Water Air Soil Pollut: Focus (2008) 8:3–21

DOI 10.1007/s11267-007-9137-7

A Multiscale Approach for Assessing the Interactions

of Environmental and Biological Systems in a Holistic
Health Risk Assessment Framework
Panos G. Georgopoulos

Received: 15 November 2006 / Accepted: 22 February 2007 / Published online: 10 August 2007
# Springer Science + Business Media B.V. 2007

Abstract Advances in computing processing power 1 Introduction: The Evolution of Environmental

and in availability of environmental and biological data Risk Assessment
have allowed the development and application of
comprehensive modeling systems that utilize a holistic, Advances in computational technologies (e.g. affordable
integrated, approach for assessing the interactions of cluster and grid computing hardware; efficient software
environmental and biological systems across multiple for the management and analysis of massive, distributed,
scales of spatiotemporal extent and biological organiza- multiscale and multidimensional datasets; fast algorithms
tion. This approach allows mechanism-based environ- for numerical simulation and uncertainty analysis) and
mental health risk assessments in a person-oriented the development of widely accessible databases of
framework, which accounts for simultaneous exposures environmental, physicochemical, biological, demograph-
to contaminants from multiple media, routes, and path- ic, and other information are forcing a major “paradigm
ways. The conceptual basis and example applications of shift” in the approaches for analyzing and quantifying the
the Modeling ENvironment for TOtal Risk (MENTOR), complex interactions of human beings (and other
and the DOse–Response Information ANalysis system biological entities) and their environment. Human
(DORIAN) are presented. activities continuously modify the environment on a
variety of scales, from indoor to global, and the resulting
Keywords Comprehensive modeling systems . changes of environmental properties act as stressors that
DORIAN . MENTOR . Environmental health . can affect human and ecological health. Assessing the
Risk assessments . Exposures to mixtures health risks associated with environmental factors
requires one to understand and quantify, in a mechanistic
way, the events and processes involved in the “environ-
mental health sequence” (presented schematically in
Fig. 1) from “source” (e.g. the release or the formation
of a stressor, such as a chemical or a radiological
contaminant or a biological agent in an environmental
medium) to “outcome” (e.g. development of an envi-
P. G. Georgopoulos (*)
ronmentally caused disease).
Computational Chemodynamics Laboratory (CCL),
Environmental and Occupational Health Sciences Institute Human health state reflects multiscale body “system
(EOHSI), UMDNJ Robert Wood Johnson Medical School dynamics” that involve interactions among multiple
and Rutgers University, levels (scales) of biological organization (genome, tran-
170 Frelinghuysen Road – Room 308,
scriptome, proteome, metabolome, cytome, physiome)
Piscataway, NJ 08854, USA
e-mail: [email protected] that are in turn affected by various types of environmen-
url: www.ccl.rutgers.edu tal (“extragenomic”) factors. In fact, what are commonly
4 Water Air Soil Pollut: Focus (2008) 8:3–21

Fig. 1 Schematic representation of the “environmental health sequence” from “source” to “outcome,” involving a series of
environmental and biological “steps”

referred to as “Gene-Environment” interactions occur at performed on a “stressor-by-stressor basis” (e.g. for

various steps of the exposure-to-effect sequence, as individual chemical, radiological, or biological agents)
genes may be controlling processes that affect exposure, and for a given environmental medium (e.g. atmo-
dose, toxicokinetics, and toxicodynamics; at the same sphere, groundwater, etc.) typically associated with a
time, extragenomic factors and development/aging may single exposure route (e.g. inhalation, ingestion, dermal
also control various aspects of genome dynamics absorption, etc.; see Table 1). This practice has evolved
(Fig. 2). The statement, “Genetics loads the gun, but over time to allow consideration of multiple contam-
environment pulls the trigger” (Judith Stern, Professor inants present in multiple media and associated with
of Nutrition and Internal Medicine, University of different exposure routes. Nevertheless, the focus has
California at Davis) is often made. This statement is, remained on contaminant-specific and route-specific
of course, a “grand simplification,” but a very useful risk characterization, either for a hypothetical “maxi-
one, that is affecting both popular perception and mally exposed” individual or for a general population
evolving approaches toward mechanistic environmental with simplified distributions of demographic and
health risk assessments. “Timing” and combination of physiological attributes. In recent years, however, a
exposures as well as behavior (which can be affected major shift has been taking place through the develop-
by genetics and can modify the environment and one’s ment of “person-oriented” (i.e. anthropocentric) “ho-
exposures) are also critical for an individual’s risk. The listic” approaches and models that aim to account for
genetic code for any individual can be seen as a “set of total (“cumulative” and “aggregate”) exposures of
initial conditions” for a dynamic biological system that individuals (or of populations consisting of such
will evolve under the influence of environmental individuals) to co-occurring stressors (e.g. mixtures of
conditions, which depend critically on human behavior. contaminants present in the air inhaled and in the water
A “person-specific,” anthropocentric approach, which and food digested by the person; Buck et al. 2003;
takes into account all the above, is therefore necessary Christensen et al. 2003; NUREG 2002; Price et al.
for realistic risk characterization. 2003; Price and Chaisson 2005; USEPA 2003b, 2006;
In the past, assessing the human impact on the WHO 2005). These new holistic, “systems-based” ap-
environment and the subsequent impact of environ- proaches focus on individual persons, real or “virtual,”
mental change on human well-being, was typically with well defined physiological, socioeconomic, etc.
Water Air Soil Pollut: Focus (2008) 8:3–21 5

Fig. 2 Human health state reflects multiscale body “system dynamics” (genome, transcriptome, proteome, metabolome, cytome,
physiome) that are affected by environmental (“extragenomic”) factors

attributes, and take into account how the detailed vant dose (e.g. inhalation rates, metabolic transforma-
activities of these persons in space and time affect their tion/elimination rates, etc.). Proceeding a step further,
“microenvironments” and their corresponding expo- person-oriented approaches aim to take advantage of
sures to stressors, as well as how they affect the information on genetic and other factors that may
physiological processes determining biologically rele- determine individual susceptibility to environmental

Table 1 The evolving focus of environmental human and ecological health risk analysis

Past: single pathway analysis Present: multiple pathway analysis Future: integrated “person-oriented” systems analysis
of risk of risk of risk

Single contaminant Multiple contaminants Mixtures of contaminants with environmental and

biological interactions
Multiple contaminant sources Multiple contaminant sources Multiple co-occurring chemical and nonchemical
stressors affecting an individual
Single medium environmental Linked fate and transport in different Dynamically integrated multimedia fate and transport in
fate and transport environmental media the environmental and biological systems
Single exposure route Multiple exposure routes Aggregate/cumulative exposure and dose analysis
Phenotype-based toxicity Phenotype-based toxicity with Mechanistic linkage of phenotype with genotype
susceptibility considerations
Primary human health criteria for Chemical and exposure-route specific Aggregated risk for diverse human populations (with
individual contaminants risk for “standard individuals” susceptible subpopulations)
Qualitative uncertainty Quantitative uncertainty Quantitative uncertainty and variability resolved for
specific environmental and biological processes
6 Water Air Soil Pollut: Focus (2008) 8:3–21

stressors. The current explosion in toxicoinformatic environmental, biological, physiological, demographic,

(genomic, transcriptomic, proteomic, metabonomic, etc. parameters (see Appendix for a representative list
etc.) data is expected with time to provide critical of such databases). A major issue in implementing
understanding of the interindividual variability in consistent source-to-dose modeling is sequentially
responses to various environmental factors and of related going from global/regional to local, neighborhood,
disease susceptibility, which will eventually give rise to and eventually personal resolution. MENTOR provides
truly “personalized” risk assessments. “tools” that link regional and local information with
The following sections present a summary overview microenvironmental conditions and human activities,
of a continuing research effort, funded primarily by the as shown schematically in Fig. 3, which is adapted
US Environmental Protection Agency (USEPA), to from concepts in Georgopoulos et al. (1997) and
develop, evaluate, and apply mechanistic and diagnostic USEPA (2003a).
computational modeling tools intended to support In order to provide “user-oriented” implementations
comprehensive analyses of all steps in the “environmen- of MENTOR for specific applications, a number of
tal health sequence” of Fig. 1. This effort has resulted in “customized” versions have been developed, as follows:
the evolution of two “libraries of software compo-
& MENTOR-1A (Georgopoulos et al. 2005a)
nents,” involving both modeling and data modules,
employs a “one atmosphere” approach to charac-
developed in C++, Java, and Matlab, and operating, in
terize simultaneous exposures of individuals or
conjunction with database engines, on customized
populations to multiple, co-occurring atmospheric
Linux clusters. These libraries constitute the Modeling
contaminants (e.g. ozone, fine particles, air toxics,
ENvironment for TOtal Risk studies (MENTOR) that
etc.). The “one atmosphere” approach places
addresses the “source-to-dose” steps, and the DOse–
emphasis on accounting for the dynamic physical
Response Information ANalysis system (DORIAN) for
and chemical interactions of the contaminants, in
the biological “dose-to-effect” steps. It should be noted
both ambient air and in specific residential,
that the analyses supported by MENTOR and DORIAN
occupational, and vehicular microenvironments.
are in principle “bi-directional,” i.e. allowing not only
calculations of dose and biological effect from envi- & MENTOR-4M (Georgopoulos et al. 2005b, 2006)
ronmental and exposure information, but also, under provides a unified multiroute/multipathway model-
certain conditions, the reconstruction of environmental ing framework for aggregate and cumulative
exposure patterns from appropriate biomarker data. exposure assessments. The focus is on contami-
nants that are present in multiple environmental
media and on mixtures of such contaminants.
2 The Modeling Environment for Total Risk & MENTOR-3P is a modular, “generalized” phys-
Studies (MENTOR) iologically-based pharmacokinetic modeling
framework for human populations that allows si-
MENTOR is an open computational toolbox that multaneous consideration of multiple, co-occurring
provides modeling and data analysis tools to facilitate chemicals in a consistent manner, while incor-
the assessment of cumulative (i.e. over time) and porating information for attributes of intra- and
aggregate (multipathway) exposures to mixtures of inter-individual variation and variability, either
environmental contaminants, by following a mechanis- physiological or biochemical, from various recent
tically consistent probabilistic source-to-dose modeling databases (CDC 2005; The Lifeline Group 2006).
approach. MENTOR utilizes existing models, when & MENTOR-2E provides computational tools appro-
available, and also provides new approaches to “fill priate for characterizing exposures specifically for
gaps” in the source-to-dose sequence (Georgopoulos et emergency events, as a means for improving
al. 2005a, b; Georgopoulos and Lioy 2006). Thus, planning for emergency response. Accordingly,
MENTOR links dynamic numerical models for envi- emphasis is given to the critical attributes of phys-
ronmental fate/transport and for human exposure and icochemical processes across the various temporal
dose calculations; these models are coupled with up-to- and spatial scales that are relevant to the evolution of
date national, regional, and local (currently primarily the emergency event (Georgopoulos et al. 2004;
from the USA) databases of environmental, micro- Stenchikov et al. 2006).
Water Air Soil Pollut: Focus (2008) 8:3–21 7

Fig. 3 MENTOR supports source-to-dose modeling over multiple scales, down to resolutions relevant to exposures of individuals; it
links environmental models and databases with exposure/dose models

& MENTOR-DOT provides a wide range of state-of- population representing the population of concern for
the-art diagnostic tools, such as the Stochastic Re- the exposure period through either (a) existing data-
sponse Surface Method (SRSM) (e.g. Balakrishnan et bases from composites of past studies (for baseline
al. 2003, 2005), the High Dimensional Model assessment) or (b) study-specific information (special
Representation (HDMR) (e.g. Wang et al. 2005a), registries); (5) Estimation of multimedia levels and
and Bayesian Markov Chain Monte Carlo (MCMC) temporal profiles of pollutants in various microenvi-
optimization techniques (e.g. Balakrishnan et al. ronments (streets, residences, offices, restaurants,
2003), which allow comprehensive sensitivity/ vehicles, etc.) through either (a) field study measure-
uncertainty analysis of complex system models, ments or (b) microenvironmental mass-balance mod-
systematic complex model reduction to obtain Fast eling (air), drinking water distribution modeling
Equivalent Operational Models (FEOMs), and (water), and dietary concentration modeling (food);
efficient model/data fusion. (6) Calculation of appropriate inhalation rates, as well
as drinking water and food consumption rates for the
Typically, MENTOR simulations consist of: (1) members of the sample population, through a combi-
Estimation of (multimedia) background levels of nation of the physiological attributes of the study
environmental pollutants (in air, water, and soil) subjects and the activities pursued during the individ-
through either (a) multivariate spatiotemporal analysis ual exposure events; and (7) Biologically-based target
of monitor data or (b) regional-scale environmental tissue dose (toxicokinetic) modeling. This last step
model predictions; (2) Estimation of local multimedia provides a significant advantage over past practices in
pollutant levels in an appropriate administrative unit exposure assessment, as it allows model evaluation
(such as a census tract) or a conveniently defined grid against field measurements of biomarkers, when such
through either (a) field study measurements, (b) information is available.
subgrid “corrections” of regional model estimates, or
(c) application of a local scale environmental model; 3 The Dose–Response Information Analysis
(3) Characterization of essential demographic attrib- System (DORIAN)
utes of populations (geographic density, age, gender,
race, occupation, income, etc.); (4) Development of The DORIAN system is being developed by a USEPA-
activity event sequences for each member of a sample funded research consortium that includes UMDNJ-RW
8 Water Air Soil Pollut: Focus (2008) 8:3–21

Johnson Medical School; Rutgers University; Princeton support usage of DORIAN in real-world applications,
University; and the US Food and Drug Administration’s an “environmental bioinformatics Knowledge Base”
National Center for Toxicological Research, Center for (ebKB; see http://www.ebKB.org or http://www.
Toxicoinformatics. It is complementing MENTOR by EnvironmentalBioinformatics.org – Fig. 5) has been
providing components that mechanistically address the developed and is being updated regularly to include
biological phenomena taking place in the dose-to-effect advancements in this field. A representative selection
part of the “environmental health sequence” of Fig. 1. from the wide spectrum of databases that are linked
This is allowing the completion of comprehensive through ebKB can be found in Tables 2 and 3 in the
toxicity and risk assessment studies by incorporating Appendix.
toxicogenomic information that is becoming available A specific objective of the DORIAN effort is to
from various transcriptomic, proteomic, and metabo- produce generalized, integrated, physiologically based
nomic laboratory studies (the complementary structures models for the “coupled” toxicokinetics and toxico-
of MENTOR and DORIAN are shown schematically dynamics of contaminants of concern and their
in Fig. 4). DORIAN includes ebTrack, which expands mixtures (Abdel-Rahman and Kauffman 2004; Dan-
the features of ArrayTrack (Tong et al. 2003), by hof et al. 2007). These models are designed so as to
incorporating a range of options for the analysis of describe quantitatively both the processes affecting
proteomic and metabonomic datasets, in addition to the contaminant in the organism (absorption, distri-
providing additional analysis options for microarray bution, metabolism, elimination) and the processes
gene expression data (e.g. Ouyang et al. 2004). To resulting to toxicity due to the contaminant. So, the

Fig. 4 DORIAN complements MENTOR by coupling toxicoinformatic databases and biologically-based dose–response models to
the components of MENTOR, to support the analysis of the complete environmental “source-to-outcome” health sequence of Fig. 1
Water Air Soil Pollut: Focus (2008) 8:3–21 9

biologically-based toxicodynamic models link target are regularly incorporated in the DORIAN system to
tissue molecular and cellular events (e.g. receptor ensure its relevance and usefulness.
activation, changes in ion channel functions, etc.) to
consequent biochemical and physiological changes.
The DORIAN development effort benefits directly 4 Examples: Selected Case Studies
from a wide range of ongoing activities in computa-
tional cell biology (e.g. Slepchenko et al. 2002; Various problem-specific implementations of MEN-
Takahashi et al. 2003), computational physiology (e.g. TOR have been developed and applied to a wide
Crampin et al. 2004; Strategy for the EuroPhysiome range of environmental issues including: regional
(STEP) Consortium 2006), toxicogenomics (e.g. NRC ozone pollution (Foley et al. 2003); urban and local
2005; UK Environment Agency 2003; USEPA 2004), scale inhalation exposures to co-occurring ozone,
systems toxicology (e.g. USEPA 2003b; BMBF 2002; particulate matter and air toxics (Georgopoulos et al.
Waters et al. 2003) and other related fields, taking 2005a; Isukapalli et al. 2005); multimedia and multi-
place in North America, Europe, Japan, New Zealand, pathway exposures to copper (Georgopoulos et al.
and elsewhere. Outcomes from these research efforts 2006), to mercury and its compounds (Wang et al.

Fig. 5 The environmental bioinformatics Knowledge Base (ebKB) is an evolving compendium of computational tools, databases, and other
pertinent information that is needed for the systematic analysis of environment–organism interactions that occur over multiple scales
10 Water Air Soil Pollut: Focus (2008) 8:3–21

2005b), to arsenic (Georgopoulos et al. 2005b, 2007), Figure 8 provides an example of biologically-based
to trichloroethylene (Wang et al. 2005a), etc. Special calculations of target tissue doses for exposure to
focus has been given in the evaluation of novel mixtures of metals and their compounds, utilizing
methods for systematic simplification of complex MENTOR-3P. Figure 9 shows example results of
models (e.g. Wang et al. 2005a) and for uncertainty prototype source-to-dose assessments of arsenic expo-
analysis and reduction (e.g. Balakrishnan et al. 2003). sures and of corresponding target tissue doses, which
A summary review of the range of past applications of were performed using the MENTOR-4M and MEN-
MENTOR can be found in Georgopoulos and Lioy TOR-3P platforms, for a sample population in the
(2006). Development and application of DORIAN USA. These studies included physiologically-based
components and assemblage of related data modules calculations of the toxicokinetics of different forms of
commenced in 2005 and up-to-date information on arsenic for all the individuals of the virtual population
progress and current activities related to DORIAN is considered. Specifically, Fig. 9a shows predicted
posted regularly on the web site www.ebCTC.org. cumulative arsenic (total and inorganic) exposure
Selected new results are presented here from applica- distributions from inhalation, food intake, drinking
tions of coupled MENTOR and DORIAN modules (for water consumption, and non-dietary routes and Fig. 9b
environmental and biological processes, respectively) shows predicted cumulative distributions of inorganic
to problems involving human exposures to contami- arsenic (AsIII+AsV) and organic arsenic species
nants that are associated with a variety of toxicological (MMA+DMA) internal dose in kidney and liver, for
endpoints. Figures 6 and 7 show respectively, the the population of Franklin County, OH (Georgopoulos
compartmental structures of the environmental and et al. 2005b).
biological modeling frameworks employed in MENTOR Figure 10 shows an example outcome of a MENTOR-
and DORIAN. 1A application involving the prediction of PM2.5

Fig. 6 Schematic depiction of the modular, multiscale, modeling framework of MENTOR for assessing environmental “material
flows” and resulting human exposure to mixtures of contaminants present in different media
Water Air Soil Pollut: Focus (2008) 8:3–21 11

concentrations and corresponding high-end population from indoor sources. One of the many factors affecting
doses for the population of the city of Philadelphia, PA, the biologically relevant doses shown in Fig. 10b and c
USA. Figure 10a shows 24-h averaged local outdoor is human activity; in the simulations shown here,
concentrations on July 19, 1999 for 482 urban spatiotemporal distributions of human activities were
Philadelphia census tracts, derived from hourly PM2.5 derived from information contained in the Consolidat-
predictions of the Community Multiscale Air Quality ed Human Activity Database (CHAD – Stallings et al.
(CMAQ) model (Byun and Ching 1999) that were 2002) and the aerosol dosimetry module of MENTOR-
“scaled” at census tract level using the Bayesian 3P was used to calculate the respiratory deposition for
Maximum Entropy (BME) method (Christakos et al. virtual individuals of the simulation. Figure 10d shows
2001), which “fuses” all available information (from an example of the importance of considering activity
both modeling and observations), taking into account levels in dosimetry calculations: experimental human
spatial and temporal trends simultaneously. Figure 10b dosimetry data (Jaques and Kim 2000; Daigle et al.
shows the corresponding 95th percentiles, for each 2003) collected under conditions of moderate exercise
census tract, of 24-h aggregated total inhalation doses are compared to predictions from the Multiple Path
from both outdoor and indoor sources. The color Particle Dosimetry (MPPD2 – CIIT 2006) and from
scheme shows quantiles of the concentration and the the International Commission on Radiological Protec-
dose distributions; the blank census tracts represent tion (ICRP – Jarvis et al. 1996) models as well as with
airports and other areas not considered in the study predictions from MENTOR-3P (it should be noted that
(Georgopoulos et al. 2005a). Figure 10c shows the the predictions from the three models do not deviate
cumulative distribution function for total PM2.5 dose from each other and from the measurements in the case
from outdoor sources and the corresponding total dose of resting conditions). These results demonstrate the

Fig. 7 The physiologically-based toxicokinetic modules of designed so as to account for intra-individual and inter-
MENTOR and DORIAN aim to characterize uptake and target individual variability within a human population, including
tissue dose for cumulative and aggregate exposure; they are the effects of development and aging
12 Water Air Soil Pollut: Focus (2008) 8:3–21
Fig. 8 Simulated hepatic “Standard” 70 kg male consuming a 1 mg oral
concentration profiles of dose each of As(V), Cr(VI), MeHg, Pb, and Cd
–1
metals and metabolites for a 10
standard reference male
ingesting a mixture of met-
als (specified in legend)

–2
10

Concentration (mg/L)
–3
10

As(V)
–4 As(III)
10 MMA
DMA
Cr(III)
MeHg
Pb
Cd

0 1 2 3 4
Time (days)

importance of considering human activities and micro- multiple biological levels (genes, proteins, metabolites)
environmental conditions in assessing dosages for to determine the corresponding impact on bionetwork
individuals and populations. (signaling, regulatory, metabolic) dynamics. Numerous
Figure 11 depicts schematically how the environ- studies in the emerging field of toxicogenomics aim to
mental health risk assessment process in the DORIAN relate susceptibility of individuals to environmental
framework is applied to connect genotypes and pheno- agents by identifying genes that are expressed differen-
types to assess disease susceptibility with respect to tially in the presence of these agents. Genetic variability
specific environmental agents. This requires data/infor- in these genes (e.g., presence of Single Nucleotide
mation integration on the effects of xenobiotics across Polymorphisms [SNPs]) may be associated with in-

Fig. 9 a Predicted cumulative arsenic (total and inorganic) (MMA+DMA) species internal dose distributions of kidney and
exposure distributions from inhalation, food intake, drinking liver, for the population of Franklin County, OH. Calculations
water consumption, and non-dietary routes and b predicted were performed with the MENTOR-4M and MENTOR-3P
cumulative inorganic arsenic (AsIII +AsV) and organic arsenic models
Water Air Soil Pollut: Focus (2008) 8:3–21 13

creased (or decreased) susceptibility to the effects of the tational tools for assessing and analyzing the information
environmental agents. However, in general, a phenotype arising from new toxicogenomic studies, in conjunction
is the result of the collective response of a group of with the information available in numerous existing
genes (gene network). Furthermore, gene regulation is bionomic databases (see Table 3 in Appendix). Typical
distributed over multiple levels (genes and messenger components of this approach include: (a) the develop-
RNA, proteins, and metabolites) and it is necessary to ment of regulatory networks of signal transduction
identify and characterize processes across the entire integrated with hormonal and metabolic networks; (b)
bionetwork of interactions involved in the expression of the analysis of relevant available data (transcriptomic,
the genes of concern. DORIAN brings together compu- proteomic, metabolomic, lipidomic, etc.) for the contam-

Fig. 10 a 24-h averaged local outdoor concentrations on July airports and other areas not considered in the study. c Cumulative
19, 1999 for 482 urban Philadelphia, PA, USA census tracts, distribution function for total PM2.5 dose from outdoor sources
derived from hourly PM2.5 predictions of the Community and the corresponding total dose from indoor sources;
Multiscale Air Quality (CMAQ) model that were “scaled” at d Experimental aerosol dosimetry data under moderate exercise
census tract level, using the Bayesian Maximum Entropy (BME) conditions (Jaques and Kim 2000; Daigle et al. 2003) compared
method; b Corresponding 95th percentiles, for each census tract, to predictions of the Multiple Path Particle Dosimetry (MPPD2 –
of 24-h aggregated total inhalation doses from both outdoor and CIIT 2006) and International Commission of Radiological
indoor sources. The color scheme shows quantiles of concen- Protection (ICRP – Jarvis et al. 1996) models, and the inhalation
trations/dose distribution; the blank census tracts represent dosimetry module of MENTOR-3P (identified as CCL)
14 Water Air Soil Pollut: Focus (2008) 8:3–21

Fig. 11 Environmental health risk assessment process aims to (e.g. SNPs) to altered enzyme function and metabolic processes
connect genotypes and phenotypes to assess disease suscepti- and finally to variation in disease susceptibility by elucidating
bility to environmental agents by integrating data/information the biological mechanisms involved in signaling and gene
across multiple biological levels and determining bionetwork regulatory processes [the hypothetical gene-protein-metabolite
dynamics: the framework that is presented schematically here, bionetwork of the left side of the figure has been adapted from
as implemented in DORIAN, aims to relate genotypic variation Brazhnik et al. (2002)]
inants and endpoints of concern; (c) the identification of and deployment of methods that rely on a systematic
transcription factor binding sites in the promoter regions integration of exposure and biological processes for
of gene regulatory clusters; and (d) the identification of understanding the “coupled dynamics” of environmental
key network nodes. This approach and the related and human health states (see also Schwartz and Collins
computational tools thus support the elucidation of 2007). As such methods evolve toward maturity and
biological action mechanisms and allow the development widespread acceptance, they can be reasonably
of quantitative models that relate genotypic variation to expected to provide various opportunities for rethink-
variability in the signaling, gene-regulatory and metabol- ing and reevaluating environmental and public health
ic processes involving environmental contaminants, policy practices, by taking into account the variability
which in turn affect the distribution of responses (health among individuals that simultaneously experience
impact) within a human population. multiple, possibly interacting, environmental stressors.

5 Conclusions
Acknowledgments Support for this work has been provided
primarily by the USEPA-funded Environmental Bioinformatics
The various applications of MENTOR to a wide range and Computational Toxicology Center (ebCTC) under STAR
of environmental problems, and the recent applications Grant No. GAD R 832721-010, and the USEPA funded Center for
Exposure and Risk Modeling (CERM) under Cooperative Agree-
of combined MENTOR and DORIAN modules that ment no. CR-83162501. This work has not been reviewed by and
were reported here, demonstrate the feasibility and the does not represent the opinions of the funding agency. Appreci-
potential of holistic, “person-oriented” approaches in ation is extended to the research team of CCL, with special thanks
studying environmental health issues. The selected to Profs S. Isukapalli and S. W. Wang, as well as to A. Sasso, Y. C.
Yang, and P. Shade. Thanks are also due to Prof P.J. Lioy (CERM),
references listed in this work demonstrate that there is
Prof W. Welsh (ebCTC), Dr W. Tong (USFDA-NCTR Center for
extensive activity in North America, Europe, Japan, Toxicoinformatics), and to the numerous USEPA and EOHSI
New Zealand, and elsewhere, towards the development collaborators who have contributed to this research.
Water Air Soil Pollut: Focus (2008) 8:3–21 15

Appendix
Table 2 A representative subset of databases (with website reference) that are available for providing data for use in MENTOR
applications (see http://www.ebKB.org for a more extensive list)

Exposure Databases

Environmental releases
HazDat – Hazardous Substance Release and Health Effects Database (ATSDR) http://www.atsdr.cdc.gov/hazdat.html
NEI – National Emission Inventory (air emissions; USEPA) http://www.epa.gov/ttn/chief/net/
TRI – Toxics Release Inventory (multimedia releases; USEPA) http://www.epa.gov/tri/
USGS Pesticide Use Database (USGS) http://ca.water.usgs.gov/pnsp/rep/
ofr00250/
NCFAP Pesticide Use Database (NCFAP) http://www.ncfap.org/ncfap/
nationalsummary1997.pdf
NPIRS National Pesticide Information Retrieval System (USDA/PPIS) http://ppis.ceris.purdue.edu/npublic.htm
Geography/topography/land use/vegetation
Digital Elevation Data (NRCS) http://www.ncgc.nrcs.usda.gov/products/
datasets/elevation/
NED – National Elevation Dataset (USGS) http://ned.usgs.gov/
LandScan USA (High Resolution Population Distribution Project; ONRL) http://www.ornl.gov/sci/gist/landscan/
landscanUSA/index.html
LULC – Land Use and Land Cover (USGS) http://edc.usgs.gov/products/landcover/
lulc.html
NLCD – National Land Cover Dataset (USGS) http://landcover.usgs.gov/natllandcover.
php
MODIS Satellite Land, Ocean, Atmosphere Products (NASA) http://modis.gsfc.nasa.gov/data/dataprod/
index.php
Meteorology/hydrology
ARS – Agricultural Research Service Water Database (precipitation and streamflow http://hydrolab.arsusda.gov/wdc/arswater.
data; USDA) html
ASOS/AWOS – Automated Surface and Weather Observing Systems (FAA) http://www.faa.gov/
NCDC – National Climatic Data Center (NOAA) http://www.ncdc.noaa.gov/oa/ncdc.html
NWS – National Weather Service (NOAA) http://www.nws.noaa.gov/
Environmental/microenvironmental contaminant levels
AQS – Air Quality System (measurements of outdoor concentrations for criteria and http://www.epa.gov/ttn/airs/airsaqs/
toxic air pollutants; USEPA) manuals/AQSUserGuide.pdf
CEP – Cumulative Exposure Project (modeled estimates of outdoor and exposure http://www.epa.gov/sab/pdf/ihea9604.pdf
concentrations for air toxics at census tract levels; USEPA)
EMAP – Environmental Monitoring and Assessment Program (ecological monitoring http://www.epa.gov/emap/
data; USEPA)
NADP – National Atmospheric Deposition Program (data for the chemistry of http://nadp.sws.uiuc.edu/
precipitation for monitoring of geographical and temporal long-term trends; NADP)
NATA – National Air Toxics Assessment 1996 and 1999 (modeled estimates of outdoor http://www.epa.gov/ttn/atw/nata1999/
and exposure concentrations for air toxics in census tract levels; USEPA)
NAWQA – National Water Quality Assessment Data Warehouse (measurements of http://water.usgs.gov/nawqa/
chemical, biological, and physical water quality data collected from major river basins
and aquifers; USGS)
NCOD – National Contaminant Occurrence Database (measurements of sample data for http://www.epa.gov/safewater/data/ncod/
both regulated and unregulated contaminants in public water systems; USEPA)
NGA – National Geochemical Atlas (stream sediment and solid sample media; USGS) http://tin.er.usgs.gov/metadata/ofr-98-622.
faq.html
NHEXAS – National Human Exposure Assessment Survey (Measurements of http://www.epa.gov/nerl/research/nhexas/
multimedia (air, drinking water, food) concentrations for toxic metals and VOCs; nhexas.htm
USEPA)
NWIS – National Water Information System (USGS) http://waterdata.usgs.gov/nwis
16 Water Air Soil Pollut: Focus (2008) 8:3–21

Table 2 (continued)

Exposure Databases

RIOPA – Relationship of Indoor, Outdoor, and Personal Air (HEI) http://www.healtheffects.org/Pubs/st130.

htm
SDWIS/FED – Safe Drinking Water Information System/Federal Version (USEPA) http://www.epa.gov/safewater/sdwisfed/
sfed2.html
STORET – Storage and Retrieval (water quality monitoring data; USEPA) http://www.epa.gov/storet/
TDS – Total Diet Study (contaminant measurements of US food items; USFDA) http://www.cfsan.fda.gov/~comm/tds-hist.
html
TEACH – Toxicity and Exposure Assessment for Children’s Health http://www.epa.gov/teach/teachdatabase.
(literature summaries – 16 chemicals of concern; USEPA) html
WQN – Water Quality Network (stream and watershed; USGS) http://pubs.usgs.gov/fs/FS-013-97/
Demographics, activity and food consumption
AHS – American Housing Survey (USCB) http://www.census.gov/hhes/www/
housing/ahs/ahs.html
CHAD – Consolidated Human Activity Database (USEPA) http://www.epa.gov/chadnet1/index.html
CSFII – Continuing Survey of Food Intakes by Individuals (USDA) http://www.barc.usda.gov/bhnrc/
foodsurvey/Products9496.html
NHANES – National Health and Nutrition Examination Survey (CDC) http://www.cdc.gov/nchs/nhanes.htm
NHAPS – The National Human Activity Pattern Survey (USEPA) http://www.nature.com/jea/journal/v11/n3/
abs/7500165a.html
NMFS – National Marine Fisheries Service (estimates of recreational anglers’ catch in http://www.st.nmfs.gov/st1/recreational/
the USA; NOAA) index.html
US Census Population Database (USCB) http://www.census.gov/population/www/
TIGER – Topologically Integrated Geographic Encoding and Referencing system http://www.census.gov/geo/www/tiger/
(USCB) index.html
Physiology
ICRP – International Commission on Radiological Protection (ICRP) http://www.icrp.org
P3M – Physiological Parameters for PBPK Modeling (The Lifeline Group) http://www.thelifelinegroup.org/p3m
NHANES – National Health and Nutrition Examination Survey (CDC) http://www.cdc.gov/nchs/nhanes.htm
Biomarkers
NHANES – National Health and Nutrition Examination Survey (CDC) http://www.cdc.gov/nchs/nhanes.htm
NHEXAS – National Human Exposure Assessment Survey (USEPA) http://www.epa.gov/nerl/research/nhexas/
nhexas.htm
NCEA Biomarkers Database (USEPA) http://cfpub.epa.gov/ncea/cfm/
recordisplay.cfm?deid=85844

Table 3 A representative subset of databases (with website reference) that are available for providing data for use in DORIAN
applications (see http://www.ebKB.org for a more extensive list)

Biological Databases

Genomics/transcriptomics
ArrayExpress (Public repository for microarray data; EMBL-EBI) http://www.ebi.ac.uk/arrayexpress/
ArrayTrack (Public bioinformatics resource for DNA microarray and systems http://www.fda.gov/nctr/science/centers/
biology; US FDA) toxicoinformatics/ArrayTrack/
Chemical Effects in Biological Systems (CEBS; NIH) http://cebs.niehs.nih.gov
CIBEX – Center for Information Biology gene EXpression database (Gene http://cibex.nig.ac.jp/index.jsp
expression database system; DDBJ)
Database of Transcribed Sequences (DoTS; A human transcript index; http://www.allgenes.org
University of PA)
dbSNP (Database of Single Nucleotide Polymorphisms; NCBI-NIH) http://www.ncbi.nlm.nih.gov/SNP/
dbZach (Toxicogenomic database; Michigan State University) http://dbzach.fst.msu.edu
Water Air Soil Pollut: Focus (2008) 8:3–21 17

Table 3 (continued)

Biological Databases

EDGE – Environment, Drugs and Gene Expression (rResource for toxicology- http://edge.oncology.wisc.edu
related gene expression information; University of Wisconsin – Madison)
EMBL Nucleotide Sequence Database (EMBL-EBI) http://www.ebi.ac.uk/embl/Documentation/
Entrez Gene (Searchable database of genes; NCBI-NIH) http://www.ncbi.nih.gov/entrez/query.fcgi?
db=gene
Gene Expression Omnibus (Gene expression repository; NCBI-NIH) http://www.ncbi.nlm.nih.gov/geo/
Gene Finder (Search genes based on search criteria; NCI) http://cgap.nci.nih.gov/Genes/GeneFinder
GeneLoc (Integrated map for each human chromosome; Weizmann Institute http://bioinfo2.weizmann.ac.il/geneloc/index.
of Science) shtml
Genomatix Suite (transcription factors, pathways; Genomatix Software GmbH) http://www.genomatix.de/
Human Genome Browser (database of the human genome; UC Santa Cruz) http://genome.ucsc.edu/cgi-bin/hgGateway
Human Genome Database (GDB; RTI) http://www.gdb.org/
DrugMatrix (toxicogenomics and pharmacology; Iconix) http://www.iconixpharm.com/
KEGG genes database (collection of gene catalogs for genomes; Kyoto University) http://www.genome.jp/kegg/genes.html
Marker Maps (Mapping data of genetic markers; CHLC-NIH) http://gai.nci.nih.gov/html-chlc/ChlcMaps.
html
NCBI Nucleotide Sequence Database (NCBI-NIH) http://www.ncbi.nlm.nih.gov/entrez/query.
fcgi?db=Nucleotide
PharmGKB – (Knowledge base for relationships among drugs, diseases, http://pharmgkb.org
and genes; Stanford University)
SymAtlas (Experimental gene functionalization datasets; GNF) http://symatlas.gnf.org/SymAtlas/
Tox-MIAMExpress (links biological endpoint data with gene expression data; EBI) http://www.ebi.ac.uk/tox-miamexpress/
TransFac (database on eukaryotic transcription factors, their genomic binding sites http://www.gene-regulation.com/pub/
and DNA-binding profiles; Biobase) databases.html#transfac
TransPath (data visualization and modeling and for the analysis of gene expression http://www.gene-regulation.com/pub/
data; Biobase) databases.html#transpath
Bioinformatics
Biological Biochemical Image Database (Biological pathways, macromolecular http://bbid.grc.nia.nih.gov/
structures, gene families, and cellular relationships; NIH)
BioModels (Database of annotated published biological models; EMBL-EBI) http://www.ebi.ac.uk/biomodels/
Comparative Toxicogenomics Database (Interactions between chemicals and genes/ http://ctd.mdibl.org/
proteins in organisms; Mount Desert Island Biological Laboratory)
ExPASy – Expert Protein Analysis System – Sequence Retrieval System (Network http://www.expasy.org/cgi-bin/search-
browser for databanks in molecular biology; SIB) biochem-index
Integr8 (Database of complete genomes and proteomes; EMBL-EBI) http://www.ebi.ac.uk/integr8/EBI-Integr8-
HomePage.do
OmicBrowse (Integrative databases of the multi-dimensional “omic space”; RIKEN) http://omicspace.riken.jp/gps/index.html
Structural Biology Software Database (University of Illinois) http://www.ks.uiuc.edu/Development/
biosoftdb/
TIGR gene index (Analysis of transcribed sequences for various organisms; TIGR) http://www.tigr.org/tdb/tgi
Cheminformatics
Cambridge Structural Database (Small molecule crystal structures; CCDC) http://www.ccdc.cam.ac.uk/products/csd/
ChEBI – Chemical Entities of Biological Interest (Dictionary of small chemical http://www.ebi.ac.uk/chebi/
compounds and molecular entities; EMBL-EBI)
ChemBank (Data from small molecules; Harvard University) http://chembank.broad.harvard.edu/
ChemIDplus (Structure and nomenclature information of chemicals cited in NLM http://chem.sis.nlm.nih.gov/chemidplus/
databases; NLM)
KEGG LIGAND Database (Databases of chemical substances and reactions relevant http://www.genome.ad.jp/ligand/
to biological systems; Kyoto University)
Klotho: Biochemical Compounds Declarative Database (University of Missouri) http://www.biocheminfo.org/klotho/
NCI DIS 3D (3-D structures of over 400,000 pharmaceutical drugs; NIH-NCI) http://dtp.nci.nih.gov/docs/3d_database/
dis3d.html
18 Water Air Soil Pollut: Focus (2008) 8:3–21

Table 3 (continued)

Biological Databases

Nucleic Acid Database (3-D structural information about nucleic acids; Rutgers http://ndbserver.rutgers.edu/
University)
PubChem (Biological activities of small molecules; NCBI-NIH) http://pubchem.ncbi.nlm.nih.gov/
Structure-Activity Relationships (SAR) Toxicity Database (International http://rsi.ilsi.org/devtoxsar.htm
Life Sciences Institute)
Cytomics
Apoptosis-DB (The Burnham Institute) http://www.apoptosis-db.org
Dynamic Signaling Maps (Hippron Physiomics Inc.) http://www.hippron.com/hippron/index.html
GenAge Database (genes related to senescence:; FUNDP) http://genomics.senescence.info/genes/index.
html
PathArt (mammalian signaling and disease pathways; Jubilant Biosys) http://jubilantbiosys.com/ppa.htm
ResNet Pathway Database (eukaryotic molecular interactions; Ariadne Genomics) http://www.ariadnegenomics.com/products/
resnet/
SPAD – Signaling Pathway Database (genetic information and signal transduction http://www.grt.kyushu-u.ac.jp/spad/index.
systems; Kyushu University) html
Metabonomics
BOND – Biomolecular Object Network Databank (Thomson Corporation) http://www.unleashedinformatics.com/index.
php?pg=products
BRITE – Biomolecular Relations in Information Transmission Expression http://www.genome.jp/brite/
(mapping of genomic and molecular data; Kyoto University)
Case Pathways Database System (biological pathways data and visualization tools; http://nashua.cwru.edu/PathwaysWeb/
Case Western Reserve University)
CGAP – Cancer Genome Anatomy Program (Pathways Search Portal; NIH-NCI) http://cgap.nci.nih.gov/Pathways/
ExPASy – Expert Protein Analysis System (Biochemical Pathways; SIB) http://www.expasy.org/cgi-bin/search-
biochem-index
HumanCyc (metabolic pathways and genome; SRI International) http://humancyc.org/
IPA – Ingenuity Pathways Analysis (Ingenuity Systems) http://www.ingenuity.com/products/
pathways_analysis.html
KEGG – Kyoto Encyclopedia of Genes and Genomes (manually drawn http://www.genome.jp/kegg/
pathway maps; Kyoto University)
MetaCyc (experimentally-determined metabolic pathways; SRI International) http://www.metacyc.org/
Pathway Database (metabolic pathways; Protein Lounge) http://www.proteinlounge.com/
pathway_home.asp
Pathway Interaction Database (PID; NIH) http://pid.nci.nih.gov/
Reactome (core pathways and reactions; CSHL/EBI) http://www.reactome.org/
Proteomics
AMDIS – Automated MS Deconvolution and Identification System http://www.nist.gov/srd/nist1a.htm
(mass spectral reference library; USEPA, NIH, NIST)
BOND – Biomolecular Object Network Databank (Thomson Corporation) http://www.unleashedinformatics.com/index.
php?pg=products
Blocks (multiply aligned ungapped segments corresponding to the most highly http://blocks.fhcrc.org/
conserved regions of proteins; Fred Hutchinson Cancer Research Center)
BMRB – BioMagResBank (NMR spectra on proteins, peptides, and nucleic acids; http://www.bmrb.wisc.edu/
University of Wisconsin – Madison)
BRENDA – Enzyme Database (Cologne University) http://www.brenda.uni-koeln.de/
CluSTr (hierarchy of cluster of related proteins; EMBL-EBI) http://www.ebi.ac.uk/clustr/
Database of Macromolecular Movement (conformational changes in proteins; http://molmovdb.mbb.yale.edu/molmovdb/
Yale University)
DIP – Database of Interacting Proteins (experimentally determined interactions http://dip.doe-mbi.ucla.edu/
between proteins; UCLA)
Enzyme Structures Database (known enzyme structures in PDB; EBI) http://www.ebi.ac.uk/thornton-srv/databases/
enzymes/
Water Air Soil Pollut: Focus (2008) 8:3–21 19

Table 3 (continued)

Biological Databases

IMGT/3Dstructure-DB (protein structure query; IMGT) http://imgt3d.igh.cnrs.fr/

InterPro/InterProScan (database of protein families, domains and functional sites; http://www.ebi.ac.uk/InterProScan/
EMBL-EBI)
iProClass (databases for protein families, functions and pathways, interactions, http://pir.georgetown.edu/iproclass/
structures and structural classifications, genes and genomes, ontologies, literature,
and taxonomy; GU-PIR)
Markers List (protein markers; Lacroix) http://www.geocities.com/m.lacroix/
marqueurs/lismark.htm
PDB – Protein Data Bank (RCSB) http://www.rcsb.org/pdb/home/home.do
PFD – Protein Folding Database (biophysical data from experimental protein http://pfd.med.monash.edu.au/cgi-bin/
folding studies; Victorian Bioinformatics Consortium) WebObjects/pfd
PRINTS (protein fingerprints; University of Manchester) http://umber.sbs.man.ac.uk/dbbrowser/
PRINTS/
PROSITE (protein families and domains; SIB ExPASy) http://us.expasy.org/prosite/
Protein Database (protein sequences; NIH NCBI) http://www.ncbi.nlm.nih.gov/entrez/query.
fcgi?db=Protein
Protein Sequence Database (GU-PIR) http://pir.georgetown.edu/pirwww/dbinfo/
pir_psd.shtml
Proteome Bioknowledge Library (protein interactions; Incyte) https://www.proteome.com/control/tools/
proteome
Topology of Protein Structure (University of Glasgow) http://www.tops.leeds.ac.uk/
UniProt – Universal Protein Resource (protein sequence and function; SIB) http://www.expasy.uniprot.org/index.shtml
UniProtKB – Universal Protein Resource Knowledgebase (protein function, http://www.expasy.org/cgi-bin/sprot-search-ful
classification, and cross-reference; SIB)
Physiomics
Blood/Brain-Barrier Information (University of Arizona) http://users.ahsc.arizona.edu/davis/bbb.htm
Cardiac Anatomical Database (Johns Hopkins) http://www.ccbm.jhu.edu/software/card.php
ERED – Environmental Residue-Effects Database (biological effects and tissue http://el.erdc.usace.army.mil/ered/
concentrations measurements; US Army Core of Engineers, USEPA)
Glandular Organ Development Database (complete info from macroscopic level http://www.ana.ed.ac.uk/anatomy/database/
description to genetics; Hunter and Davies) orghome.html
Human Anatomy Online (animation/graphics; Intellimed) http://www.innerbody.com/index.html
ICRP – International Commission on Radiological Protection (reference anatomical http://www.icrp.org/
and physiological values for occupational settings; ICRP)
JavaMan (computer model of human physiology; University of Adelaide) http://www.health.adelaide.edu.au/paed-anaes/
javaman/
LONI Atlases (brain structure and function; UCLA) http://www.loni.ucla.edu/Atlases/
Neurodatabase (database of neurophysiology; Cornell University) http://neurodatabase.org/dataserver/
NHANES – National Health and Nutrition Examination Survey (CDC) http://www.cdc.gov/nchs/nhanes.htm
P3M – Physiological Parameters for PBPK Modeling (The Lifeline Group) http://www.thelifelinegroup.org/p3m
Pathophysiology of the Digestive System (Colorado State University) http://arbl.cvmbs.colostate.edu/hbooks/
pathphys/digestion/
Pathophysiology of the Endocrine System (Colorado State University) http://arbl.cvmbs.colostate.edu/hbooks/
pathphys/endocrine/
PBPK parameter database (anatomical, physiological, biochemical, and http://www.hsl.gov.uk/capabilities/
physicochemical data; Health and Safety Laboratory) pbpk_database.htm
Primate Info Net (anatomy and physiology of tissues and organ systems; http://pin.primate.wisc.edu/aboutp/anat/
University of Wisconsin – Madison) index.html
Visible Human Project (3D representations of normal anatomy and physiology; NIH) http://www.nlm.nih.gov/research/visible/
visible_human.html
Whole Brain Atlas (Harvard University) http://www.med.harvard.edu/AANLIB/home.
html
20 Water Air Soil Pollut: Focus (2008) 8:3–21

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