The Toxicologist - Society of Toxicology

ferentiation, and 3) how mixtures of phthalates behave when combined with other
phthalates or with other toxicants? In the mixture studies we have examined the
postnatal development of male rat offspring after in utero exposure to 1) pairs of
AR antagonists, 2) pairs of phthalates, 3) phthalates with AR antagonists, 4) five
phthalates, 5) seven chemicals (four pesticides and three phthalates), 6) ten chemicals
(four pesticides and six phthalates) and 7) the potent Ah receptor agonist
2,3,7,8-tetrachlorodibenzodioxin plus a phthalate. We also have examined the effects
of these chemicals on fetal male rat hormone levels and testicular gene expression
levels. Results of these studies demonstrate that only Dose Addition models accurately
predict the effects of these mixtures on male rat sexual differentiation. For
example, when ten chemicals were administered in utero, 100% of the males displayed
reproductive tract malformations as predicted by Dose Addition models
whereas Response Addition models predicted that none of the males would be malformed.
We propose that the regulatory framework for cumulative risk assessments
should not be based upon common mechanisms of toxicity, as this under-predicts
the effects of mixtures of chemicals with dissimilar mechanisms of toxicity. Rather,
the framework should be based upon the disruption of common fetal targets or systems
during development regardless of the mechanism of toxicity. This abstract
does not necessarily reflect EPA policy. NTP, NIEHS/EPA Interagency Cooperative
Research Agreement HHS Y1-ES-8014-01; EPA RW75922855-01-0.
563 THE NRC REPORT ON PHTHALATES AND
CUMULATIVE RISK ASSESSMENT: FOCUS ON
CUMULATIVE RISK AND COMMON ADVERSE
OUTCOMES.
D. A. Cory-Slechta. Department of Environmental Medicine, University of Rochester
Medical Center, Rochester, NY.
This NRC Committee was asked to consider whether cumulative risk assessment
should be considered for phthalates as well as approaches that might be used for
that purpose and even more broadly with other chemicals. The Committee favored
a cumulative risk assessment for phthalates, since humans are exposed to multiple
phthalates all commonly associated with the ‘phthalate syndrome’ that exhibits
many features similar to the human testicular dysgenesis syndrome. In approaching
this cumulative risk assessment, the Committee recommended a major shift in
strategy that it also considered should be broadly applicable across chemical exposures.
The basis of this strategy was a shift from the current focus of cumulative risk
assessment on structurally/ mechanistically-related chemicals (e.g., dioxin-like
compounds, OPs) or chemicals with overlapping geographical use, to an approach
that focuses on cumulative risks arising from chemical exposures that produce common
adverse outcomes, i.e., shared physiological consequences, as per the common
adverse effect of phthalates on male reproductive function. Since phthalate syndrome
arises from androgen insufficiency, the Committee recommended that in a
cumulative risk assessment for phthalates, other chemical and non-chemical factors
that likewise lead to androgen insufficiency, regardless of the mechanism by which
they produce androgen insufficiency, should be considered cumulatively with phthalates.
Further, the Committee recommended that this strategy be applied to other
common adverse outcomes, e.g., studying the cumulative impact of chemicals in
combination that have individually been shown to result in IQ reduction, e.g., lead,
methylmercury, PCBs. A focus on common adverse outcomes should actually facilitate
and expedite the shift from single chemical to cumulative risk assessment as
the approach defines those agents that should be considered in combination for a
common adverse outcome, thereby both circumscribing the ‘mixtures’ problem and
placing risk assessment in a public health context.
564 U.S. ENVIRONMENTAL PROTECTION AGENCY’S (EPA)
CUMULATIVE RISK ASSESSMENT OF THE
PHTHALATES.
J. B. Strong. U.S. EPA, ORD/NCEA, Washington, DC.
Phthalates are a group of chemicals used in the manufacturing of polyvinyl plastics
and other materials, such as pharmaceuticals, detergents, toys, cosmetic and personal
care products, medical devices, and food packaging and wrap, to increase flexibility
and pliability. Humans are exposed to various phthalates in the environment,
including through direct contact with these products. Epidemiological studies have
demonstrated a possible association between exposure to phthalates and indicators
of potential effects on the developing fetus at exposure levels that are similar to
background levels observed in the population. In 2008, EPA elicited external expert
consultation from the National Academies of Science (NAS) in the evaluation of issues
and approaches related to cumulative hazard and dose-response assessment of
phthalates. In the report released following this consultation, the committee recommended
that EPA select phthalates and other chemicals (i.e., other agents that cause
androgen insufficiency or block androgen-receptor signaling) for inclusion in a cumulative
risk assessment based on common adverse outcomes and not focus exclusively
on structural similarity or on similar mechanisms of action. An IRIS Human
Health Risk Assessment for the Phthalates is currently underway. This assessment
includes the following phthalates: dibutyl phthalate (DBP), di(2-ethylhexyl)phthalate
(DEHP), butyl benzyl phthalate (BBP), di-isobutyl phthalate (DIBP), diisononyl
phthalate (DINP), and dipentyl phthalate (DPP). This assessment will include
noncancer and cancer qualitative and quantitative human health effects
information and estimation of risk where the data are available. The assessment will
also address the specific recommendations presented in the NAS report on cumulative
risk for phthalates. Issues related to the cumulative risk assessment of the phthalates
include: consideration of chemicals for inclusion (based on common adverse
outcome); determination of methods to predict combined effects; and
selection of endpoints to serve as the basis for a cumulative risk assessment for the
phthalates.
565 ASSESSING THE CONTRIBUTION OF INDIVIDUAL
STRESSORS IN ASSESSMENTS OF CUMULATIVE RISKS
FROM CHEMICAL AND NON-CHEMICAL STRESSORS.
P. S. Price 1 and D. L. Michael 2 . 1 Toxicology & Environmental Research & Consulting,
The Dow Chemical Company, Midland, MI and 2 TERA, Cincinnati, OH.
In the NRC reports Science and Decisions: Advancing Risk Assessment and Phthalates
and Cumulative Risk Assessment: The Task Ahead the U.S. EPA is challenged to move
towards cumulative risk assessment and away from chemical-by-chemical approaches
to determining public health. The U.S. EPA has more than decade of experience
in assessing cumulative risks and has recently release a significant resource
documents on cumulative risk assessment. Despite the importance of cumulative
risk assessments, there are major challenges that have limited the number of cumulative
assessments performed. Cumulative risk assessments are population based,
thus separate assessments are required for different populations. Site-specific information
will play a critical role in such assessments. In any population the combination
of exposures to chemical and non-chemical stressors varies from person-to-person
and from moment-to-moment. These complexities affect both the
determination of the cumulating risks and the contributions of any one stressor.
Simulation modeling is expected to play a major part in the assessment of cumulative
risks. Modeling provides an effective means of tracking and combining the impacts
of exposures to stressors that occur by multiple routes and sources. These
models include exposure, PBPK, and biologically-based dose-response models
(BBDR) which become more effective when they are linked so that data and assumptions
in exposure models are passed on to PBPK and BBDR models. This session
will present a review of the technical issues for each step of the cumulative risk
assessment process. Therefore it is important that we begin with an overview from
an NRC committee member who authored the report and follow up with presentations
from leading speakers on the various phases of the dose-to-response modeling
process—exposure, kinetics, and dose-response. Finally, we will present a statistical
model for the evaluation of the impact of cumulative risks that can assist in ranking
or screening cumulative risks.
566 ADVANCING CUMULATIVE RISK ASSESSMENT AND
IMPACT EVALUATION.
L. Zeise 1 , A. D. Kyle 2 , J. Faust 1 and G. V. Alexeeff 1 . 1 Cal/EPA Office of
Environmental Health Hazard Assessment, Oakland, CA and 2 School of Public
Health, University of California at Berkeley, Berkeley, CA.
The recent National Research Council (NRC) report “Science and Decisions” concludes
that the processes of regulatory risk assessment and the decision-making it
supports are bogged down. Major chemical specific risk assessments can take longer
than 10 years; uncertainty, inherent in the process, contributes to the gridlock. At
the same time, communities disproportionately impacted by environmental exposures
express concern that risk assessments are narrowly focused on a limited number
of chemicals, typically from a single source, and ignore non-chemical stressors.
Also a second NRC report, “Phthalates and Cumulative Risk Assessment,” notes
the importance of cumulative risk assessment in evaluating the combined impact of
multiple phthalates and other chemicals on male reproductive development.
“Science and Decisions” recommends short and long term actions for implementing
cumulative risk assessment, emphasizing those that will enhance its utility for
discriminating among options for decision-making. They include the development
of databases and default approaches to address non-chemical stressors and guidelines,
and simplified analytic tools for timely screening assessments and to facilitate
stakeholder involvement in assessment. Finally, community stakeholders often call
for better assessment of cumulative environmental impacts, including considerations
of livability, environmental degradation and community vulnerability. We
present and reflect on NRC recommendations for cumulative risk assessment in the
context of California’s efforts to develop a framework and tools for cumulative impact
assessment.
SOT 2010 ANNUAL MEETING 121