The Toxicologist - Society of Toxicology

for integrating epidemiology and animal results from the published literature have
become increasingly important to regulatory agencies as evidenced by recently proposed
EPA draft guidance and science advisory panel reviews in 2010 on this subject.
Of special importance are evaluations of developmental neurobehavioral data
for children’s health RA. Chlorpyrifos (CPF) is used as a case study to illustrate a
framework for systematic and transparent review of published neurobehavioral literature
for human health RA. Steps include (1)identify human pesticide uses and
exposure patterns so that relevance of duration,route and dose levels in animal studies
can be determined;(2)evaluate exposure measures used in human studies relative
to what is understood about mode of action, metabolism and pharmacokinetics;(3)define
criteria for inclusion and utility of studies for RA;(4)tabulate both
presence and absence of all findings, direction of change, key methods and exposure
period from human and animal studies;(5)evaluate historical control data to assess
reliability of methods and variability of control behavior especially when there is
limited dose response data from one lab;(6)evaluate patterns of associations (or lack
of associations) within and across different studies with respect to the following
guideposts: consistency, dose-response, strength of association, temporality (taking
into consideration frequency, intensity, timing and duration of exposure), as well as
hypothesized modes of action. Based on this approach, we conclude that quantitative
RA based on cholinesterase inhibition are adequately protective of developmental
neurobehavioral effects reported in the literature for CPF.
863 DEVELOPMENT OF SURFACE CLEAN UP LEVELS FOR
ACUTE AND CHRONIC EXPOSURE TO TARGET
CHEMICALS.
J. M. Martinez 1 , S. A. Hines 2 and D. J. Chappie 2 . 1 Office of Emergency
Management, U.S. EPA, Cincinnati, OH and 2 Battelle, Cincinnati, OH.
Solid surface contamination, such as that resulting from indoor pesticide applications
or residual contamination from releases of chemical weapons, is increasing
recognized as a knowledge gap in the development of suitable decontamination
strategies and standards to ensure appropriate clean-up. This is especially important
when planning for reoccupation of a public facility contaminated with toxic agents
that may persist in the environment for various lengths of time. Contaminated surfaces
pose a challenge for assessment due to the lack of generally accepted dermal
exposure methodologies as well as appropriate techniques to integrate surface wipe
measurements with exposure point concentrations. Currently, there are no formal
risk-based screening levels for chemical weapons or pesticides to determine if results
from surface samples or wipe samples confirm the solid surfaces were successfully
decontaminated or need to be re-evaluated before reoccupation. To develop surface
clean up screening levels, we performed a careful evaluation of all surface contamination
assessment methodologies proposed for the World Trade Center and home
methamphetamine lab clean ups. Based on careful analysis of these methods and
the chemical properties of toxicants, we present putative surface wipe screening levels
for both chronic and acute exposures for a list of target chemicals.
864 USING PBPK/PD MODELS TO INCORPORATE
CHEMICAL AND NON-CHEMICAL STRESSORS INTO
CUMULATIVE RISK ASSESSMENT: A CASE STUDY OF
PESTICIDE EXPOSURES.
S. C. Wason 1, 2 , T. J. Smith 1 , M. J. Perry 1 and J. I. Levy 1 . 1 Environmental Health,
Harvard School of Public Health, Boston, MA and 2 Gradient, Cambridge, MA.
Sponsor: A. Lewis.
Cumulative risk assessment has been proposed as an approach to evaluate health
risks associated with simultaneous exposure to multiple chemical and non-chemical
stressors. Physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD)
models can allow for inclusion and evaluation of multiple stressors, including nonchemical,
but studies have not leveraged PBPK/PD models to jointly consider these
disparate exposures in a cumulative risk context. In this study, we focused on exposures
to organophosphate (OP) pesticides for children in urban low-income environments,
where these children would be simultaneously exposed to other pesticides
(e.g. pyrethroids) and non-chemical stressors that may modify the effects of
these exposures (e.g. diet). We developed a methodological framework to evaluate
chemical and non-chemical stressor impacts on OPs, utilizing an existing
PBPK/PD model for chlorpyrifos. We evaluated population-specific stressors that
would influence OP doses or acetylcholinesterase (AChE) inhibition, the relevant
PD outcome. We incorporated the impact of simultaneous exposure to pyrethroids
and dietary factors on OP dose through the compartments of metabolism and PD
outcome within the model, and simulated combinations of stressors across multiple
exposure ranges and potential body weights. Our analyses demonstrated that both
chemical and non-chemical stressors can influence the health implications of OP
exposures, with up to 5-fold variability in AChE inhibition across combinations of
stressor values for a given OP dose. We demonstrate an approach for modeling OP
risks in the presence of other population-specific environmental stressors, providing
insight about co-exposures and variability factors that most affect OP health risks
and contribute to children’s cumulative health risk from pesticides. This framework
can be used to inform cumulative risk assessment for any compound affected by
chemical and non-chemical stressors through metabolism or PD outcomes.
865 ASSESSMENT OF AGGREGATE PERINATAL EXPOSURE
TO BPA.
D. A. Sarigiannis 1, 2 and S. Karakitsios 1 . 1 Institute for Health and Consumer
Protection, European Commission - Joint Research Centre, Ispra, Varese, Italy and
2 Chemical Engineering, Aristotle University of Thessaloniki, Thessaloniki, Greece.
Sponsor: L. Birnbaum.
The pharmacokinetic behavior of Bisphenol A, especially in the perinatal period is
subject to large controversy. Recent epidemiological findings regarding inhaled
BPA revealed that even at low levels of overall daily intake (0.5 μg/kg_bw) male sexual
dysfunction was observed. This study aims to investigate (a) the exposure to
BPA of the developing fetus during the perinatal period and reduce the uncertainty
regarding internal dose determinants (fetus sulfation and BPA_Glu deconjugation
by β-glucuronidase in the placenta; and (b) the effect of administration route on
BPA bioavailability. For this purpose, a dynamic lifetime PBTK model was developed,
capable of estimating the BPA biologically effective dose throughout several
developmental stages for different administration routes. The model integrates
steady state and dynamic Markov chain Monte Carlo simulations for uncertainty
assessment. The biologically effective dose of the fetus during gestation is linked to
the levels of BPA in the mother blood due to its high lipophilicity and the relatively
small molecular weight. Fetal BED was calculated to be only slightly lower than the
one of the mother. Sensitivity analysis showed that this parameter is determining
for placental concentration and affects the overall fetal exposure with a sensitivity
coefficient of 0.67, much higher than the contribution of the fetal intrinsic clearance
(sensitivity coefficient of 0.4), confirming thus the importance of de-conjugation.
BPA bioavailability from inhalation exposure in adults is significantly higher
than when BPA is orally administrated (6 times higher for the same intake rate) due
to lack of first pass metabolism prior to systemic circulation entrance. Exposure to
5 μg/m3 of BPA in the air corresponds to a steady state concentration in plasma
equal to 0.22 μg/L. In neonates, whose overall clearance capability is limited to almost
20% of adults, differences in BPA bioavailability for different administration
routes are limited to 50%.
866 USE OF A PBPK/PD MODEL TO DERIVE AGE-
SPECIFIC INTERSPECIES (UF A ) AND
INTERINDIVIDUAL (UF H ) UNCERTAINTY FACTORS
FOR CHLORPYRIFOS.
P. S. Price 1 , P. M. Hinderliter 2 and T. S. Poet 2 . 1 Toxicology & Environmental
Research & Consulting, The Dow Chemical Company, Midland, MI and 2 Battelle
Pacific Northwest Division, Richland, WA.
Risk assessments of chemicals use uncertainty factors for establishing safe levels of
exposure. The default values for these factors do not necessarily reflect current
knowledge of a chemical’s mechanism of action or our growing ability to quantitatively
predict internal doses and responses in humans using physiologically based
pharmacokinetic/dynamic (PBPK/PD) models. A PBPK/PD model of variability
in response (RBC cholinesterase inhibition) to chlorpyrifos exposure in two age
groups in humans (adults and three year olds) was developed. The model was used
to derive complete values (including both kinetic and dynamic components) for the
interspecies (UF A ) and interindividual (UF H ) uncertainty factors. The approach
used to determine UF A is to design simulations of human populations that predict
the dose levels in humans that are directly comparable to the animal BMD or
BMDL. The approach used for UF H is to directly model the variation in human response,
at relevant dose levels and regimens, and use the model results to determine
the size of the interindividual uncertainty factor necessary to address the variation
that occurs across different fractions of the population. Finally, data from age-appropriate
animal studies and age-specific models of human sensitivity are used to
derive separate values of UF A and UF H for each age group. These age-specific values
avoid the need for extrapolating from adults to children. Values of UF A and UF H
were developed for cholinergic responses to chlorpyrifos based on a BMDL 10 determined
in a recent acute oral study in rats. Values of UF A were calculated to be