Toxicology 313 (2013) 160–173

Contents lists available at ScienceDirect

Toxicology
journal homepage: www.elsevier.com/locate/toxicol

Application of data fusion in human health risk assessment for hydrocarbon

mixtures on contaminated sites夽
Roberta Dyck a,∗ , M. Shafiqul Islam a , Amin Zargar a , Asish Mohapatra b,1 , Rehan Sadiq a
a
School of Engineering, Okanagan Campus, The University of British Columbia, 3333 University Way, Kelowna, BC V1V 1V7, Canada
b
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 a b s t r a c t

Article history: The exposure and toxicological data used in human health risk assessment are obtained from diverse and
Received 23 April 2012 heterogeneous sources. Complex mixtures found on contaminated sites can pose a significant challenge to
Received in revised form 9 November 2012 effectively assess the toxicity potential of the combined chemical exposure and to manage the associated
Accepted 24 November 2012
risks. A data fusion framework has been proposed to integrate data from disparate sources to estimate
Available online 3 December 2012
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.
Keywords:
The Joint Directors of Laboratories Data Fusion architecture was selected as the data fusion architec-
Data fusion
Human health risk assessment
ture and Dempster–Shafer Theory (DST) was chosen as the technique for data fusion. For neurotoxicity
Contaminated sites response analysis, neurotoxic metabolites toxicological data were fused with predictive toxicological
Dempster–Shafer theory data and then probability-boxes (p-boxes) were developed to represent the toxicity of each compound.
Petroleum hydrocarbons 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 DST’s 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 com-
ponent 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. Uncer-
tainty 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 toxicologi-
cal end points. Exposure data are variable by nature, but uncertainty
is also inevitable – it is impossible to completely characterize a site
夽 Disclaimer: This paper uses material from a report that was prepared under con-
tract 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 reflect 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), shafiqul.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 incom-
plete data. Complex mixtures found on contaminated sites can pose
a significant 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 sufficient or consistent data about the environmen-
tal 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
conflicting 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, distribu-
tion, 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
 R. Dyck et al. / Toxicology 313 (2013) 160–173
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 tar-
get 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 addi-
tivity 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, special-
ized data fusion techniques (Fig. 1) can be incorporated into the
HHRA framework earlier suggested by National Academy of Sci-
ences (NAS, 2009).
Data fusion is a process used to generate a combined estimate
from data originating from multiple sources. The resultant esti-
mate 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 five senses give us dif-
ferent 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
161
specifically include the consideration of data from in vitro, animal,
and whole body studies. Accuracy is improved by data fusion by
allowing us to include more information about the system. In a
deterministic approach, we may ignore information about some
study results in favour of one particular study and in doing so we
may also neglect to propagate any uncertainty in the study results.
Results of data fusion can be more informative because we can
incorporate weighting of each dataset which allows us to give more
weight in our final result to studies that we consider more credible,
more reliable, or more relevant.
A data fusion framework has been proposed to integrate data
from disparate sources to estimate potential risk for various public
health issues (Sadiq et al., 2011). The proposed framework attempts
to integrate various toxicological datasets from different biological
organizational criteria (gene, cellular, tissue, and organ level) and
integrates data from multiple sources. To demonstrate the effec-
tiveness of the proposed data fusion framework, an illustrative
example for a hydrocarbon mixture is presented.
2. Data fusion
Data fusion has been used in a number of settings to resolve
conflict (disagreement) between datasets. Military applications
include threat assessment and surveillance. More recently, data
fusion’s application has been expanded in commercial applications
162 R. Dyck et al. / Toxicology 313 (2013) 160–173

Table 1
Recent examples of data fusion techniques in HHRA and public health (Zargar et al., 2012).

Data fusion technique Application areas Sources

Statistical Genomic data fusion Lanckriet et al. (2004)

GIS overlay (heuristic approach) Assessment of UneXploded Ordnance (UXO) contamination Johnson et al. (2009)
Bayesian inference Multi-study and multi-endpoint BMD Schmitt (2006)
UXO detection Zhang et al. (2003)
Assessment of UXO contamination Johnson et al. (2009)
Syndrome surveillance Banks et al. (2012)
Disease surveillance Burkom et al. (2011)
Dempster–Shafer theory Risk assessment of water treatment Démotier et al. (2006)
Drinking water quality Sadiq and Rodriguez (2005)
Microbial water quality in distribution network Sadiq et al. (2006)
Assessment of UXO contamination Johnson et al. (2009)
Artificial neural networks Air pollution level monitoring Barron-Adame et al. (2009)
Fuzzy sets Risk assessment of ambient air quality Ping et al. (2010)
Not specified Public health biosurveillance Khan et al. (2010)
Gene prioritization Aerts et al. (2006)

such as robotics, manufacturing, sensor technology, medical
diagnosis, GIS and remote sensing. Data fusion is also becoming
a valuable tool for handling the data involved in HHRA. Table 1
provides some examples of data fusion techniques used in HHRA
and public health applications (Zargar et al., 2012). The main goals
of data fusion include (Boström et al., 2007; Zargar et al., 2012)
• refining data and improving data quality,
• creating additional inferences and increasing benefit from data,
and
• improving understanding and decision.
The different formulae available for dealing with conflicting data
sets depend on the method that was used to model the data, e.g., in
a possibilistic (fuzzy sets theory) or in a probabilistic (e.g., Bayesian
inferencing) setting. The framework or technique chosen for resolv-
ing the conflict depends on the nature of the problem, including
the presence of additional types of uncertainty in the data (e.g.,
incompleteness).
2.1. Data fusion architecture
According to Esteban et al. (2005), “before undertaking a data
fusion task, a strategy needs to be established to facilitate the solu-
tion of the problem in a robust and organized manner”. A data fusion
architecture is a platform that connects databases with data fusion
algorithms and techniques. The techniques are the mathematical
models used to combine several sources of datasets. The architec-
ture provides a strategy to gather the data from different sources
and integrate data at various levels. Due to the numerous possi-
ble scenarios and the variability between them, it would not be
possible to use a specific architecture for all situations (Esteban
et al., 2005). The architecture is only the framework in which spe-
cific “methods” can be used. The “levels” of fusion are interpreted
differently in different architectures. For some applications, such
as threat assessment from surveillance, the levels could be pixels,
features and images. In a similar analogy for HHRA applications, the
levels can correspond to different organization levels such as gene,
cell, tissue, organ and individual.
The Joint Directors of Laboratories (JDL) Data Fusion (DF) frame-
work (Llinas et al., 2004; Steinberg et al., 1999; Steinberg and
Bowman, 2004) is a popular model that was originally developed
for military applications. It includes four main levels (Esteban et al.,
2005):
• Level 1: Object Refinement – locates and identifies objects using
attributes of the object from multiple sources.
• Level 2: Situation Assessment – uses incomplete information
from level one to create a picture related to observed events.
• Level 3: Threat assessment – uses results from level 2 to analyze
the advantages and disadvantages to taking a course of action
from several possible opportunities.
• Level 4: Process refinement – provides a feedback loop to monitor
the performance of the first three levels and optimize allocation
of sensors.
The flexibility of this architecture is one of its key strengths.
Satpathy and Mohapatra (2009) modified the JDL DF architec-
ture for use in cyber security applications. The modification reduced
the number of levels to three as shown in Fig. 2:
• Low level fusion – includes data cleaning, data transformation
and data reduction to improve the quality and reduce the quantity
of data,
• High level fusion – uses classification and clustering to extract
useful patterns in the data for the interpretation of activities and
context.
• Decision level fusion – pertinent patterns are identified and
potential actions are evaluated to draw inferences about future
outcomes.
2.2. Data fusion models (techniques)
Zargar et al. (2012) defines data fusion models (or techniques) as
mathematical models that combine multiple data for a feature into
single data. While data fusion architectures are designed to provide
a frame of reference for discussing fusion, recognizing applicable
problems and categorizing solutions, the data fusion models are
the actual solutions used (Llinas et al., 2004). In most data fusion
architectures, it is possible to incorporate data fusion models at
several levels. Some of the popular models include
• Statistical data fusion (classical inference)
• Bayesian inference
• Dempster–Shafer Theory (DST)
• Artificial Neural Networks
• Fuzzy fusion.
Dempster–Shafer Theory (DST) was used in this case study.
One advantage of DST is its ability to express both variability and
uncertainty simultaneously. Variability, also known as aleatory
uncertainty, refers to natural variations present in sampled popu-
lations. In HHRA this type of uncertainty can be present in the
spatio-temporal distribution of concentration of contaminants
present in environmental samples as well as exposure factors (e.g.,
 R. Dyck et al. / Toxicology 313 (2013) 160–173
Fig. 2. Modified 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, inhala-
tion 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 sys-
tem (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 con-
structed 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 verti-
cal distance represents the uncertainty. When multiple sources of
data are available which are likely to be conflicting, there are a
number of different “rules” that can be used for data fusion (combi-
nation) under DST (Ferson et al., 2003), depending on the situation.
Some commonly used rules are Dempster’s rule (Dempster, 1967),
Yager’s 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 identification) is followed by dose response (toxic-
ity) 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 pro-
posed 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.
163
3.1. Problem formulation
The NAS (2009) report places emphasis on the planning, scoping and problem
formulation steps of the risk assessment process. Stakeholders are involved with
risk assessors in a dynamic discussion about the extent of the problem and the
issues of concern, while risk assessors establish the breadth, depth and focus of the
assessment (NAS, 2009).
Step 1: Planning and scoping
Planning and scoping for HHRA has been expanded by NAS (2009) to include
more input from stakeholders early in the process. This step outlines the depth
and breadth of the study.
Step 2: Problem formulation
The more technical aspects of the problem are evaluated at this stage includ-
ing sources, stressors, receptors, exposure pathways and potential adverse human
health effects. As the problems are introduced, options for remediation or mitiga-
tion can be proposed so that the HHRA answers the right questions.
Step 3: Suitability of risk-based assessment
The complexity of the problem and availability of the data will govern whether or
not a detailed risk assessment should be done. At this stage, a type of screening or
preliminary assessment can rule out further detailed analysis if the problem does
not warrant further study.
3.2. Low level fusion
Step 4: Data collection
Data are collected from a variety of sources in this step. Spatial and temporal
variability is taken into consideration for collection of data on site. The data required
for the exposure assessment may include detailed analysis of samples, modelling
of contaminant transport, and human exposure factors.
Step 5: Data estimation
Data that are collected requires further preparation through data reduction, data
transformation and data clean-up. This allows data from diverse sources to be
expressed in similar ways for further fusion at a later step in the process. This
also allows the combination of large quantities of data.
Step 6: Assessment method selection
At this stage the data are further evaluated to determine the suitability of quan-
titative risk assessment. Complex mixtures should be evaluated at this stage to
determine which method of handling data regarding mixtures is most appropriate.
3.3. Feature level fusion
Steps 7 and 8 are not necessarily conducted sequentially; rather they may be
done simultaneously.
164 R. Dyck et al. / Toxicology 313 (2013) 160–173
Fig. 3. Existing human health risk assessment protocol (Sadiq et al., 2011).
Step 7: Dose–response assessment
Dose response data collected Step 4 are fused here to include different end points,
different organization levels and/or different compounds (in the case of complex
mixtures).
Step 8: Exposure assessment
Exposure assessment is conducted to estimate the dose delivered to the tar-
get organs to produce a deleterious effect. Data fusion can be used to integrate
data regarding different sources, stressors, exposure pathways, exposure routes,
absorption by the body, and receptor sensitivities.
3.4. Decision level fusion
Step 9: Risk characterization
During risk characterization, the probability of harm in receptors or populations
is evaluated.
Step 10: Relative cost benefit analysis and selection of management options
The cost-benefit analysis can include monetary costs, as well as social and cultural
costs. Risk management options can be evaluated for their utility.
Step 11: Reporting, guidelines and implementation
Reporting of the assessment is summarized to implement the management deci-
sions as well as identifying the requirements for further research. One important
aspect of reporting is careful explanation of assumptions, uncertainty in the meth-
ods and variability in the population and data.
These steps are examined and explained further in the following case study of
F1 hydrocarbon contamination.
3.5. Current and proposed approaches for development of reference concentration
(RfC)
In the dose–response step of HHRA, the current “weight of evidence” approach
can be used to calculate an RfC for a given chemical or mixture of chemicals (Schmitt,
2006).2 The RfC is calculated using either the “no observed adverse effects level”
(NOAEL) or the “Benchmark Dose” (BMD) approaches. The NOAEL method uses the
highest concentration in animal or human studies for which no adverse effect was
observed. The NOAEL is divided by uncertainty factors for
• interspecies differences (when only animal studies are available, typically 10-
fold),
• intraspecies differences (consideration of sensitive individuals within the popu-
lation, typically 10-fold),
• deficiencies in the toxicological dataset (lack of chronic studies, lack of reproduc-
tive studies, lack of NOAEL, etc., typically 3- to 10-fold), and
• considering the nature and severity of the potential effects (3- to 10-fold; Health
Canada, 2010a).
The BMD method uses the dose associated with a given response rate (Bench-
mark Response, BMR) in a given toxicology data set (usually 1–10%). Mathematical
models are used to model the response rate for a particular toxic effect. The BMD
method also incorporates uncertainty factors for interspecies and intraspecies dif-
ferences, consideration of the nature and severity of the effects, and also some
deficiencies in the dataset (e.g., lack of chronic studies). No uncertainty factor is
used in the case that no NOAEL is found because uncertainty related to low-dose
extrapolation is already considered within the BMD method (Health Canada, 2010a).
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 involv-
ing data on one study, species or health endpoint. When there are multiple studies
and one study is identified 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 differ-
ent studies conflict (Schmitt, 2006). [An illustration of the use of BMD for multiple
studies is given in Supplementary Information.] A BMD is calculated for each rel-
evant 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.
4. A case study for F1 hydrocarbon contaminated site
4.1. Background
The presence of various potentially toxic chemicals on contam-
inated sites can lead to environmental, human health and financial
liabilities (Health Canada, 2010b). One common cause of contami-
nation is spilling and leakage during the storage, transfer and use
of hydrocarbons on industrial, commercial and government sites.
A collection of sites, which reflect many of the features common
on hydrocarbon contaminated sites, has been used to demonstrate
the framework. A risk assessment has been carried out for a collec-
tion of similar commercial sites which have been contaminated by
long term spilling of gasoline on the ground surface and leakage of
gasoline from underground storage tanks in the subsurface. During
the description of the case study, details of each step have been
described.
4.1.1. Problem formulation
Step 1: Planning and scoping
The site-specific concentration data used for this case study
were presented by Sevigny et al. (2003). The study data were
collected from 5 sites in western Canada that had underground
gasoline storage tanks with similar tank size and fuel types. The
tanks at each of the sites were in active use for a period of
25–30 years, followed by decommissioning (which included tank
removal as well as removal of some of the hydrocarbon con-
taminated soils). In the study, soil vapours were collected and
 R. Dyck et al. / Toxicology 313 (2013) 160–173 165

Table 2
Summary of carbon fractions recommended by CCME (2008) and Edwards et al. (1997).

Fraction EC # Corresponding TDI (mg/kg d) RfC (mg/m3 ) Critical effect used by TPHCWG
TPHCWG subfractions to derive criteria

F1 C6 –C10 Aromatics C>7 –C8 –a –a –a

C>8 –C10 0.04 0.2 Hepatotoxicity, neurotoxicity
Aliphatics C6 –C8 5.0 18.4 Neurotoxicity
C>8 –C10 0.1 1.0 Hepatic and haematological changes

F2 C>10 –C16 Aromatics C>10 –C12 0.04 0.2 Decreased body weight
C>12 –C16 0.04 0.2 Decreased body weight
Aliphatics C>10 –C12 0.1 1.0 Hepatic and haematological changes
C>12 –C16 0.1 1.0 Hepatic and haematological changes

F3 C>16 –C34 Aromatics C>16 –C21 0.03 NAb Nephrotoxicity

C>21 –C34 0.03 NAb Nephrotoxicity
Aliphatics C>16 –C21 0.1 1.0 Hepatic granuloma
C>21 –C34 2.0 NAb Hepatic granuloma

F4 C>34 –C50 Aromatics C>34 0.03 NAb Nephrotoxicity

Aliphatics C>34 20.0 NAb Hepatic granuloma

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 con-
centrations of hydrocarbon components were estimated using the
Johnson–Ettinger 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, ethylben-
zene, 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 sur-
rounding 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 treat-
ment,
• passive barriers for the receptor buildings to reduce vapour intru-
sion,
• 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 hydrocar-
bons. 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 groundwa-
ter. For the purposes of this case study, we are only concerned
with the volatile hydrocarbons that we will refer to as Frac-
tion 1 (F1) aliphatic hydrocarbons (as defined by the Canadian
Council of Ministers of the Environment (CCME, 2008), based
upon work by Edwards et al. (1997) for the Total Petroleum
Hydrocarbons Criteria Working Group (TPHCWG) which elute
in the C6 to C10 range during laboratory analysis. The carbon
fractions are summarized in Table 2 along with the tolerable
daily intake (TDI) and RfC for each subfraction. Other strategies
for separating hydrocarbon mixtures into fractions have been
proposed (Park and Park, 2010); however, the consideration of
the impacts of changes in the fractions is outside the scope of
this study.
(b) Receptor pathways
In order to assess the risk to the receptors, it is necessary
to estimate the concentrations of hydrocarbons present in
the groundwater, soil gas, indoor air, outdoor air, dust or air-
borne particulate, surface water, sediments, and food in order
to assess exposure through ingestion, inhalation and dermal
contact routes.
For the purposes of this case study, it has been assumed that
the release of gasoline has been predominantly from the under-
ground storage tanks; therefore, the release would occur in soil
and groundwater. The F1 hydrocarbons are both soluble and
volatile and can be present in the groundwater, as well as in
the unsaturated zone of soil above the groundwater. For the
purposes of this case study, we are not considering ground-
water use as we are assuming that the site is located in the
city and the use of groundwater for drinking within the city
would be unlikely. Because the contamination originated from
underground storage tanks and remains in the subsurface, it
is assumed that dermal contact with impacted soil is limited.
Therefore, the most important pathway is intrusion of vapours
into the building and the most important route of exposure is
inhalation of vapours.
(c) Receptor characteristics
The receptors for the hydrocarbons in the case study site are
the occupants of commercial and residential properties adja-
cent to the site. The people on commercial sites are expected
to be mostly adults with exposure durations of 10 h per day,
5 days a week, and 48 weeks per year. The residences are
assumed to house people of all ages, who may be home 24 h a
day 7 days a week.
Impacts of exposure to F1 hydrocarbons may vary in differ-
ent sub groups of population. Acute exposures may result in
respiratory and neurological health effects. Longer term effects
can include hepatic and haematological changes, decreased
body weight and respiratory irritation and inflammation
166 R. Dyck et al. / Toxicology 313 (2013) 160–173
(Massachusetts Department of Environmental Protection
(MADEP), 2003). In the case of inhalation exposures, the most
exposed receptors are considered to have a reasonable max-
imum of 70 years continuous exposure at the identified site,
unless actual exposure averaging times are known (i.e., years
spent at a location where receptors have potential for intake
of the contaminants).
Step 3: Suitability of risk-based assessment
The impacts of gasoline constituent compounds can be acute or
chronic. There are numerous studies addressing exposure and tox-
icity for hydrocarbon exposure in animals and in humans (Agency
for Toxic Substances and Disease Registry (ATSDR), 1995). The path-
ways and routes of exposure are generally well understood and
explained. Based on the availability of data, the severity of the
effects and the nature of the compounds, a risk-based assessment
is possible and suitable.
There are several levels of HHRA that are recommended in
Canada (Health Canada, 2010a). A screening assessment may be
qualitative or semi-quantitative (e.g., comparison of environmen-
tal concentrations to established criteria), but does not generally
include site-specific risk assessment. Preliminary Quantitative Risk
Assessment and Detailed Quantitative Risk Assessment are more
complex. Where there are data available and the risks warrant,
detailed quantitative risk assessment should be done. In this case,
there is sufficient evidence and potential for harm to allow a
detailed risk assessment.
(a) Mixtures
Many contaminated sites involve chemical mixtures. Gaso-
line is a complex mixture of hydrocarbons which contains over
150 individual compounds present in a range of quantities. For
such complex mixtures, it can be prohibitive to consider the tox-
icity of each compound individually if sufficient toxicity data are
not available for each compound.
(b) Whole mixture toxicity
Where sufficient data are available related to the whole mix-
ture or a sufficiently similar mixture, one BMDL or RfC can be
derived for the entire mixture. Alternatively, when there are
data regarding a group of similar mixtures, we must evaluate
the toxicity of our mixture of interest against the toxicity of the
known mixture for which more data are available.
(c) Components toxicity
If there are insufficient data to consider the entire mixture as
a whole, there are a number of ways that the toxicity informa-
tion for the individual components of the mixture can be used to
evaluate the toxicity of the mixture. For constituents of the mix-
ture which are toxicologically similar to each other and to the
properties of the mixture as a whole, dose addition methods are
commonly used. These include relative potency factor, toxicity
equivalence factor and hazard index methods. If there are insuf-
ficient toxicity data for numerous components of the mixture,
quantitative structure activity relationships (QSAR) could also
be helpful in determining the potential toxicity of a compound.
Additionally, interactions between chemicals in the mixture
could lead to effects that are greater or less than additive.
The use of surrogate chemical toxicity represents a method
that is commonly used for chemical mixtures. In the case of
hydrocarbons in the C6 –C10 range, the toxicity of commercial
hexane has been used to represent the toxicity of the C6 –C8
range of the hydrocarbon fraction (Edwards et al., 1997). It was
concluded that consideration of hexane’s toxicity will be protective
of other hydrocarbons in that range. This method may neglect the
relative prevalence of the compounds in the F1 fraction, and also
overlook interactions leading to effects that are either greater or
less than additive. This consideration is also based mainly on neu-
rotoxic properties of hexane, while newer reports are questioning
whether or not that would be protective of irritancy, especially
in cases where the hexane concentration is low (Wilson Scientific
Consulting Inc. and Meridian Environmental Inc., 2007).
The ultimate choice of method for risk assessment of chemi-
cal mixtures can only be made following collection and analysis of
toxicology data for the mixture as a whole, as well as the compo-
nents of the mixture. For F1 hydrocarbons in this case study, there
is insufficient evidence for the consideration of the mixture as a
whole, therefore individual components will be considered based
on their toxicity.
4.1.2. Low level data fusion
Step 4: Data collection
In this step, data were collected for all identified pos-
sible sources, stressors, transport pathways, exposure routes,
chemical combinations, end points receptors, and population
vulnerabilities. As discussed above in problem formulation, the
most likely exposure pathway is inhalation following vapour
migration to the indoor environment. Exposure models for
vapour intrusion are available from Health Canada (2008) and
Johnson and Ettinger (1991). Background and typical vapour
concentrations are available from literature (Sevigny et al.,
2003), as well as the American Petroleum Institute website
(http://www.api.org/ehs/groundwater/bioattenuation.cfm).
The CCME Canada-Wide Standards (CWS) for Petroleum Hydro-
carbons (PHC) were derived using the TPHCWG analysis by
Edwards et al. (1997). Recent studies (Park and Park, 2010) sug-
gest the use of other hydrocarbon fractionation systems, and
Equilibrium Environmental Inc. (2005) suggested that the use of n-
hexane as a surrogate is over-conservative. The percent of n-hexane
in weathered gasoline and in the weathered F1 fraction is relatively
small, and may be insignificant in comparison to the concentrations
of other compounds in the fraction (e.g., octane or heptane). It is also
possible that while not evidently toxic individually, mixtures could
result in effects that are greater than additive which may elicit sim-
ilar toxic effects as n-hexane (MADEP, 2003). Due to these factors,
it may be advisable to consider the toxicity of each component and
then fuse them to form a single toxicity for the entire F1 fraction.
The relative amounts of the components of the F1 hydrocarbon
fraction present on a contaminated site will vary based on the origi-
nal source of contamination, the subsurface contaminant transport,
weathering, and the degradation of the hydrocarbons over time.
Typical mass fractions and percent by weight for components of
gasoline were provided by ATSDR (1999). The relative percent of
each compound in the F1 mixture will be used to provide weighting
to the toxicity of each compound in the mixture for determination
of the total toxicity for the mixture, as explained in Step 5.
Toxicology data for F1 hydrocarbons have been summarized
by Edwards et al. (1997), by the ATSDR Toxicological Profiles for
Total Petroleum Hydrocarbons (1999) and Gasoline (ATSDR, 1995),
by MADEP (2003) as well as the CCME Canada-Wide Standard
for Petroleum Hydrocarbons (PHC) in Soil: Scientific Rationale
Supporting Technical Document (2008), and the CCME Toxicity
Reference Value (TRV) Advisory Sub Group 2005 Review of Canada-
Wide Standards for Petroleum Hydrocarbons in Soil. Data regarding
the human health endpoints can also be obtained from literature.
Available toxicological data were reviewed for each compo-
nent of F1. The compounds and summaries of the relevant studies
are presented in tables in Supplementary Information (API, 1982,
1983; Bahima et al., 1984; Biodynamics Inc., 1978; Bus et al., 1979;
Carpenter et al., 1978; Cavender et al., 1984; Criteria Group for
Occupational Standards, 1983; Dunnick et al., 1989; Egan et al.,
 R. Dyck et al. / Toxicology 313 (2013) 160–173
1980; Equilibrium, 2005; Frontali et al., 1981; Galvin and Bond,
1999a,b; Howd et al., 1982; Huang et al., 1989, 1992; Ichihara et al.,
1998; IRDC, 1992; Litton Bionetics, 1979; Lungarella et al., 1984;
MacEwen and Vernot, 1985; Malley et al., 2000; Mast et al., 1987,
1988; NTP, 1991; Olson et al., 1986; Ono et al., 1981, 1982; Parnell
et al., 1988; Perbellini et al., 1986; Pryor et al., 1982; Rabovsky et al.,
1986; Sanz et al., 1995; Sayre et al., 1986; Serve et al., 1991, 1992,
1993, 1994, 1995; Takeuchi et al., 1981; Valentini et al., 1994; Yuasa
et al., 1996).
Step 5: Data estimation
Before performing toxicity assessment, it is essential to define
what would be considered an adverse effect. The US EPA (2012)
defines an adverse effect as “A biochemical change, functional
impairment, or pathologic lesion that affects the performance of
the whole organism, or reduces an organism’s ability to respond to
an additional environmental challenge”. As such, it is possible to
identify adverse effects of chemical exposures from toxicity stud-
ies that demonstrate clinical responses, physiological effects and
histopathological effects.
After collection of data from sources listed above, for different
media and different exposure routes, lower level data fusion was
carried out. The studies included were limited to studies which
• were conducted on rats,
• considered sub-chronic exposure (less than 6 months),
• considered inhalation, and
• used neurotoxicity as an endpoint.
As a more generalized approach, studies conducted on other
species for other exposure durations, pathways and endpoints
could also be fused using conversion factors and weighting as
advised by toxicologists.
(a) Construction of p-boxes and data fusion
The first step in the data fusion was the derivation of p-boxes for
the toxicity of each substance. Each p-box was constructed for the
PDF of a data source. One of the benefits of data fusion using DST is
the ability to convert words (qualitative terms) into probabilities.
This is especially useful where we want to capture expert opinion
on our data. Our experts can define certain “signals” or responses in
studies as being “low”, “medium” or “high”. These words are con-
verted into p-boxes which represent, not only the categories which
the experts have designated (Fig. 4, x-axis on p-box plots, but also
the probability or confidence they have in that assessment (Fig. 4, y-
axis on p-box plots). Details regarding the construction of p-boxes
is provided in Supplementary Information. General information is
provided here.
Three types of evidence were summarized including neu-
rotoxic response, formation of neurotoxic metabolites, and
structure–activity relationships. These types of evidence were
summarized from the studies themselves (Tables S-V and S-VI Sup-
plementary Information) or from the summary provided by Galvin
and Bond (1999a) and Equilibrium (2005). Based on comments
made in the studies or in the summaries, the neurotoxic response
was allocated a rating of “No” when no neurotoxic response was
noted, and “Low”, “Medium” or “High” dependant on the strength
of the response, and how much the response could be attributed
to the compound of interest. For example, for 2-methylpentane in
a study by Ono et al. (1981), the response was described as “no
significant difference in motor nerve conduction velocity, motor
distal latency; mixed nerve conduction velocity (distal); significant
difference in mixed nerve conduction velocity (proximal) after 8
weeks” and was allocated a rating of medium. This allocation would
167
be highly subjective and depend strongly on the judgement of the
assessor and would therefore be an excellent opportunity for toxi-
cologists to improve the assessment. The production of metabolites
was determined by reporting in the studies (yes or no, depending on
if they were reported as present), as was the structural potential for
neurotoxic metabolites to be formed (which was described in the
summary by Equilibrium (2005) as having a structure favourable
to neurotoxicity of much greater, greater, equal, less than or much
less than that of n-hexane). The definition of the response as high,
medium or low and the structural considerations are areas that
could be further refined by expert opinion of toxicologists.
The input used for data fusion is shown in Table 3. The p-boxes
shown in Fig. 4 were generated as follows:
• Three types of evidence are considered, Response, Metabolites
and SAR.
• The responses of “no”, “low”, “medium” or “high” were allocated
toxicity index values in %.
• The p-boxes for response (labelled (1) in Fig. 4) represent
◦ no response (0% on the x-axis which represents toxicity),
◦ low response (0–33% on the x-axis, with probabilities indicated
by the y-axis for each value of x between 0% and 33%),
◦ medium response (33–66% on the x-axis, with probabilities
indicated by the y-axis for each value of x between 33% and
66%) and
◦ high response (66–100% on the x-axis, with probabilities indi-
cated by the y-axis for each value of x between 66% and 100%).
• The p-boxes for metabolite show 0 or 100% on the toxicity index
(x-axis) in Fig. 4.
• The p-boxes for SAR represent structure favourable to neurotox-
icity compared to n-hexane
◦ much less than (0–5% on the x-axis),
◦ less than (5–35% on the x-axis),
◦ equal to (35–65% on the x-axis)
◦ greater than (65–95% on the x-axis) or
◦ much greater than (95–100% on the x-axis).
• The values for each evidence type for each of the compounds
considered are listed in Table 3.
• The studies for each compound were given a Study number which
corresponds to number (2) in Fig. 4. The p-boxes from the evi-
dence type for each study (labelled (1)) were fused (using DST
mixture rule – see Supplementary Information for more detail
on the technique) to form the p-boxes labelled (2) in Fig. 4 which
represent the toxicity indicated by each individual study for the
different compounds considered. The compounds are grouped in
Fig. 4 at (2) because in fusing the different evidence types, there
were only 5 different p-boxes that resulted due to the similarity
in the response in the studies for the different compounds.
• The p-boxes labelled (2) represented various studies for each
compound. The studies for each compound were fused to provide
a p-box representing toxicity for each compound shown at num-
ber (3).
• Each p-box at number (3) representing a compound in the F1
mixture was allocated a weight based on its percent of the mass
composition in the mixture (labelled (4)).
• The resultant p-box (labelled (5)) is the fused p-box for all the
compounds shown at (3), weighted according to the percent mass
indicated at (4).
This was done including all of the components of the F1 hydro-
carbon mixture for which there were studies indicating the toxicity
relative to the types of evidence used here and where the percent
mass in the mixture was known. This did not include n-hexane.
The p-box for n-hexane is constructed to indicate that n-hexane
is toxic. This is represented by the vertical line at 50%. This toxic-
ity was allocated to n-hexane because it was the compound that
 168
Table 3
Data fusion input for F1 in weathered gasoline, inhalation, rats only, sub-chronic, up to 6 months.

C Compound Author Duration Resp. 1 Resp. 2 Metabolite SAR SAR Study Mass % in Recalc’d %
gasoline in F1

2-Methylpentane Frontali et al. (1981) 14 wk, 9 h/d, 5 d/wk No 0% 0 « 0–5% C6 -1 8.12 28.14
(summarized by Galvin
and Bond (1999a))
API (1982, 1983) 22 h/d, 7 d/wk Low 0–33.3% 0 « 0–5% C6 -2
Up to 6 mo
API (1982, 1983) 22 h/d, 7 d/wk No 0% 0 « 0–5% C6 -3
Up to 6 mo
Egan et al. (1980) 22 h/d, 7 d/wk No 0% 0 « 0–5% C6 -4
Up to 6 mo
6
3-Methylpentane Frontali et al. (1981) 14 wk, 9 h/d, 5 d/wk No 0% 0 « 0–5% C6 -5 5.18 18.0

R. Dyck et al. / Toxicology 313 (2013) 160–173

(summarized by Galvin
and Bond (1999b))
API (1982, 1983) 22 h/d, 7 d/wk Low 0–33.3% 0 « 0–5% C6 -6
Up to 6 mo
API (1982, 1983) 22 h/d, 7 d/wk No 0% 0 « 0–5% C6 -7
Up to 6 mo
Egan et al. (1980) 22 h/d, 7 d/wk No 0% 0 « 0–5% C6 -8
Up to 6 mo
Cyclohexane (from Frontali et al. (1981) 9 h/d, 5 d/wk 1500 ppm No 0% 0 « 0–5% C6 -9 1.75 6.07
summary in
Equilibrium (2005))
10 h/d, 6 d/wk 2500 ppm
Malley et al. (2000) 6 h/d, 5 d/wk, 14 w Med 33.3–66.6% 0 « 0–5% C6 -10
n-Hexane See studies in Table S-VI 6.32 21.9

Heptane Takeuchi et al. (1981) 12 h/d, 7 d/wk, 16 wk No 0% 1 < 5–35% C7 -1 2.76 9.58
Frontali et al. (1981) 9 h/d, 5 d/wk, 30 wk No 0% 1 < 5–35% C7 -2
7
Bahima and 6 h/d, 5 d/wk, 12 wk No 0% 1 < 5–35% C7 -3
Menendez-Gallego (1984)
2-Methylhexane Perbellini et al. (1986) and No 0% 0 « 0–5% C7 -4 3.49 12.1
Sayre et al. (1986)

2,5-Dimethylhexane Serve et al. (1991) No 0% Not reported < 5–35% C8 -1 Inconclusive

8
3,4-Dimethylhexane Sanz et al. (1995) In vitro 3,4-dimethylhexane No 0% Not reported » 95–100% C8 -2

9 n-Nonane Carpenter et al. (1978) 6 h/d, 5 d/wk, 12 wk No 0% 1 < 5–35% C9 -1 0.60 2.04

10 n-Decane Criteria Group for 18 h/d, 7 d/wk, 123 d No 0% 0 < 5–35% C10 -1 0.63 2.18
Occupational Standards
(1983)
100
 R. Dyck et al. / Toxicology 313 (2013) 160–173 169

Fig. 4. Multi-study and multi-compound inference for F1 neuropathic toxicity in rats using Dempster–Shafer 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 stud-
ies, 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
varying concentrations based on the source chemical and the
amount of weathering, therefore it is recommended to consider F1
as a mixture.
4.1.3. Feature level fusion
Step 7: Dose–response assessment
High level or feature level data fusion can be illustrated using
a case adapted from Schmitt (2006). Schmitt (2006) uses two
sources of data in the derivation of BMDL: findings from multiple
empirical studies along with data calculated from a mechanistic
model. The proposed framework can be applied to this data. In
the case of F1 hydrocarbons, the toxicity of each compound con-
sidered was applied to the PDF of the NOAEL concentrations from
studies on n-hexane, for which there were much more toxicity
170 R. Dyck et al. / Toxicology 313 (2013) 160–173

Fig. 5. p-Box of neurotoxicity NOAEL for F1 hydrocarbon mixture.

data. The p-boxes for the toxicities were separated into upper and The NOAEL from the dose–response assessment applies for rats
lower CDFs and multiplied by the distribution for NOAEL by Monte in a sub-chronic study. Where NOAEL values were not available, the
Carlo simulations using the software @Risk (Palisade Corporation, lowest observed adverse effect level (LOAEL) values were divided
2010). The separation of the p-box into upper and lower CDFs by an uncertainty factor of 10. Other uncertainty factors that can
should represent the possible values (upper CDF) and probable be applied include
values (Lower CDF) because the “true” CDF lies somewhere within
these two. The combined p-box for the upper and lower limits • 10 for interspecies differences
of the NOAEL for F1 mixture is shown in Fig. 5. This p-box was • 10 for intraspecies differences and
generated by placing the upper and lower CDFs on one plot. • 3 or deficiencies in the data set.
Step 8: Exposure assessment
In this case only vapour inhalation was considered as an expo-
sure pathway because the sub-surface soil would not be available No uncertainty factor is being used for the severity of toxic
for dermal contact or accidental ingestion on a paved site. Also, effects, as a factor was included in calculating the combined NOAEL
groundwater in the city is not usually used for consumption for F1.
or irrigation. As a result, the relevant pathways are soil and The RfC is calculated by dividing the NOAEL by the uncertainty
groundwater contamination to soil vapours through cracks in the factors. The NOAEL in this case was presented as a p-box. While
residential foundation to the residents inside. there is software available to multiply p-boxes together, for com-
putational simplicity in this case we used the average of the upper
and lower bound 95th percentiles which is 639 mg/m3 . This results
Hydrocarbon vapour concentrations have been measured in the
in an RfC of 2.13 mg/m3 . This value is calculated only for the pur-
soil. Sevigny et al. (2003) used the Johnson Ettinger vapour intru-
poses of illustrating the approach. This should not be interpreted
sion model to estimate indoor air concentrations in the buildings.
as a new RfC or TDI.3
Probability distributions for the exposure factors for the recep-
In order to compare this to the exposure doses, we used the
tors are used to estimate exposures. The exposure assessment was
inhalation rate and body weight of each age group to generate an
conducted using exposure factors provided by Health Canada for
age-specific TDI.
residential and occupational exposures.
Health Canada (2010a) recommends the following equation for
indoor inhalation of contaminant vapours Step 10: Relative cost-benefit analysis and selection of manage-
 mg/kg  Cia × IRA × AFinh × ET
ment options
Dose = A cost benefit analysis should always be conducted to assess the
d RW potential management options. The cost benefit analysis is outside
of the scope of work of this case study.
where Cia is the concentration of contaminant in indoor air
Step 11: Reporting, guideline and implementation
(mg/m3 ); IRA is the air inhalation rate (m3 /day); AFinh is the rel-
The Health Canada Guidance on Complex human health detailed
ative absorption factor for inhalation (unitless); ET is the exposure
quantitative risk assessment for chemicals (Health Canada, 2010a)
term (unitless); and BW is the body weight (kg).
presents a suggested report outline. This outline could be used to
PDFs for each of the exposure factors were combined with the
form the basis for reporting for this case study, however, the intent
site indoor vapour concentrations using Monte Carlo simulations.
of this case study is the demonstration of the use of data fusion in
In this case, the absorption factor for inhalation is assumed to be
HHRA, not the actual risk assessment for this site.
1. Because the receptors are residents that have the potential to be
exposed 24 h a day for a lifetime, it is conservative to assume that
the exposure term is also 1.

4.1.4. Decision level fusion 3

These results do not necessarily reflect the opinion of Health Canada nor is it
Step 9: Risk characterization Health Canada guidance.
 R. Dyck et al. / Toxicology 313 (2013) 160–173
5. Discussion
The case study considered only those compounds for which
sufficient data were available on toxicity as well as percent compo-
sition in the gasoline on site. The CCME F1 hydrocarbon mixture was
considered to consist only of aliphatic hydrocarbons with equiva-
lent carbon numbers C6 –C10 . The health end point considered was
neurotoxicity for sub-chronic exposure. The case study did not con-
sider
• contaminants other than CCME F1 hydrocarbons,
• other fraction strategies for classifying hydrocarbon mixtures,
• other health effects including respiratory irritation and reproduc-
tive 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 histo-
logical responses
• formation of neurotoxic metabolites
• chemical structure favouring the formation of neurotoxic
metabolites (structure–activity relationship).
The neurotoxic responses reported in the studies were allo-
cated 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 consid-
ered. Where these opinions differed, data fusion could be used to
address the conflict 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 compo-
nents. 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 con-
ducted 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 dose–response evalua-
tions 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, accu-
rate 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.
171
Data fusion as a tool for toxicologists conducting or evaluating
HHRA does have some limitations. These mathematical constructs
are somewhat unfamiliar in the field of toxicology. This unfamil-
iarity might make it difficult for the analyst to choose data fusion
architecture and methods. The results of the data fusion may be
significantly affected by the choice of fusion method. This is partly
because each of the fusion methods handle conflict differently.
Therefore, a solid understand of the fusion methods and the cir-
cumstances which make one preferable is important but attainable.
Data fusion methods are somewhat limited by the data that is
available. Analysts require sources of data that are sufficiently sim-
ilar in order to conduct data fusion. In this case study, only one end
point, one exposure route and one species were considered: other
weighting factors would need to be added for extrapolation to those
conditions. The selection and use of the data fusion methods are fur-
ther complicated by the different types of uncertainty that can be
present. While data fusion allows the selection of different meth-
ods for modelling uncertainty (e.g., possibilistic, probabilistic, and
fuzzy), the selection of those methods often depends heavily on the
dataset. Computational complexity can increase when some of the
data are presented in probabilities while others are presented in
possibilities.
Another limitation specific to this application is the uncertainty
in exposure. Generally, a hydrocarbon mixture on a contaminated
site is not uniform. The composition will also change with time.
Differences in spatial and temporal variation were not considered
here. In spite of these limitations, data fusion is a useful tool for
combining data from numerous sources in a way that preserves
information about uncertainty.
6. Summary and conclusions
Uncertainty occurs in HHRA due to data used in the assessment
which can be incomplete, conflicting, vague or ambiguous. Com-
plex chemical mixtures can present further uncertainty due to the
differences in toxicity between the components in the mixture.
To address these uncertainties, a data fusion framework for HHRA
was proposed to integrate toxicity information from three evidence
types for components of the F1 hydrocarbon mixture. The Joint
Directors of Laboratories (JDL) Data Fusion (DF) framework was
chosen as the data fusion architecture, in which DST was imple-
mented as the data fusion technique. The use of p-boxes allowed
for consideration of probabilities and uncertainty.
The case study considered was a contaminated site which
historically contained underground gasoline tanks. The CCME
hydrocarbon fraction F1, corresponding to C6 –C10 , was considered
as a complex mixture for which risk assessment was required. Data
were reviewed for the toxicity of the components of the mixture.
Three types of evidence were considered for neurotoxicity
1. neurotoxic response,
2. presence of neurotoxic metabolites, and
3. structure–activity relationships.
Toxicity data for the components of the mixture were com-
bined with toxicity data for n-hexane due to the greater amount
of information available for n-hexane. The resulting RfC for the
C6 –C10 mixture was lower than RfCs given by other sources (CCME,
2008; Edwards et al., 1997) for C6 –C8 , and higher than that given
for C8 –C10 .
Future data fusion studies are recommended and should include
consideration of
• contaminants other than CCME F1 hydrocarbons, other frac-
tion strategies for classifying hydrocarbon mixtures, other health
172 R. Dyck et al. / Toxicology 313 (2013) 160–173
effects including respiratory irritation and reproductive effects,
emerging system biology datasets integration and application of
data fusion
• Human Health/Public Health Data Fusion
• interactions between mixture components which would cause
effects that are greater or less than additive, chronic or acute
exposure, toxicity studies on animals other than rats, toxicity
studies for oral or dermal exposure, and
• other data fusion techniques (such as those listed in Section 2.2).
The inclusion of data fusion as a tool in future HHRA provides
an opportunity to address uncertainties, inconsistencies and lack
of information. Complex mixtures represent one area where such
data fusion would address specifically the variable nature of the
components of complex mixtures and allows the risk assessor to
use the available data to the fullest extent.
Conflict of interest statement
The authors declare that there are no conflicts of interest.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tox.2012.11.010.
References
Aerts, S., Lambrechts, D., Maity, S., Van Loo, P., Coessens, B., De Smet, F., Tranchevant,
L.C., De Moor, B., Marynen, P., Hassan, B., Carmeliet, P., Moreau, Y., 2006. Gene
prioritization through genomic data fusion. Nat. Biotechnol. 24 (5), 537–544.
API (American Petroleum Institute), 1982. Med. Res. Pub. 32-30226, October.
API (American Petroleum Institute), 1983. Med. Res. Pub. 30-32846.
ATSDR, 1995. Toxicological Profile for Gasoline. US Department of Health and Human
Services. Public Health Service Agency for Toxic Substances and Disease Registry.
ATSDR, 1999. Toxicological Profiles for Total Petroleum Hydrocarbons (TPH). US
Department of Health and Human Services. Public Health Service Agency for
Toxic Substances and Disease Registry.
Bahima, J., Menendez-Gallego, M., 1984. Identification of volatile metabolites of
inhaled n-heptane in rat urine. Toxicol. Appl. Pharmacol. 76 (3), 473–482.
Banks, D., Datta, G., Karr, A., Lynch, J., Niemi, J., Vera, F., 2012. Bayesian CAR models for
syndromic surveillance on multiple data streams: theory and practice. Inform.
Fusion 13 (2), 105–116.
Barron-Adame, J.M., Cortina-Januchs, M.G., Vega-Corona, A., Andina, D., Martinez-
Echevarria, J.I.S., 2009. Data fusion and neural network combination method for
air pollution level monitoring. In: 7th IEEE International Conference on Indus-
trial Informatics, 2009 (INDIN 2009).
Biodynamics Inc., 1978. 26 Week Inhalation Toxicity Study of n-Hexane in the Rat.
American Petroleum Institute, Washington, DC. EPA -FYI-AX-1081-0137.
Boström, H., Andler, S.F., Brohede, M., Johansson, R., Karlsson, A., van Laere, J., Niklas-
son, L., Nilsson, M., Persson, A., Ziemke, T., 2007. On the definition of information
fusion as a field of research. School of Humanities and Informatics Available
from: http://his.diva-portal.org/smash/get/diva2:2391/FULLTEXT01
Burkom, H.S., Ramac-Thomas, L., Babin, S., Holtry, R., Mnatsakanyan, Z., Yund, C.,
2011. An integrated approach for fusion of environmental and human health
data for disease surveillance. Stat. Med. 30, 470–479.
Bus, J.S., White, E.L., Tyl, R.W., Barrow, C.S., 1979. Perinatal toxicity and metabolism of
nhexane in Fischer-344 rats after inhalation exposure during gestation. Toxicol.
Appl. Pharmacol. 51 (2), 295–302.
Carpenter, C.P., Geary Jr., D.L., Myers, R.C., Nachreiner, D.J., Sullivan, L.J., King,
J.M., 1978. Petroleum hydrocarbon toxicity studies XVII: animal response to
n-nonane vapor. Toxicol. Appl. Pharmacol. 44 (1), 53–62.
Cavender, F., Casey, H., Salem, H., Graham, D., Swenberg, J., Gralla, E., 1984. A 13-
week vapor inhalation study of n-hexane in rats with emphasis on neurotoxic
effects. Fundam. Appl. Toxicol. 4 (2), 191–201.
Canadian Council of Ministers of the Environment (CCME), 2005. Toxicity Reference
Value (TRV) Advisory Sub Group, 2005 Review of Canada-Wide Standards for
Petroleum Hydrocarbons in Soil: Report of the Toxicity Reference Value (TRV)
Advisory Sub Group.
CCME, 2008. Canada-Wide Standard for Petroleum Hydrocarbons (PHC) in Soil: Sci-
entific Rationale Supporting Technical Document. January 2008 PN 1399. ISBN:
978-1-896997-77-3.
Criteria Group for Occupational Standards, 1983. Scientific Basis for Swedish Occu-
pational Standards IV. Natl. Board Occupational Safety and Health, Sweden, pp.
161–169.
Dasarathy, B.V., 1997. Sensor fusion potential exploitation – innovative architectures
and illustrative applications. Proc. IEEE 85, 24–33.
Démotier, S., Schön, W., Denoeux, T., 2006. Risk assessment based on weak infor-
mation using belief functions: a case study in water treatment. IEEE Trans. Syst.
Man Cybern. Part C 36 (3), 382–396.
Dempster, A.P., 1967. Upper and lower probabilities induced by a multivalued map-
ping. Ann. Math. Stat. 38 (2), 325–339.
Dunnick, J., Graham, D., Yang, R., Haber, S., Brown, H., 1989. Thirteen-week toxicity
study of n-hexane in B6C3F1 mice after inhalation exposure. Toxicology 57 (2),
163–172.
Edwards, D.A., Androit, M.D., Amoruso, M.A., Tummey, A.C., Bevan, C.J., Tveit, A.,
Hayes, L.A., Yongren, S.H., Nakles, D.V., 1997. Development of Fraction Specific
Reference Doses (RfDs) and Reference Concentrations (RfCs) for Total Petroleum
Hydrocarbons (TPH). Volume 4 of the Total Petroleum Hydrocarbon Criteria
Working Group Series. Amherst Scientific Publishers, Amherst, MA.
Egan, G., Spencer, P., Schaumburg, H., Murray, K.J., Bischoff, M., Scala, R., 1980.
n-Hexane-free hexane mixture fails to produce nervous system damage. Neu-
rotoxicology 1, 515–524.
Equilibrium Environmental Inc., GlobalTox Toxicology Focused Solutions and
Wilson Scientific Consulting Inc., 2005. Evaluation of issues related to the
development of updated petroleum hydrocarbon constituent toxicity reference
values and development of an updated toxicity reference value for C6–C10
aliphatic hydrocarbons.
Esteban, J., Starr, A., Willetts, R., Hannah, P., Bryanston-Cross, P., 2005. A Review of
data fusion models and architectures: towards engineering guidelines. Neural
Comput. Appl. 14, 273–281.
Ferson, S., Kreinovich, V., Ginzburg, L., Myers, D.S., Sentz, K., 2003. Constructing prob-
ability boxes and Dempster–Shafer structures. Sandia Report SAND2002-4015.
Frontali, N., Amantaini, M.C., Spagnolo, A., Guarcini, A.M., Saltari, M.C., Brugnone, F.,
Perbellini, L., 1981. Experimental neurotoxicity and urinary metabolites of the
C5–C7 aliphatic hydrocarbons used as glue solvents in shoe manufacture. Clin.
Toxicol. 18 (12), 1357–1367.
Galvin, J., Bond, G., 1999a. 2-Methylpentane(isohexane), CAS#107-83-5. J. Toxicol.
Environ. Health A 58 (1–2), 81–92.
Galvin, J., Bond, G., 1999b. 3-methylpentane (isohexane) CAS#96-14-0. J. Toxicol.
Environ. Health A 58 (1-2), 93–102.
Health Canada, 2008. Federal Contaminated Site Risk Assessment in Canada: Part
VIII: Guidance for Soil Vapour Intrusion Assessment at Contaminated Sites, Draft.
Health Canada, Contaminated Sites Division, Safe Environments Programme,
Ottawa, ON.
Health Canada, 2010a. Federal Contaminated Site Risk Assessment in Canada, Part
V: Guidance on Complex Human Health Detailed Quantitative Risk Assessment
for Chemicals (DQRACHEM), Version 1.0, Draft. Health Canada, Contaminated
Sites Division, Safe Environments Programme, Ottawa, ON.
Health Canada, 2010b. Environmental and Workplace Health-Contaminated Sites,
Available from: http://www.hc-sc.gc.ca/ewh-semt/contamsite/index-eng.php
(visited 13.07.10).
Hers, I., 2010. Recent developments for assessment and management of soil vapour
intrusion, Dr. Ian Hers, GolderAssociates Ltd. Vancouver, BC. In: MEIA 2nd
Annual Remediation & Prevention Conference, February 25, 2010. Winnipeg,
Manitoba.
Howd, R., Bingham, L., Steeger, T., Rebert, C., Pryor, G., 1982. Relation between sched-
ules of exposure to hexane and plasma levels of 2,5-hexanedione. Neurobehav.
Toxicol. Teratol. 4 (1), 87–91.
Huang, C., Kato, K., Shibata, E., Sugimura, K., Hisanaga, N., Ono, Y., Takeuchi, Y., 1989.
Effects of chronic n-hexane exposure on nervous system-specific and muscle-
specific proteins. Arch. Toxicol. 63 (5), 381–385.
Huang, J., Shibata, E., Kato, K., Asaeda, N., Takeuchi, Y., 1992. Chronic exposure to
n-hexane induces changes in nerve-specific marker proteins in the distal periph-
eral nerve of the rat. Hum. Exp. Toxicol. 11, 323–327.
Ichihara, G., Saito, I., Kamijima, M., Yu, X., Shibata, E., Toida, M., Takeuchi, Y., 1998.
Urinary 2,5-hexanedione increases with potentiation of neurotoxicity in chronic
coexposure to n-hexane and methyl ethyl ketone. Int. Arch. Occup. Environ.
Health 71 (2), 100–104.
IRDC, 1992. 6-Month continuous inhalation exposures of rats to hexane mixtures –
Phase 1.
Johnson, P.C., Ettinger, R.A., 1991. Heuristic model for predicting the intrusion
rate of contaminant vapors into buildings. Environ. Sci. Technol. 25 (8),
1445–1452.
Johnson, K., Minor, C., Guthrie, V., Rose-Pehrsson, S.L., 2009. Intelligent data fusion
for wide-area assessment of UXO contamination. Stoch. Environ. Res. Risk
Assess. 23 (2), 237–252.
Lanckriet, G.R.G., Deng, M., Cristianini, N., Jordan, M.I., Noble, W.S., 2004. Kernel-
based data fusion and its application to protein function prediction in yeast. In:
Proceedings of the Pacific Symposium on Biocomputing, pp. 300–311.
Khan, A.S., Fleischauer, A., Casani, J., Groseciose, S.L., 2010. The next public health
revolution: public health information fusion and social networks. Am. J. Public
Health 100 (7), 1237–1242.
Litton Bionetics, 1979. Teratology Study in Rats n-Hexane. Unpublished Study Pre-
pared for American Petroleum Institute. Kensington, MD.
Llinas, J., Bowman, C., Rogova, G., Steinberg, A., 2004. Revisiting the JDL data fusion
model II. In: Svensson, P., Schubert, J. (Eds.), Proceedings of the Seventh Inter-
national Conference on Information Fusion (FUSION 2004).
Lungarella, G., Barni-Comparini, I., Fonzi, L., 1984. Pulmonary changes induced in
rabbits by longterm exposure to n-hexane. Arch. Toxicol. 55 (4), 224–228.
MacEwen, J.D., Vernot, E.H., 1985. Chronic inhalation exposure of experimental
animals to methylcyclohexane. Toxic Hazards Research Unit Annual Technical
Report, AAMRL-TR-85-058, pp. 33–45.
 R. Dyck et al. / Toxicology 313 (2013) 160–173
Malley, L.A., Bamberger, J.R., Stadler, J.C., Elliot, G.S., Hansen, J.F., Chiu, T., Grabowski,
J.S., Pavkov, K.L., 2000. Subchronic toxicity of cylcohexane in rats and mice by
inhalation exposure. Drug Chem. Toxicol. 23 (4), 539–553.
Massachusetts Department of Environmental Protection (MADEP), 2003. Updated
Petroleum Hydrocarbon Fraction Toxicity Values for the VPH/EPH/APH
Methodology. Prepared by: Office of Research and Standards, Massachusetts
Department of Environmental Protection. Boston, MA.
Mast, T.J., Decker, J.R., Clark, M.L., Rossignol, E., Westerberg, R.B., McCulloch, M.,
et al., 1987. Inhalation developmental toxicology studies: teratology study of
n-hexane in rats. Report No. NIH-YO1-ES-70153. Pacific Northwest Laboratory,
Richland, WA.
Mast, T.J., Decker, J.R., Stoney, K.H., Westerberg, R.B., Evanoff, J.J., Rommereim,
R.L., Weigel, R.J., 1988. Inhalation developmental toxicology studies: teratology
study of n-hexane in mice. Report No. NIH-Y01-ES-70153. Pacific Northwest
Laboratory, Richland, WA.
National Academy of Sciences (NAS), 2009. Science and Decisions: Advancing Risk
Assessment. National Academy Press, Washington, DC.
National Toxicology Program (NTP), 1991. Report on the Toxicity Studies of n-
Hexane in B6C3F1 Mice. Research Triangle Park, NC.
Olson, C.T., Yu, K.O., Hobson, D.W., Serve, M.P., 1986. The metabolism of n-octane in
Fischer 344 rats. Toxicol. Lett. 31 (2), 147–150.
Ono, Y., Takeuchi, Y., Hisanaga, N., 1981. A comparative study on the toxicity of n-
hexane and its isomers on the peripheral nerve. Int. Arch. Occup. Environ. Health
48 (3), 289–294.
Ono, Y., Takeuchi, Y., Hisanaga, N., Iwata, M., 1982. Neurotoxicity of petroleum ben-
zene compared with n-hexane. Int. Arch. Occup. Environ. Health 50, 219–229.
Palisade Corporation, 2010. @RISK for Excel, Risk Analysis Add-in for Microsoft Excel,
Version 5.5.1: Industrial Edition.
Park, I.S., Park, J.W., 2010. A novel total petroleum hydrocarbon fractionation strat-
egy for human health risk assessment for petroleum hydrocarbon-contaminated
site management. J. Hazard. Mater. 179, 1128–1135.
Parnell, M., Henningsen, G., Hixson, C., Yu, K., McDonald, G., Serve, M., 1988. The
metabolism of methylcyclohexane in Fischer 344 rats. Chemosphere 17 (7),
1321–1327.
Perbellini, L., Brugnone, F., Cocheo, V., De Rosa, E., Bartolucci, G., 1986. Identifica-
tion of the n-heptane metabolites in rat and human urine. Arch. Toxicol. 58 (4),
229–234.
Ping, J., Chen, B., Husain, T., 2010. Risk assessment of ambient air quality by
stochastic-based fuzzy approaches. Environ. Eng. Sci. 27 (3), 233–246.
Pryor, G., Bingham, L., Dickinson, J., Robert, C., Howd, R., 1982. Importance of sched-
ule of exposure to hexane in causing neuropathy. Neurobehav. Toxicol. Teratol.
4, 71–78.
Rabovsky, J., Judy, D., Pailes, W., 1986. In vitro effects of straight chain alkanes (n-
hexane through n-dodecane) on rat liver and lung cytochrome P450. J. Toxicol.
Environ. Health 18, 409–421.
Sadiq, R., Rodriguez, M.J., 2005. Predicting water quality in the distribution system
using evidential theory. Chemosphere 59 (2), 177–188.
Sadiq, R., Najjaran, H., Kleiner, Y., 2006. Investigating evidential reasoning for the
interpretation of microbial water quality in a distribution network. Stoch. Envi-
ron. Res. Risk Assess. 21 (1), 63–73.
Sadiq, R., Islam, M.S., Zargar, A., Dyck, R., 2011. Risk Assessment Framework for
Contaminated Sites: A Critical Review and Potential Applications of Data Fusion
Methods. Health Canada, Calgary, AB, p. 121.
Sanz, P., Flores, I., Soriano, T., Repetto, G., Repetto, M., 1995. In vitro quantitative
structure–activity relationship assessment of pyrrole adducts production by
gamma-diketone forming neurotoxic solvents. Toxicol. In Vitro 9 (5), 783–787.
Satpathy, S., Mohapatra, A., 2009. A data fusion based digital investigation model
as an effective forensic tool in the risk assessment and management of
cyber security systems. In: The 6th International Conference on Cybernetics
173
and Information Technologies, Systems and Applications: CITSA 2009, July
10th–13th, 2009. Orlando, FL, USA.
Sayre, L., Shearson, C., Wongmongkolrit, T., Medori, R., Gambetti, P., 1986. Structural
basis of gamma-diketone neurotoxicity: non-neurotoxicity of 3,3-dimethyl-2,5-
hexanedione, a gamma-diketone incapable of pyrrole formation. Toxicol. Appl.
Pharmacol. 84, 36–44.
Schmitt, K., 2006. Combining information in human health risk assessment. Avail-
able from: http://gradworks.umi.com/32/02/3202383.html (visited 07.09.10).
Sentz, K., Ferson, S., 2002. Combination of evidence in Dempster–Shafer theory.
Sandia Report SAND2002-2835.
Serve, M.P., Bombick, D., Roberts, J., McDonald, G., Mattie, D., Yu, K., 1991. The
metabolism of 2,5-dimethylhexane in male Fischer 344 rats. Chemosphere 22
(1-2), 77–84.
Serve, M.P., Bombick, D.D., Clemens, J.M., McDonald, G.A., Mattie, D.R., 1992. The
metabolism of 2-methylheptane in male Fischer 344 rats. Chemosphere 24 (5),
517–524.
Serve, M.P., Bombick, D.D., Clemens, J.M., Mcdonald, G.A., Hixson, C.J., Mattie, D.R.,
1993. The metabolism of 3-methylheptane in male Fischer rats. Chemosphere
26 (9), 1667–1677.
Serve, M.P., Bombick, D.D., Clemens, J.M., Rezek, T.M., Mcdonald, G.A., Mattie, D.R.,
1994. The metabolism of 4-methylheptane in male Fischer 344 rats. Chemo-
sphere 28 (9), 1571–1579.
Serve, M.P., Bombick, D., Baughman, T., Jarnot, B., Ketcha, M., Mattie, D., 1995.
The metabolism of n-nonane in male Fischer 3-44 rats. Chemosphere 31 (2),
2661–2668.
Sevigny, J.H., Tindal, M.J., Robins, G.L., Staudt, W., Servin, L., 2003. Importance of
different volatile petroleum hydrocarbon fractions in human health risk assess-
ment. Hum. Ecol. Risk Assess. 9 (4), 987–1001.
Steinberg, A., Bowman, C., White, F., 1999. Revisions to the JDL data
fusion model. Available from: http://oai.dtic.mil/oai/oai?verb=
getRecord&metadataPrefix=html&identifier=ADA391479
Steinberg, A., Bowman, C., 2004. Rethinking the JDL data fusion levels,
NSSDF JHAPL. Available from: http://scholar.google.com/scholar?hl=en&btnG=
Search&q=intitle:Rethinking+the+JDL+data+fusion+levels#0 (visited 07.09.10).
Takeuchi, Y., Ono, Y., Hisanaga, N., 1981. A comparative study of the toxicity of npen-
tane, n-hexane, and n-heptane to the peripheral nerve of the rat. Clin. Toxicol.
18 (12), 1395–1402.
United States Environmental Protection Agency (US EPA), 2000. Supplemen-
tary Guidance for Conducting Health Risk Assessment of Chemical Mixtures,
EPA/630/R-00/002. Risk Assessment Forum Technical Panel, Washington, DC.
US EPA, 2012. Integrated Risk Information System (IRIS). Available from:
http://www.epa.gov/iris/help gloss.htm (accessed 28.03.12).
Valentini, F., Agnesi, R., Vecchio, L.D., Bartolucci, G., De Rosa, E., 1994. Does n-heptane
cause peripheral neurotoxicity? A case report in a shoemaker. Occup. Med. 44
(2), 102–104.
Wilson Scientific Consulting Inc. and Meridian Environmental Inc., 2007. Review of
the irritancy of C6-C8 aliphatics. No. H4002-040953/001/XSB, C6-C8 Aliphatics
HECS-SEP-BC 06/07-35.
Yager, R.R., 1987. On the Dempster–Shafer framework and new combination rules-1.
Inform. Sci. 41 (2), 93–137.
Yuasa, J., Kishi, R., Eguchi, T., Harabuchi, I., Kawai, T., Ikeda, M., Sugimoto, R., Mat-
sumoto, H., Miyake, H., 1996. Investigation on neurotoxicity of occupational
exposure to cyclohexane: a neurophysiological study. Occup. Environ. Med. 53
(3), 174–179.
Zargar, A., Dyck, R., Islam, M.S., Mohapatra, A., Sadiq, R., 2012. Data fusion methods
for human health risk assessment: review and application. J. Hum. Ecol. Risk
Assess., in press.
Zhang, Y., Collins, L., Carin, L., 2003. Unexploded ordnance detection using Bayesian
physics-based data fusion. Integr. Comput. Aided Eng. 10 (3), 231–247.