The Toxicologist - Society of Toxicology

for the propyl series can be used for extrapolation of results of rat toxicology studies
(e.g., no-observed adverse effect levels) to human-equivalent values for exposure to
propyl acetate or propanol.
2295 USING MARGINS OF EXPOSURE AS A SEGREGATION
TOOL FOR RISK ASSESSMENT OF TOBACCO SMOKE
TOXICANTS.
S. Fiebelkorn, F. H. Cunningham and C. Meredith. Group R&D, British
American Tobacco, Southampton, United Kingdom.
Identification of tobacco smoke toxicants has received significant attention during
recent years. Key examples include establishment of the World Health
Organisation (WHO) Study Group on Tobacco Product Regulation (TobReg) and
most recently, in 2009, the Family Smoking Prevention and Tobacco Control Act.
There is a clear focus to develop lists of tobacco toxicants which may guide proposal
of limits, recommendations for lowering and/or routine monitoring. We suggest
development of a quantitative risk assessment paradigm, using multiple assessment
techniques to estimate the contribution of individual toxicants to smoking-related
diseases, with the aim of establishing priorities for risk reduction research. As an initial
model, we propose adoption of the Margins of Exposure (MOE) model, following
European Food Safety Authority (EFSA) guidelines. An MOE is a ratio between
a benchmark dose (derived from existing toxicological dose-response data)
and estimated human exposure. Compounds with computed MOEs >10,000 are
considered to be “low priority for risk management actions”. Our approach is to
calculate MOE values for individual tobacco smoke toxicants from a range of published
toxicity studies and from published data on yields from machine smoking to
determine consistency within available data sets. Computed MOEs enable segregation
of toxicants into high and low priority groupings for risk reduction research
depending on their relationship to the critical MOE value of 10,000. For example,
following this procedure, carcinogenicity data sets for 1,3-Butadiene yield MOEs
all below 10,000 whereas MOEs for vinyl chloride are all above 10,000. Using noncancer
end-points for cresol(s) yields MOEs that are all above 10,000. We propose
that estimation of MOEs for smoke toxicants is a useful first step towards prioritisation
of toxicants for risk reduction research. Future developments will invoke
more complex, but physiologically more relevant paradigms, such as physiologically-based
pharmacokinetic (PBPK) modelling to ascertain the importance of a
toxicant to smoking-related diseases.
2296 USE OF CONTROL BANDING AND SENSORY
IRRITATION (RD 50 ) DATA TO ASSESS OCCUPATIONAL
EXPOSURE VALUES FOR N-PROPYL, N-BUTYL, AND
N-PENTYL PROPIONATE.
S. M. Krieger 1 , D. R. Geter 1 , T. J. Cawley 1 , M. Osterloh-Quiroz 2 and J. A.
Hotchkiss 1 . 1 The Dow Chemical Company, Midland, MI and 2 Dow Europe GmbH,
Horgen, Switzerland.
N-propyl, n-butyl, and n-pentyl propionate are colorless liquid chemical intermediates
used in the production of pharmaceuticals, anti-fungal agents, agrochemicals,
plastics, plasticizers, rubber chemicals, dyes, artificial flavors, and synthetic
perfumes. In addition, they are used as solvents in low VOC coating formulations.
Inhalation is the primary route of potential occupational exposure to these materials.
No occupational threshold limit values (TLV) are currently established for this
solvent family. Atrophy, degeneration and necrosis of the olfactory epithelium are
the most sensitive repeat inhalation observations of the above mentioned propionates.
Inhalation No-Observed-Effect Concentrations (NOEC) range from 50-
500 and 50-750 ppm for subacute and subchronic toxicity, respectively; 500-2000
ppm for reproductive and developmental toxicity, and 500-3200 ppm for neurotoxicity.
A control banding (matrix) approach may be used to identify a range of
permissible occupational exposure concentrations. Based on the available repeat inhalation-exposure
data, TLVs in the range of 1-10 ppm for nasal toxicity and 10-
100 ppm for systemic toxicity were derived. Perceived irritation of the nose, throat
and eyes is recognized as a critical effect and often used to derive TLVs. The TLV
for many irritant chemicals falls within a range 0.01 - 0.1 RD 50 , with 0.03 often
used as the appropriate value (RD 50 = concentration causing a 50% reduction in
baseline respiration rate). We experimentally established RD 50 values of 535 and
668 ppm for n-propyl and n-butyl propionate, respectively (ASTM Method E 981-
04). Calculated TLVs based on 0.03 times the RD 50 yielded values of 16.1 and 20.0
ppm for n-propyl- and n-butyl propionate, respectively. These values are in agreement
with the repeat inhalation derived TLVs and support the use of RD 50 in calculating
these data.
2297 ASSESSING NON-CANCER HEALTH RISK FROM
INHALED PCBS.
G. M. Lehmann 1 and J. Schaum 2 . 1 ORD, U.S. EPA, Research Triangle Park, NC
and 2 ORD, U.S. EPA, Washington, DC.
Exposure to polychlorinated biphenyls (PCBs) has been associated with adverse
health effects in humans, including hepatotoxicity, altered thyroid hormone homeostasis,
immunotoxicity, reproductive effects, and developmental neurobehavioral
toxicity. Contaminated food consumption has historically been the major contributor
to PCB body burden, but contamination of indoor air may also contribute in
some exposure scenarios. Although chronic oral reference values have been derived
for PCBs, derivation of inhalation values is challenging due to a profound lack of
data. Dosimetric adjustments are sometimes applied to use oral reference values as a
basis for derivation of inhalation reference values. Such route-to-route extrapolation
introduces uncertainty into human health risk analysis, as it requires certain
basic assumptions in order to establish similarity between the oral and inhalation
routes. With PCBs, further uncertainty results from differences between oral and
inhalation exposures unique to this chemical class. These differences occur because
PCBs are chemical mixtures made up of a variety of individual congeners. The degree
of congener chlorination in a PCB mixture is an important determinant of the
mixture’s physicochemical properties and toxicity. Volatile congeners tend to be less
chlorinated, less persistent, and less toxic than those found in food. Chronic oral
reference values are currently available for two PCB mixtures: Aroclors 1016 and
1254. Aroclor 1016 contains lower-chlorinated PCB congeners than Aroclor 1254.
Because inhalation exposure favors lower-chlorinated PCB congeners, the Aroclor
1016 reference value may be more representative than the Aroclor 1254 value for
assessment of inhalation exposure risk. However, uncertainties remain regarding the
relative toxicities of these PCB mixtures and the application of their oral reference
values to inhalation exposure risk. This presentation will explore these uncertainties
and identify critical areas of research needed to improve risk estimation for inhaled
PCBs. The views expressed here do not reflect the views or policies of the U.S. EPA.
2298 STRUCTURE-ACTIVITY MODELS FOR CHEMICAL
INHALATION HEALTH GUIDANCE VALUES.
C. J. Collar 1 , T. Miller 2 , R. M. Garrett 2 and E. Demchuk 1 . 1 Division of
Toxicology and Environmental Medicine, ATSDR/CDC, Atlanta, GA and
2 Department of Defense, Washington, DC. Sponsor: B. Fowler.
Acute Exposure Guideline Levels (AEGLs) are thoroughly examined data for airborne
concentrations of hazardous chemicals. These chemical concentrations are
defined as the human threshold limits at five exposure periods ranging from ten
minutes to eight hours. Health effects are categorized by the National Academy of
Sciences (NAS) as non-disabling (AEGL-1), disabling (AEGL-2), and lethal
(AEGL-3). However, AEGLs are finalized for less than sixty compounds, and less
than two-hundred are considered interim; far less than the number of potential airborne
hazards to the human population. We employed the AEGLs data at the eight
hour exposure period, to construct quantitative structure-activity relationship
(QSAR) models capable of predicting provisional health guidance values (HGVs)
for airborne chemical hazards that have no guidance assigned by the NAS. These
models are statistically significant with R 2 and Q 2 values greater than 0.70 and
0.50, respectively. Since QSAR modeling is driven by uniformity and quantity of
underlying data, point-of-departure and endpoint grouping factors can be employed
to gain insight into how the model is formulating HGV estimates and what
can be done to increase the estimation performance. Hence, we have begun this
process by assessing the point-of-departure information. The AEGLs datasets were
split into subsets of human and rat data and new models were built. With statistical
significance comparable or better than parent models, these species-specific models
were individually analyzed and also employed to validate each other; the compounds
of the first model were used as a testing dataset for the second model and
vice versa. In the future we plan to: (1) employ additional endpoint grouping factors,
(2) model the remaining four time periods, and (3) incorporate other HGVs
into the models.
2299 THORACIC DAMPING AND THE RELATIONSHIP
BETWEEN PENH OF THE THORACIC AIR-FLOW (I T )
AND TIDAL MIDEXPIRATORY FLOW (EF 50 ).
D. G. Frazer, J. S. Reynolds, W. T. Goldsmith, W. G. McKinney, M. C. Jackson
and A. A. Afshari. HELD, CDC / NIOSH, Morgantown, WV. Sponsor: A. Hubbs.
The thoracic air-flow pattern can be modeled as a response to the action of the respiratory
muscles. That response can be viewed as being either under-damped, when
I T is initially higher then decays toward the end of exhalation, or damped when I T
is initially lower and then rises toward the end of exhalation. Both Penh(I T ) and the
SOT 2011 ANNUAL MEETING 493