The Toxicologist - Society of Toxicology

Humans are also exposed to manganese by inhalation and orally through food and
drinking water; manganese deficiency is rare. An assessment of the current scientific
evidence for potential health effects associated with exposure to inorganic Mn
compounds has been conducted. The literature review targeted primary studies of
health effects, toxicokinetics, and mechanisms of action published between Jan 1,
2005, and July 31, 2010, searching the bibliographic databases
MEDLINE/PubMed, TOXLINE, EMBASE, and the HuGENet literature database.
Studies published prior to 2005 were identified using secondary sources. The
identification, selection, and quality evaluation of studies employed systematic review
methods to avoid bias. The assessment adopts a weight of evidence approach
to consider hazard to human health with respect to carcinogenicity, mutagenicity,
reproductive and developmental toxicity, pulmonary toxicity, neurotoxicity and
other repeated dose endpoints. For the critical neurotoxicity endpoint, this presentation
also discusses: integration of new tissue dosimetry information based on recently
developed pharmacokinetic models for Mn; available data on possible modifiers
of risk such as iron deficiency, genetic variants, and age; recent information
on mechanisms of action; and identifies data gaps that should be filled to
strengthen the scientific basis on which assessments of the potential health risks of
Mnmaybebased.
2462 ADVANCING PREDICTIVE ECOTOXICOLOGY
TESTING AND ENVIRONMENTAL RISK ASSESSMENT
IN THE 21 ST CENTURY.
M. Embry 1 and D. Volz 2 . 1 ILSI HESI, Washington, DC and 2 University of South
Carolina, Columbia, SC.
Following the publication of the National Research Council (NRC) Report on
Toxicity Testing in the 21st Century: A Vision and a Strategy increased attention
has been given to the development and use of new technologies and methods for
toxicity testing. It is hoped that these new approaches will aid in the design of a routine
testing strategy that will provide data that are applicable to the broadest possible
range of chemicals, endpoints, and lifestages, while also providing greater detail
concerning mode of action and dose/concentration-response, and reducing the
overall costs, animal use, and time spent on testing. This Tox21 vision has impacted
testing approaches for not only human health, but also ecological risk assessment.
Therefore it is important to address these current initiatives aimed at advancing regulatory
ecotoxity testing strategies. Novel approaches that could be integrated into
an intelligent, tiered ecotoxicity testing strategy are under development.
Additionally, concepts for utilizing chemical mode of action and/or adverse outcome
pathways as a basis for developing 21st century test methods and associated
predictive tools, initially developed as part of a SETAC Pellston workshop, have
been expanded on several fronts. Advances in the application of QSAR and modeling
approaches, cell-based assays, and ‘omics methodologies as well as recent OECD
efforts to develop a fish testing framework will be highlighted. Our focus will be to
discuss approaches to coordinate the development of new human health and environmental
toxicity testing strategies, share key lessons and advances and create effective
partnerships between human health and ecotoxicology communities.
2463 ADVERSE OUTCOME PATHWAYS AND SYSTEMS
BIOLOGY AS CONCEPTUAL APPROACHES TO
SUPPORT DEVELOPMENT OF 21 ST CENTURY TEST
METHODS AND EXTRAPOLATION TOOLS.
D. L. Villeneuve 1 , M. R. Embry 2 and D. C. Volz 3 . 1 U.S. EPA Mid-Continent
Ecology Division, Duluth, MN, 2 ILSI Health and Environmental Sciences Institute,
Washington, DC and 3 Department of Environmental Health Sciences, University of
South Carolina, Columbia, SC.
The proposed paradigm for “Toxicity Testing in the 21st Century” supports the
development of mechanistically-based, high-throughput in vitro assays as a potential
cost effective and scientifically-sound alternative to some whole animal hazard
testing. To accomplish this long-term goal, it is necessary to (1) identify and catalog
common adverse outcome pathways (AOPs) and (2) based on these pathways,
strategically develop a focused battery of assays with proven predictive value. The
concept of AOPs provides an organizing framework for linking cellular-level responses
to endpoints conventionally considered in ecological risk assessment (e.g.,
effects on survival, growth/development, and reproduction). Defining and cataloging
AOPs provides a scientific foundation for development of toxicity pathway
assays with predictive power. Systems biology is the scientific study of dynamic interactions
among elements that comprise biological systems. The goal of systems
biology is to understand and predict emergent properties of these complex systems.
The approaches of systems biology can be used to understand the intersections
and interactions among AOPs, in the context of relevant homeostatic and al-
528 SOT 2011 ANNUAL MEETING
lostatic functions that modulate outcomes as a function of stressor intensity (e.g.,
dose), exposure duration, and other toxicologically relevant variables. Thus, systems
biology can (1) help optimize an AOP-based in vitro testing framework and
(2) aid the development of toxicodynamic extrapolation models needed for quantitative
risk assessments. This presentation will highlight the utility of these two
conceptual approaches, AOPs and systems biology, in evolving strategies for 21st
century toxicity testing, using examples and products from recent international expert
workshops with participants from academia, industry, government, and nongovernmental
organizations.
2464 ADVANCES AND OUTLOOKS FOR QSARS IN
ECOTOXICOLOGY.
S. A. Villalobos 1 , S. E. Belanger 2 and P. Ranslow 3 . 1 Nalco, Naperville, IL, 2 Procter
& Gamble, Cincinnati, OH and 3 Consortium for Environmental Risk Management,
Hallowell, ME.
For the successful regulation of chemicals in commerce, authorities typically require
reliable data on the effects and fate of such chemicals in humans and the environment.
The norm is to provide this information using well-defined protocols for a
variety of endpoints. Unlike the markets for therapeutic drugs, biocides and pesticide
agrochemicals that require data rich registration packages prior to commercialization,
the registration packages for industrial chemicals have been historically data
poor. In its broadest definition, Quantitative Structure-Activity Relationships
(QSARs) are algorithms used to predict specific properties directly from the chemical
structure and without experimental testing. QSARs are used to estimate toxic
effect (even exposure) concentrations, physical and/or chemical properties, environmental
fate, etc. QSARs are increasingly viewed as a cost effective way to estimate
ecological and health effects of chemicals by regulatory agencies around the
world but also by industry, academia, nongovernment and private organizations.
QSARs also play a vital role as part of the overall 3R’s strategy on animal testing
(Replace, Reduce, Refine). They can be a tool to evaluate adequacy of data and are
useful in cases where data availability is incomplete and/or when there are differences
in test methods (e.g., OECD versus USEPA guidelines). The technology behind
QSARs has had such improvements that historical conservative views of their
use in environmental risk assessments can now be mitigated and a reliable degree of
certainty is obtainable. In spite of advances, most of the current use by regulatory
agencies remains on priority setting for existing chemicals and assessments for new
chemicals. This talk will highlight the most recent advancements in QSAR modeling
in ecological risk assessment as well as areas where improvement is needed, including
prediction of chronic toxicity, use with inorganic chemicals, mixtures, and
increased regulatory acceptance.
2465 FISH EMBRYO AND CELL LINE ASSAYS AS POTENTIAL
ALTERNATIVES FOR FISH TOXICITY TESTS.
K. Schirmer 1 , K. Tanneberger 1 , M. Knöbel 1, 3 , N. Kramer 2 , J. Hermens 2 , S.
Scholz 3 , N. Bols 4 , L. Lee 5 and C. Hafner 6 . 1 Eawag, Swiss Federal Institute of
Aquatic Science and Technology, Dübendorf, Switzerland, 2 Institute of Risk
Assessment Sciences, University of Utrecht, Utrecht, Netherlands, 3 UFZ, Helholtz
Centre for Environmental Research, Leipzig, Germany, 4 University of Waterloo,
Waterloo, ON, Canada, 5 Wilfrid Laurier University, Waterloo, ON, Canada and
6 Hydrotox GmbH, Freiburg, Germany. Sponsor: M. Embry.
Fish are the most frequently used vertebrates in regulatory ecotoxicology. As vertebrates,
they are legally protected animals. Therefore, alternatives to reduce or replace
fish tests for risk assessment of chemicals and industrial effluents are of high
societal importance. In addition to being more ethical and economical, alternative
approaches may also offer better insights into the modes of action underlying the
toxicity of chemicals to fish. The goal of the CEllSens project is to improve fish embryo
and fish cell line assays to achieve international acceptance as alternatives to
the acute fish toxicity test, which uses death as an integrative but crude endpoint.
The hypothesis is that acute toxicity is in most cases caused by a non-specific interference
of the chemicals with cell membranes, which are also presented as a target in
fish embryo/cells. Indeed, toxicity correlation analysis between fish acute toxicity
and fish embryo or cell line data revealed a very good agreement for non-specific,
directly acting chemicals. However, it also became evident that compounds with
high volatility and hydrophobicity are under-predicted in their toxicity in the
small-scale alternative assays unless exposure concentrations are carefully verified.
Moreover, specific modes of toxic action and the metabolic capabilities need to be
understood; indeed lack or insufficient activity of specific metabolizing enzymes in
cells and embryos was one cause for outliers from the in vivo-in vitro correlation.
We suggest that dosing methods need to be developed that provide stable exposure
concentrations in the small scale assays and that systems biology approaches could
be a key to understand the functional capabilities of alternative experimental models
to respond to chemical exposure in general.