The Toxicologist - Society of Toxicology

1930 DEVELOPMENT OF A RELATIVE SOURCE
CONTRIBUTION FACTOR FOR DRINKING WATER
CRITERIA: THE CASE OF HEXAHYDRO-1, 3, 5-
TRINITRO-1, 3, 5-TRIAZINE (RDX).
B. Gadagbui 1 , J. Patterson 1 , S. S. Kueberuwa 3 , A. Rak 2 , R. S. Kutzman 2 , G.
Reddy 4 and M. S. Johnson 4 . 1 Toxicology Excellence For Risk Assessment, Cincinnati,
OH, 2 Noblis Inc., Alexandria, VA, 3 U.S. Environmental Protection Agency,
Washington, DC and 4 U.S. Army Center for Health Promotion and Preventive
Medicine, Aberdeen Proving Ground, MD.
In protecting human health, the application of fate, transport, and exposure data
are essential in the development of chemical-specific criteria for drinking water.
There are few environmental regulations, standards, or guidance values for hexahydro-1,3,5-trinitro-1,3,5-triazine
(RDX), but an increasing number of states are developing
such for RDX. RDX is a synthetic chemical, which is not known to occur
naturally. It is a military munitions explosive with limited civilian uses. Available
data suggest that RDX is not anticipated to be a national exposure concern. This assessment
presents a relative source contribution (RSC) factor for RDX. An RSC accounts
for all sources and non-occupational exposures from RDX and apportions
these amounts to each source so that an individual’s total dose does not exceed the
reference dose. The application of the Exposure Decision Tree approach (subtraction
method), recommended by the U.S. EPA, was used. An exposure model identified
the relevant potential sources for highly exposed receptors proximate to an
area where RDX was released. Potentially contaminated media include soil,
groundwater, and surface water. Potential exposure pathways include ingestion of
soil, water, and contaminated local crops and fish; dermal contact with soil; and
water used in bathing. These pathways are limited to areas that are in close proximity
to current or former military bases where RDX may have been released into the
environment. Given the physical/chemical properties and the available environmental
occurrence data on RDX (from military sites), there are adequate data to
support a chemical-specific RSC for RDX of 50% for drinking water. The opinions
are those of authors and do not necessarily reflect the opinions of the U.S. EPA or
the Dept. of the Army.
1931 ISSUES IN USING HUMAN VARIABILITY
DISTRIBUTIONS TO ESTIMATE LOW-DOSE RISK.
W. A. Chiu 1 , K. S. Crump 2 and R. Subramaniam 1 . 1 U.S. Environmental
Protection Agency, Washington, DC and 2 Louisiana Tech University, Ruston, LA.
Sponsor: K. Guyton.
Background: A Committee of the National Academies of Science recommended
using human variability distributions (HVDs) to estimate low-dose risks in certain
situations. In this approach (HVD modeling) log-normal distributions are estimated
from data on pharmacokinetic and pharmacodynamic variables that impact
individual sensitivities to the toxic response. These distributions are combined into
an overall log-normal distribution by assuming the variables act independently and
multiplicatively. This distribution is centered at a point of departure (POD) dose
usually estimated from animal data. The resulting log-normal distribution is used
to quantify low-dose risk. Objective: To examine the implications of various assumptions
in HVD modeling. Methods: Assumptions and data used in HVD
modeling are subjected to rigorous analysis. Results: The assumption that the variables
affecting human sensitivity vary log-normally is not scientifically defensible.
Other distributions that are equally consistent with the data provide very different
estimates of low-dose risk. HVD modeling often involves assuming that the threshold
dose, defined by dichotomizing a continuous apical response, has a log-normal
distribution. This assumption is incompatible (except under highly specialized conditions)
with assuming that the apical response itself is log-normal. However, the
two assumptions can lead to very different estimates of low-dose risk. The assumption
in HVD modeling that risk can be expressed as a function of a product of independent
variables lacks phenomenological support. An example is provided that
shows that this assumption is generally invalid. Conclusion: In view of these problems,
we recommend caution in the use of HVD modeling as a general approach to
estimating low-dose risks from human exposures to toxic chemicals. Disclaimer:
The views expressed in this poster represent those of the authors and do not reflect
the views or policies of the U.S. EPA.
1932 PROPOSED MODES OF ACTION FOR
NEUROTOXICITY INDUCED BY VARIOUS
CHLORINATED SOLVENTS.
A. Bale, S. Barone, C. S. Scott and G. S. Cooper. NCEA/ORD, U.S. EPA,
Washington, DC.
Several health assessments of chlorinated solvents, including trichloroethylene
(TCE), perchloroethylene (PERC), and dichloromethane (DCM), are underway by
the U.S. EPA’s Integrated Risk Information System (IRIS) Program. These solvents
have been shown to produce similar central nervous system (CNS) effects in animals
and humans. The observed neurotoxicological effects for this chemical class
are general CNS effects (e.g., locomotor activity changes and anxiolytic effects), visual
effects, ototoxicity, cognitive deficits, sleep cycle disturbances, imbalance, and
decrements in nerve function. Since neurotoxicological effects are consistent among
the three solvents, we hypothesized that mechanisms producing these neurological
effects may be similar. Available neuropathological and mechanistic studies were
evaluated in order to determine which molecular systems may be involved in production
of neurotoxicological outcomes. The mechanistic studies indicate that the
chlorinated solvents have several molecular targets which may, in part, explain the
observed neurobehavioral effects. PERC and TCE have been demonstrated to interact
directly with several different classes of neuronal receptors by inhibiting excitatory
receptors/channels and potentiating inhibitory receptors/channel function.
Most of the mechanistic studies evaluated effects following acute exposure durations.
Given the mechanistic information for TCE, DCM, and PERC, we provide
hypotheses for primary targets (e.g. ion channel targets) that appear to be influential
in producing the resultant neurological effect. As a result there is uncertainty in
extrapolating the acute exposure mechanistic data to chronic neurotoxicological effects
following exposures to chlorinated solvents since the molecular targets may be
affected differently following a chronic exposure. This analysis of data from multiple
chlorinated solvents underscores the need for more research to develop a model
of low level chronic human exposures to this class of compounds. These authors’
views do not necessarily reflect the views or policies of the U.S. EPA.
1933 MODELS USED TO SUPPORT EXPOSURE AND RISK
ANALYSES BY THE U.S. ENVIRONMENTAL
PROTECTION AGENCY.
P. R. Williams 1 , B. J. Hubbell 2 , E. Weber 3 , C. Fehrenbacher 4 , D. Hrdy 5 and V.
Zartarian 6 . 1 E Risk Sciences, LLP, Boulder, Co., 2 Office of Air Quality Planning and
Standards, U.S. EPA, Research Triangle Park, NC, 3 National Exposure Research
Laboratory, U.S. EPA, Athens, GA, 4 Office of Pollution Prevention and Toxics, U.S.
EPA, Washington, DC, 5 Office of Pesticide Programs, U.S. EPA, Washington, DC
and 6 National Exposure Research Laboratory, U.S. EPA, Research Triangle Park, NC.
In this presentation, we provide an overview of 35 models currently supported and
used by the U.S. EPA to assess exposures to human or ecological receptors. An understanding
of these models is important because they are often used in addition to
or in lieu of monitoring data to estimate environmental concentrations and exposures
for use in risk assessments or epidemiology studies and to support regulatory
standards and voluntary programs. Information on each models was obtained from
several sources, including available model documentation (e.g., user manuals, staff
papers, external peer reviews), interviews with model developers, and running of
the model using real or hypothetical data. The models generally represent the first
half of the source-to-outcome continuum and include 12 fate/transport models, 5
exposure models, and 8 integrated fate/transport and exposure models. Many of the
exposure models also incorporate cancer or non-cancer risk estimates, including
margin of exposure (MOE), hazard index, or toxicity equivalency factors. Each
model is summarized with respect to its intended purpose and potential applications,
level of analysis and routes of exposure, key data inputs and exposure/risk
outputs, temporal and spatial resolution, treatment of variability and uncertainty,
degree of model evaluation, level of internal and external peer review, and interactions
with other models. A discussion is also provided regarding recent and ongoing
efforts to develop integrated modeling approaches and to perform lifecycle evaluations
and retrospective analyses of existing U.S. EPA models. The information presented
here should provide a useful up-to-date resource to exposure and risk modelers
and practitioners.
1934 RISK ASSESSMENT OF METALS IN CONSUMER
PRODUCTS INTENDED FOR CHILDREN.
M. Wade, E. Sciullo, K. Day, R. Sarala, D. Chand, M. DeGuzman, J. Garcha,
F. Hussain, M. Snider and T. Behrsing. Toxic Substances Control, Cal EPA,
Sacramento, CA.
Recently concerns have been raised about toxic chemicals, especially metals, found
in consumer products (CPs). An example is lead (Pb) in children’s toys and jewelry.
We encountered numerous challenges and uncertainties in attempting to perform
risk assessments on CPs containing toxic metals. Risk assessment protocols, and
toxicity and toxicokinetic (TK) data developed for evaluating chronic exposure are
often inadequate for assessing short-term exposure to CPs; and, risk assessments for
some CPs were developed years ago. We developed a general framework for CP risk
assessment by evaluating risk and identifying uncertainties on a product-specific
basis. Potential hazards from multi-component CPs designed for children and advertised
as lead-free were evaluated by testing metal content, and extractability in
saline and dilute acid solutions mimicking mouthing and swallowing, respectively.
SOT 2010 ANNUAL MEETING 411