The Toxicologist - Society of Toxicology

ioactivity based on predicted oral equivalents and estimated human exposures
could be interpreted as a higher priority for further testing and monitoring.
Approved for publication but does not necessarily reflect Agency policy.
1011 GENOTOXICITY TESTS CONDUCTED ON A GROUP
OF STRUCTURALLY RELATED ALDEHYDES.
S. Bhatia, V. T. Politano and A. Api. RIFM, Woodcliff Lake, NJ.
To assess genotoxicity potential, Ames assays and/or in vivo mouse micronucleus
tests (MMNT) using NMRI mice were conducted on a group of 6 structurally related
aldehydes (Hexen-2-al; 2-Nonenal; 2-Dodecenal; (E)-4-Decenal; 10-
Undecenal; Benzaldehyde) that are used as fragrance materials. All the studies were
conducted according to OECD Testing Guidelines and GLP. The Ames assay (preincubation
and plate incorporation method) was conducted using Salmonella typhimurium
strains TA98, TA100, TA102, TA1535, TA1537 in the presence and
absence of S9. 2-Dodecenal, (E)-4-Decenal and 10-Undecenal (high doses ranged
from 1000 to 5000 μg/plate in the presence and absence of S9) were negative in the
Ames test. Hexen-2-al was positive only in one strain TA100 in the absence of S9 in
the pre-incubation assay but negative in the presence and absence of S9 in the plate
incorporation assays. In in vivo MMNTs the vehicle used was corn oil and high
doses ranged from 1000 to 2000 mg/kg. Approximately 24 and 48-h after dosing,
the bone marrow cells were collected for micronuclei analysis. At least 2000 polychromatic
erythrocytes (PCEs) per animal were scored for micronuclei. In all the
six aldehydes that were tested (Hexen-2-al; 2-Nonenal; 2-Dodecenal; (E)-4-
Decenal; 10-Undecenal; Benzaldehyde) no significant increases in micronuclei
were observed. It is concluded that these aldehydes are not genotoxic.
1012 CALCULATIONS FOR HYPER-ACUTE, HIGH-
CONCENTRATION INHALATION EXPOSURES.
S. N. Chesler 1, 2 , J. Moser 1, 2 and H. Salem 3 . 1 Chemical Security Analysis Center,
Department of Homeland Security, Aberdeen Proving Ground, MD, 2 Battelle
Memorial Institute, Columbus, OH and 3 Edgewood Chemical Biological Center,
Aberdeen Proving Ground, MD.
Effectively calculating exposure dose following high concentrations of inhalable
noxious gases requires tools not ordinarily utilized in conventional toxicology.
These methods include: 1) utilization of toxic load concepts when calculating total
exposure dose, and 2) allometric scaling to apply animal-derived toxicological data
to human populations. At extremely high concentrations, Haber’s Law likely does
not apply due to unique mechanisms that occur at these concentrations. Examples
of these mechanisms include apnea, debilitating chemical burns, and sensory disorientation.
In this presentation, experimental data are used to illustrate the concepts
of toxic load calculations and to estimate errors that might be encountered
when relying on Haber’s Law to calculate dose. Haber’s Law assumes exposure dose
during any time period is the gaseous concentration multiplied by exposure time:
Dose = ΣCt. The Toxic Load Model takes into account the additional toxic concentration-dependent
mechanisms and employs an exponent (n) to increase the importance
of the gaseous concentration as the concentration becomes the controlling
factor of dose: Dose = Σ(C^n)t. The exponent (n) is experimentally determined and
is the slope of the plot of log[c] vs log[t]. Examples of the calculation of n are presented
using data published in peer reviewed literature. Allometric scaling of available
toxicological values (primarily small animal) such that the values apply to humans
of weight ranging from 2 to 100 kg is discussed. The algorithm for scaling of
toxicity (mg) is multiplication of the animal toxicological value by the exponentiated
ratio of the body weights of test animals to human weight. The value of the exponent
is always less than 1 and tends toward 0.75. Allometric scaling and the derivation
of the scaling exponent are presented using examples from peer reviewed
medical and biological journals.
1013 PROPOSED ACUTE, 8-HOUR AND CHRONIC
INHALATION REFERENCE EXPOSURE LEVELS FOR
CAPROLACTAM.
D. Dodge, B. Winder, R. Blaisdell and A. Salmon. Office of Environmental
Health Hazard Assessment, California EPA, Sacramento, CA.
Caprolactam is a known irritant byproduct from the manufacture of Nylon 6.
Responses to toxic airborne levels of caprolactam include nasal and eye irritation in
humans with short-term exposure, and upper airway lesions in rats with subchronic
exposure. We based on acute reference exposure level (REL) on a 6-hr human exposure
study by Ziegler et al. (2008), with a NOAEL of 0.5 mg/m 3 for increased irritant
symptom scores. The data were inappropriate to perform benchmark dose
analysis. Thus, an uncertainty factor (UF) of √10 was applied to the NOAEL to account
for intraspecies toxicodynamic variability, resulting in an acute 1-hr REL of
160 μg/m 3 . No time adjustment (6-hr to 1-hr exposure) or toxicokinetic UF was
applied since irritation is generally dependent more on concentration than on time.
We used data on nasal and laryngeal epithelial lesions in rats to derive proposed 8-
hr and chronic RELs, based on a subchronic study by Reinhold et al. (1998). We
generated a benchmark dose estimate of 3000 μg/m 3 as the point of departure
using dichotomous modeling. We applied a time adjustment to daily 8-hr exposures,
and a human equivalency concentration adjustment from rodent to human
exposure (0.152). We used an additional interspecies toxicokinetic UF of 2 to account
for PBPK nasal tissue dose modeling that predicts a slightly greater dose to
humans. With application of a subchronic UF of 3 and a total intraspecies UF of
10, the rounded cumulative UF of 200 results in an 8-hr REL of 2 μg/m 3 . The
chronic REL (0.4 μg/m 3 ) derivation is the same as that used for the 8-hr REL, with
the exception that exposure is based on continuous, 24 hr/day exposure. Proposed
RELs from the OEHHA are subject to change based on a legally mandated public
review, and peer review by the Scientific Review Panel and are not final until that
process has been completed.
1014 PROVISIONAL ADVISORY LEVELS (PALS) FOR TEAR
GAS (CS).
C. Troxel 1 , P. McGinnis 2 , L. Koller 3 and F. Adeshina 4 . 1 CMTox., Inc., Lander,
WY, 2 Syracuse Research Corporation, Syracuse, NY, 3 Environmental Health &
Toxicology, Corvallis, OR and 4 U.S. EPA, Washington, DC.
PAL values developed by the U.S. EPA represent general public emergency exposure
limits for oral and inhalation exposures for hazardous materials corresponding
to three severity levels and durations of 24 hrs, 30 and 90 d, and 2 yr durations.
PAL 1, 2, and 3 severity levels represent the threshold for mild effects, serious/irreversible/escape-impairing
effects, and lethal effects, respectively. PALs have not
been promulgated nor have they been formally issued as regulatory guidance; they
are intended to be used at the discretion of risk managers in emergency situations
when site specific risk assessments are not available. The PAL protocol has been applied
to estimate oral and inhalation exposure limits for Tear Gas (CS). CS is a potent
irritant, with symptoms of exposure including lacrimation, blepharospasm,
erythema of the eyelids, chest tightness, coughing, nasal irritation and discharge,
salivation, throat irritation, nausea, vomiting, and cutaneous irritation. It is reported
that an aerosol concentration of 4 mg/m 3 will disperse the majority of rioters
within 1 minute, and 10 mg/m 3 will deter trained troops. With the exception of
more severe cutaneous reactions, recovery from exposure is usually rapid upon exposure
to fresh air, generally within 30 minutes after exposure. Data were available
for deriving oral PAL 2 and 3 values for 24 h, and inhalation PAL 1, 2, and 3 values
for 24 h, 30 d, 90 d, and 2 yr. Data were insufficient for derivation of an oral PAL
1 value for 24 hours, and of oral PAL 1, 2, and 3 values for 30 d, 90 d, and 2yr. PAL
estimates to be presented were based on evaluation of experimental data in humans
and animals, and were approved by the Expert Consultation Panel for Provisional
Advisory Levels in October 2008.
1015 ACUTE STUDIES OF INHALED CHLORINE IN F344
RATS SUGGEST ALTERNATIVE TO HABER’S RULE FOR
RISK EXTRAPOLATIONS.
T. S. Peay 1 , J. McKee 1 , G. A. Willson 2 , M. H. George 1 , R. H. Jaskot 1 , D. G.
Ross 1 , T. M. Moore 1 and A. M. Jarabek 1 . 1 U.S. EPA, Research Triangle Park, NC
and 2 EPL, Inc., Research Triangle Park, NC .
Chlorine (Cl2), a high-production volume air toxic, is an irritant of interest to
homeland security. Risk assessment approaches to estimate egress or re-entry levels
use an assumption based on Haber’s Rule and apply a concentration times duration
(“C x t”) adjustment to extrapolate across exposure scenarios. We conducted a set of
acute exposures to explore this assumption. F344 female rats were exposed wholebody
to inhaled Cl2 for 1 hour at 0, 6, 30 and 60 ppm; 6 hours at 0, 0.1, 1.0, 5.0
and 10 ppm; and 24 hours at 0, 0.25, 1.25, and 2.5 ppm. “C x t” equivalent levels
(ppm*hr) are 0, 0.6, 6, 30 and 60 ppm. Endpoints indicative of epithelial disruption
were evaluated, including tissue histopathology immediately post exposure and
biochemical or cellular evaluation of lavage fluids at 24-hr post exposure. Noses
were sectioned transversely to provide six standard section levels. Biochemical
analyses of nasal lavage (NAL) and bronchoalveolar lavage (BAL) fluids included
lactate dehydrogenase, N-acetyl-β-D-glucosaminidase, and total protein (TP). The
expected proximal to distal distribution of lesions (inflammation, necrosis, degeneration
and hyperplasia) with increasing concentration levels was observed but the
type, incidence and severity of each did not follow a “C x t” pattern. Duration of
exposure was a dominant determinant for the emergence of both inflammation and
hyperplasia. Inflammation tended to follow necrosis or degeneration. Both concentration
and duration were determinants of olfactory degeneration. The dose-re-
216 SOT 2010 ANNUAL MEETING