used to generate a combined estimate
from data originating from multiple sources. The resultant estimate should be more accurate and informative than the original
source data. Dasarathy (1997) compares multi-sensor systems to
the human brain. Data coming in from our ve senses give us different information about our environment. Each of these sensors
offer signals in a different format, but when combined they lead
to an enhanced understanding of our environment that allows us
to make decisions. This same analogy can be extended to other
systems which have information coming from different sources
which at times do not fully agree. In the case of HHRA, this would
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Table 1
Recent examples of data fusion techniques in HHRA and public health (Zargar et al., 2012).
Data fusion technique
Application areas
Sources
Statistical
GIS overlay (heuristic approach)
Bayesian inference
DempsterShafer theory
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Fig. 2. Modied Joint Directors of Laboratories modelling framework (adapted from Satpathy and Mohapatra, 2009). Data fusion is completed in three levels: low level, high
level and decision level fusion.
exposure duration, exposure frequency, receptor weight, inhalation rates and ingestion rates). Natural variation can also exist in
toxico-kinetics and toxico-dynamics. Epistemic uncertainty refers
to uncertainty arising from an imperfect understanding of the system (Sentz and Ferson, 2002). This type of uncertainty can occur in
models which attempt to describe processes that are unknown or
unclear. In DST, variability and uncertainty can simultaneously be
represented as a p-box (Ferson et al., 2003).
When data are expressed as a probability density function (PDF),
a series of cumulative distribution functions (CDF) can be constructed to form a p-box. The CDFs represent an upper and lower
bound on the true CDF which lies at an unknown location between
the upper and lower bounds. Therefore, the horizontal variation
(distance) represents the variability in the data, while the vertical distance represents the uncertainty. When multiple sources of
data are available which are likely to be conicting, there are a
number of different rules that can be used for data fusion (combination) under DST (Ferson et al., 2003), depending on the situation.
Some commonly used rules are Dempsters rule (Dempster, 1967),
Yagers rule (Yager, 1987), and mixture rule (Ferson et al., 2003).
A more detailed explanation of the construction of p-boxes and
their use with mixture rule in DST is provided in Supplementary
Information.
3. Methods
The existing HHRA protocol consists of four stages illustrated in Fig. 3. The
problem formulation (hazard identication) is followed by dose response (toxicity) assessment, exposure assessment and risk characterization (Sadiq et al., 2011).
Based on recommendations and guidelines by National Academy of Sciences (NAS,
2009), Science and Decisions: Advancing Risk Assessment, a general risk assessment
and management framework has been proposed (Fig. 1; Sadiq et al., 2011). The proposed framework incorporates data fusion techniques to process data from multiple
sources to represent more relevant information. The basic framework includes 11
steps that are grouped as problem formulation, low level fusion, feature level fusion,
and decision level fusion. Each of the steps is described in this section to provide an
overview of the method. The detailed analysis done in each step is presented later
in Section 4.
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Fig. 3. Existing human health risk assessment protocol (Sadiq et al., 2011).
2
Health Canada uses the terminology toxicological reference value (TRV)
instead of reference dose or reference concentration.
For deriving the RfC, either the NOAEL or BMD can be used for situations involving data on one study, species or health endpoint. When there are multiple studies
and one study is identied as being superior to others, then one study can be used
as the basis for the RfC (Schmitt, 2006). [An illustration of the use of NOAEL and one
superior study is given in Supplementary Information.] The one study is chosen, the
NOAEL is determined for that study and the RfC is calculated by dividing the NOAEL
by uncertainty factors.
The current weight of evidence approach can also be used in cases where there
are multiple health endpoints, relevant animal studies or where results from different studies conict (Schmitt, 2006). [An illustration of the use of BMD for multiple
studies is given in Supplementary Information.] A BMD is calculated for each relevant study. The toxicologist uses their judgement to choose the most sensitive
endpoint, study or species based on the lowest BMD. The benchmark dose lower
limit (BMDL) is calculated from the 95th percentile lower limit and divided by the
applicable uncertainty factors to obtain an RfC.
While expert judgement is built into the NOAEL and BMD methods of deriving
an RfC through the selection of studies to be included, some information is lost
by this selection (Schmitt, 2006). The data fusion framework proposed here allows
the incorporation of multiple studies, species or endpoints, however one study or
one BMDL is not chosen from the multiple alternatives (as done in the NOAEL and
BMD methods). Information about each study is included in the RfC and therefore
provides a more robust RfC (Schmitt, 2006). Additionally, uncertainty information
is carried through the data fusion so that we can better represent the uncertainty in
the RfC.
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Table 2
Summary of carbon fractions recommended by CCME (2008) and Edwards et al. (1997).
Fraction
EC #
Corresponding
TPHCWG subfractions
F1
C6 C10
Aromatics
Aliphatics
F2
C>10 C16
Aromatics
Aliphatics
F3
C>16 C34
Aromatics
Aliphatics
F4
C>34 C50
Aromatics
Aliphatics
TDI (mg/kg d)
RfC (mg/m3 )
C>7 C8
C>8 C10
C6 C8
C>8 C10
a
0.04
5.0
0.1
a
0.2
18.4
1.0
a
Hepatotoxicity, neurotoxicity
Neurotoxicity
Hepatic and haematological changes
C>10 C12
C>12 C16
C>10 C12
C>12 C16
0.04
0.04
0.1
0.1
0.2
0.2
1.0
1.0
C>16 C21
C>21 C34
C>16 C21
C>21 C34
0.03
0.03
0.1
2.0
NAb
NAb
1.0
NAb
Nephrotoxicity
Nephrotoxicity
Hepatic granuloma
Hepatic granuloma
0.03
20.0
NAb
NAb
Nephrotoxicity
Hepatic granuloma
C>34
C>34
EC equivalent carbon.
a
Aromatics C>6 C8 are not considered, as benzene and toluene are the only components and they are considered separately.
b
Subfraction not considered volatile, therefore RfC not determined.
analyzed from monitoring wells on site. The indoor vapour concentrations of hydrocarbon components were estimated using the
JohnsonEttinger model (Johnson and Ettinger, 1991), which is a
commonly used vapour intrusion pathway model.
At the sites presented by Sevigny et al. (2003), the leakage
and spilling of gasoline resulted in contamination of the soil
and groundwater underlying the site. The gasoline components
detected in the subsurface included benzene, toluene, ethylbenzene, xylenes (BTEX) and volatile hydrocarbons. The presence of
BTEX and volatile hydrocarbons in the environment may constitute
an immediate and long term health risk to people living in the surrounding area with respect to both cancer and non-cancer effects.
A risk assessment will be performed to evaluate potential short and
long-term human health impacts due to inhalation, ingestion and
dermal exposures.
Depending on the results of the risk assessment, there are a
number of options available for reducing the impact of the exposure
on the receptors (Hers, 2010)
further removal of the contaminated soil and groundwater,
vapour extraction fan system, with or without groundwater treatment,
passive barriers for the receptor buildings to reduce vapour intrusion,
additional ventilation in the receptor buildings, and
positive pressure ventilation within the buildings.
Step 2: Problem formulation
(a) Contaminants of concern
Gasoline contains a number of hazardous compounds,
including BTEX and a complex mixture of other hydrocarbons. A gasoline contaminated site may have different types
of hydrocarbons: C6 C10 aliphatic and aromatic hydrocarbons,
C1 C5 aliphatic hydrocarbons, hydrocarbons with equivalent
carbon numbers greater than C10 , and polycyclic aromatic
hydrocarbons. The gasoline in the subsurface weathers over
time; the components and concentrations of hydrocarbons
change as they migrate across and off the site, react with other
chemicals in the groundwater and soil, and are metabolized by
microorganisms naturally occurring in the soil and groundwater. For the purposes of this case study, we are only concerned
with the volatile hydrocarbons that we will refer to as Fraction 1 (F1) aliphatic hydrocarbons (as dened by the Canadian
Council of Ministers of the Environment (CCME, 2008), based
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Duration
Resp. 1
2-Methylpentane
(summarized by Galvin
and Bond (1999a))
No
22 h/d, 7 d/wk
Up to 6 mo
22 h/d, 7 d/wk
Up to 6 mo
22 h/d, 7 d/wk
Up to 6 mo
14 wk, 9 h/d, 5 d/wk
Low
22 h/d, 7 d/wk
Up to 6 mo
22 h/d, 7 d/wk
Up to 6 mo
22 h/d, 7 d/wk
Up to 6 mo
9 h/d, 5 d/wk 1500 ppm
Low
3-Methylpentane
(summarized by Galvin
and Bond (1999b))
n-Hexane
Heptane
7
2-Methylhexane
Resp. 2
0%
033.3%
Metabolite
SAR
SAR
Study
Mass % in
gasoline
05%
C6 -1
8.12
28.14
05%
C6 -2
5.18
18.0
No
0%
05%
C6 -3
No
0%
05%
C6 -4
No
0%
05%
C6 -5
05%
C6 -6
033.3%
No
0%
05%
C6 -7
No
0%
05%
C6 -8
No
0%
05%
C6 -9
05%
C6 -10
Med
33.366.6%
1.75
6.32
12 h/d, 7 d/wk, 16 wk
9 h/d, 5 d/wk, 30 wk
6 h/d, 5 d/wk, 12 wk
No
No
No
0%
0%
0%
1
1
1
<
<
<
535%
535%
535%
C7 -1
C7 -2
C7 -3
2.76
No
0%
05%
C7 -4
3.49
Recalcd %
in F1
6.07
21.9
9.58
Author
12.1
2,5-Dimethylhexane
3,4-Dimethylhexane
No
No
0%
0%
Not reported
Not reported
<
535%
95100%
C8 -1
C8 -2
Inconclusive
In vitro 3,4-dimethylhexane
n-Nonane
6 h/d, 5 d/wk, 12 wk
No
0%
<
535%
C9 -1
0.60
2.04
10
n-Decane
No
0%
<
535%
C10 -1
0.63
2.18
100
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Table 3
Data fusion input for F1 in weathered gasoline, inhalation, rats only, sub-chronic, up to 6 months.
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Fig. 4. Multi-study and multi-compound inference for F1 neuropathic toxicity in rats using DempsterShafer mixture fusion (averaging). p-Boxes were constructed to
represent the toxic response, generation of toxic metabolites and the structure activity relationship for compounds in the F1 range. p-Boxes for six compounds were assigned
weights according to the percent composition in the F1 range.
each other compound was compared to in the summaries of studies, and also because it is used for some derivations of toxicity for
this hydrocarbon fraction. Following this, we apply the toxicity of
the F1 mixtures to the dose response curve for n-hexane.
The resulting p-box in Fig. 4 at number (5) represents the toxicity
of the entire mixture with probabilities for each possible value on
the x-axis. This provides a more complete picture of the toxicity of
the mixture than choosing one reference compound or one study.
Step 6: Assessment method selection
In the case of a petroleum hydrocarbon site, F1 hydrocarbons
are commonly detected in the subsurface, along with BTEX. The
components of the F1 hydrocarbon fraction can be present in
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data. The p-boxes for the toxicities were separated into upper and
lower CDFs and multiplied by the distribution for NOAEL by Monte
Carlo simulations using the software @Risk (Palisade Corporation,
2010). The separation of the p-box into upper and lower CDFs
should represent the possible values (upper CDF) and probable
values (Lower CDF) because the true CDF lies somewhere within
these two. The combined p-box for the upper and lower limits
of the NOAEL for F1 mixture is shown in Fig. 5. This p-box was
generated by placing the upper and lower CDFs on one plot.
Step 8: Exposure assessment
In this case only vapour inhalation was considered as an exposure pathway because the sub-surface soil would not be available
for dermal contact or accidental ingestion on a paved site. Also,
groundwater in the city is not usually used for consumption
or irrigation. As a result, the relevant pathways are soil and
groundwater contamination to soil vapours through cracks in the
residential foundation to the residents inside.
Hydrocarbon vapour concentrations have been measured in the
soil. Sevigny et al. (2003) used the Johnson Ettinger vapour intrusion model to estimate indoor air concentrations in the buildings.
Probability distributions for the exposure factors for the receptors are used to estimate exposures. The exposure assessment was
conducted using exposure factors provided by Health Canada for
residential and occupational exposures.
Health Canada (2010a) recommends the following equation for
indoor inhalation of contaminant vapours
Dose
mg/kg
d
3
These results do not necessarily reect the opinion of Health Canada nor is it
Health Canada guidance.
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5. Discussion
The case study considered only those compounds for which
sufcient data were available on toxicity as well as percent composition in the gasoline on site. The CCME F1 hydrocarbon mixture was
considered to consist only of aliphatic hydrocarbons with equivalent carbon numbers C6 C10 . The health end point considered was
neurotoxicity for sub-chronic exposure. The case study did not consider
contaminants other than CCME F1 hydrocarbons,
other fraction strategies for classifying hydrocarbon mixtures,
other health effects including respiratory irritation and reproductive effects,
results that are greater or less than additive,
chronic or acute exposure,
toxicity studies on animals other than rats, or
toxicity studies for oral or dermal exposure.
Three types of evidence were included in the data fusion
neurotoxic responses, including clinical, physiological and histological responses
formation of neurotoxic metabolites
chemical structure favouring the formation of neurotoxic
metabolites (structureactivity relationship).
The neurotoxic responses reported in the studies were allocated values of no, low, medium or high. These responses
could be expressed in numerical values where appropriate. In this
case study, the risk assessor assigned a value to the strength of
the neurotoxic response shown in each animal study; however, in
other applications, the input of several experts could be considered. Where these opinions differed, data fusion could be used to
address the conict between the opinions. These opinions could be
weighted according to the perceived reliability or credibility of the
experts.
Toxicity data were more readily available for n-hexane than
for the other components of the mixture, therefore the n-hexane
toxicity data were considered separately from the other components. The results of the data fusion represent a more complete
picture of the toxicity than just consideration of n-hexane, because
they incorporate data from many compounds weighted by their
relative amounts in the mixture. The resulting RfC (presented for
illustrative purposes only) is 2.13 mg/m3 . This is smaller than the
RfC of 18.4 mg/m3 for C6 C8 fraction provided by CCME (2008)
and Edwards et al. (1997), but larger than that given for C8 C10 of
1.0 mg/m3 . This result was expected because the fusion was conducted for the entire range of C6 C10 . The calculated Hazard Indices
were low; however, the actual risk assessment was not the main
objective of this case study, rather the application of the proposed
data fusion framework to HHRA for complex mixtures. Data fusion
is used here in the context of conducting doseresponse evaluations and toxicity assessments in the context of human health risk
assessment; the purpose of this exercise was not to present a new
RfC for petroleum hydrocarbons, but to present the use of data
fusion in the derivation of RfCs.
For the application of this type of data fusion to other sites, accurate characterization of components and relative amounts in the
mixture would be required. Although data fusion was conducted in
this assessment for sub-chronic inhalation studies, data from oral
studies or studies with other durations (chronic or acute) could
be included in the fusion if adequate conversion factors could be
derived for comparing oral to inhalation data and sub chronic to
chronic or acute data.
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