Journal of Gerontology: BIOLOGICAL SCIENCES
2008, Vol. 63A, No. 12, 1307–1313
Copyright 2008 by The Gerontological Society of America
Cardiac and Thermal Homeostasis in the
Aging Brown Norway Rat
Christopher J. Gordon
Neurotoxicology Division, National Health Effects and Environmental Research Laboratory,
U.S. Environmental Protection Agency, Research Triangle Park, North Carolina.
The cardiovascular and thermoregulatory systems are considered to be susceptible in the aged
population, but little is known about baseline cardiac and thermoregulatory homeostasis in rodent
models of aging. Radiotransmitters were implanted in male, Brown Norway rats obtained at 4,
12, and 24 months to monitor the electrocardiogram (ECG), interbeat interval (IBI), heart rate
(HR), core temperature (Tc), and motor activity (MA). There was no significant effect of age on
resting HR and MA. Daytime Tc of the 24-month-old rats was significantly elevated above those
of the 4- and 12-month-old groups. Variability of the IBI was highest in the 24-month-old rats.
The elevation in daytime Tc beginning around 8 months of age may be a physiological biomarker
of aging and may be an important factor to consider in studies using caloric restriction–induced
hypothermia to increase longevity.
Key Words: Radiotelemetry—Heart beat variability—Core temperature—Motor activity—
Heart rate.
A
GING adults represent the fastest growing segment in
many countries. For example, in the United States the
number of people 65 years old or older will double to more
than 71 million by the year 2030 (1). There is a need to have
better experimental models to study the impact of aging on
a variety of physiological, pharmacological, and toxicological processes. Aging is associated with pathophysiological
deficits that would lead one to expect alterations in baseline
physiological processes as well as shifts in the ability to
respond to stress, toxicants, and drugs. For example,
increased formation of free radicals (2,3), the decline in
cardiovascular function (4,5), increased susceptibility to
heat and cold stress (6,7), and decreased ability to absorb,
metabolize, and excrete drugs and toxicants (8) may all
contribute to increased susceptibility.
The Brown Norway (BN) rat is a popular rodent model
for aging studies (9). The BN strain has been used to study
the effects of aging on the function of the cardiovascular,
reproductive, renal, and other systems. Even with ad libitum
access to food, the weight gain of the BN strain over its
lifetime is limited compared to that of other strains (10),
making it more amenable for autonomic and behavioral
testing of aged animals. Moreover, this strain along with the
Fischer 344 (F344) and BN/F344 hybrid are commercially
available at life stages ranging from prepubescence to senescence (e.g., National Institute of Aging, Baltimore, MD).
There is a considerable database on thermal and cardiac
homeostasis using conventional technologies that require
animal handling and attachment of probes; however, these
techniques can be stressful, resulting in artifactual changes
in the thermoregulatory and cardiovascular systems (for a
review, see 11). Radiotelemetry is an ideal means of collecting physiological data in undisturbed and unrestrained
rodents with minimal stress. Long-term, round-the-clock
telemetric monitoring would provide researchers with better
assessments of how aging affects baseline physiological
processes. A better understanding of these physiological
processes in the aging BN rat will provide a foundation for
further research on the susceptibility of aged individuals to
environmental toxicants.
It is well known that long-term caloric restriction will lead
to a prolongation in life span of rodents and other species
(10,12). The mild hypothermia induced by caloric restriction
is thought to be a contributing factor to the increase in life
span. However, very little is known regarding the natural
changes in baseline core temperature of aging animals,
which would seem to be very important for one to understand the potential benefits of caloric restriction. Radiotelemetry provides the best means of assessing subtle
changes in the core temperature of aging rodents. Hence, the
purpose of this study is to use radiotelemetry to assess the
effects of aging on the 24-hour patterns of heart rate, cardiac
arrhythmias (i.e., interbeat intervals [IBIs]), core temperature, and motor activity in male BN rats.
MATERIALS AND METHODS
Animals
In one experiment, a cross-sectional approach was taken
to study the responses of separate groups of aged rats. Male
rats of the BN strain were obtained through the National
Institute of Aging (colony operated by Harlan Laboratories,
Indianapolis, IN). The U.S. Environmental Protection
Agency (EPA) is using the BN strain to assess the potential
susceptibility of the aging population to exposure to
environmental toxicants. The animals in this study were
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eventually used to assess the effects of aging on the
cardiovascular and thermoregulatory effects of toluene (13).
All data presented in the current study were collected in
animals prior to any exposure to toluene or vehicle. BN rats
were purchased at 4, 12, and 24 months of age and were
housed individually in polycarbonate cages lined with wood
shaving bedding at an ambient temperature of 228C, relative
humidity of 50%, and 12-hour light/dark cycle (lights on at
6:00 AM). Rats were allowed several weeks to accommodate
to the animal facility before being subjected to surgery. All
protocols were approved by the Institutional Animal Care
and Use Committee.
Surgical Procedure
Heart rate, core temperature, and motor activity were
monitored in unrestrained rats using radiotelemetry (model
TA11CTA-F40; Data Sciences International, St. Paul, MN).
Rats were anesthetized with a mixture of ketamine and
xylazine (80/10 mg/kg; intraperitoneally). Once the desired
plane of anesthesia was reached, a midline incision was
made and the body of the transmitter was placed inside the
abdominal cavity and sutured to the midline (see 14). The
electrocardiogram (ECG) leads were tunneled under the skin
and positioned on the left and right sides of the thorax
allowing for the best detection of the ECG signal. The skin
was closed with wound clips, and an analgesic (buprenorphine; 0.03 mg/kg; subcutaneously) and an antibiotic
(penicillin; ;30,000 U; intramuscularly) were administered
to the rat. The temperature calibration of the transmitters
was checked after extraction from the animals to assure
proper operation of the units.
Protocol
Heart rate, ECG wave form, core temperature, and motor
activity were recorded continuously by the telemetry system
and analyzed with software provided by the manufacturer
(ART Gold, version 4.0; Data Sciences International). All
animals were monitored remotely while housed individually
in the vivarium. The ECG wave form was recorded for 10
seconds every 3 hours. Heart rate, core temperature, and
activity were recorded at 5-minute intervals.
The rats were allowed to recover from surgery for at least
10 days prior to data collection. To collect baseline data, rats
were given a clean cage of pine shaving bedding and left
undisturbed for 5 days. Food and water were provided
ad libitum. Other than a daily visual inspection to assure
the animal’s health and well-being, the animals were left
undisturbed during the monitoring period. Mean 6 standard
error of body weight of the rats at the start of the baseline monitoring period was 323 6 10 g, 352 6 12 g, and
416 6 16 g, for the 4-, 12-, and 24-month-old animals,
respectively.
Another experiment used a longitudinal approach to
follow changes in core temperature and motor activity in
aging rats. Male BN rats were obtained at 60 days of age
from Charles River Laboratory (Raleigh, NC). These
animals were housed under the same conditions as described
above, and transmitters were implanted in them to monitor
core temperature and motor activity (model TA10TA-F40;
Data Sciences International). Surgery was similar to the
above methods, except that there were no ECG leads. The
animals were allowed at least 1 week of recovery prior to
testing. Telemetry data were collected at 10-minute
intervals. These animals were from the control group of
a study to assess the effects of age on the toxicological
response to carbaryl, an anticholinesterase-based insecticide.
The baseline core temperature and motor activity were
monitored in these undisturbed rats every 2–3 months
beginning at 3 months of age and ending at 24 months of
age. These rats had been given corn oil (0.1 mL/100 g)
either immediately before or after the baseline monitoring
period. The corn oil had no apparent long lasting effects
beyond the brief response to the stress of handling and
dosing.
Data Analysis
The baseline telemetry data collected in undisturbed rats
for 5 days were analyzed using a ‘‘foldagram’’ procedure
incorporated in the Data Sciences International software.
The raw telemetry data collected for 5 days were averaged
into a single 24-hour period for each animal. Hence,
excluding noisy data points automatically excluded from
analysis, a 5-day foldagram with a 5-minute sampling time
contained 1440 data points. The 24-hour mean and standard
deviation (SD) of the telemetry data for each age group were
calculated from the foldagram. For statistical analysis to test
the effects of age on the time course of each telemetry
parameter, the foldagram data were further averaged into 12
bins each with a duration of 2 hours. Heart rate, temperature,
and activity were analyzed for statistical analysis using a
two-way repeated-measures analysis of variance (ANOVA)
with age and time as dependent variables (Sigma Stat 3.1;
Point Richmond, CA). The same 5 days of telemetry data
were used to construct periodograms using the Data
Sciences International software. The periodogram is a
modified Fourier analysis that reveals significant frequencies
and their relative power of cyclic data (15). For all analyses,
p , .05 was accepted as statistically significant.
Heart Rate Variability
The variability in heart rate was calculated with software
provided by Data Sciences International (version ART Gold
4.0). Briefly, the 10-second samples of the ECG data were
viewed for signal consistency and movement artifacts. The
R waves of the ECG were marked electronically. The interval between each R wave, the interval mean, and the SD of
the 10-second sample were calculated. IBI mean and SD
were calculated for each age group sampled at 12:00 PM
and 12:00 AM for 6 days. The coefficient of variation
(SD/mean 3 100) of the 6-day average was then calculated.
These data were analyzed for statistical significance using
two-way ANOVA with age and time of sampling as factors.
RESULTS
The foldagram analysis illustrates the distinct circadian
rhythms of heart rate, core temperature, and motor activity
in the three age groups (Figure 1). Heart rate during the
day and night was approximately 280 and 300 beats/min,
respectively. Overall, 24-hour means of the telemetry data
CORE TEMPERATURE IN THE AGING RAT
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Table 1. Mean, Standard Deviation (SD), and Percent
Coefficient of Variation (%CV) of Heart Rate,
Core Temperature, and Motor Activity
Parameter
Heart rate
Heart rate
Heart rate
Core temperature
Core temperature
Core temperature
Motor activity
Motor activity
Motor activity
Age (Months)
24-Hour Mean
SD
%CV
4
12
24
4
12
24
4
12
24
282.5 beats/min
294.9 beats/min
290.1 beats/min
37.418C
37.358C
37.648C
1.94 counts/min
2.03 counts/min
2.13 counts/min
13.9
12.7
23.3
.044
0.106
0.088
0.84
0.84
1.1
4.7
4.3
8.0
0.11
0.29
0.23
43.3
41.4
52.0
Notes: N ¼ 5 for 4-month, 6 for 12-month, and 5 for 24-month-old animals.
*Significantly different from 4- and 12-month-old groups.
Figure 1. Effect of age on the 24-hour time course of heart rate, motor
activity, and core temperature in Brown Norway rats. Five days of data were
averaged for each graph and plotted as mean 6 standard error. Repeatedmeasures analysis of variance results: heart rate, age (nonsignificant [NS]), time
(F ¼ 23.3, p , .001), Age 3 Time interaction (NS); motor activity, age (NS),
time (F ¼ 17.9, p , .001), Age 3 Time interaction (NS); core temperature,
age (F ¼ 20.6, p . .001), time (F ¼ 94.3, p , .001), Age 3 Time interaction
(F ¼ 2.07, p ¼ .006). N ¼ 5 for 4-month, 6 for 12-month, and 5 for 24-month
age groups.
indicated no significant effect of age on heart rate and motor
activity. There was, however, an increase in variability in
the aged animals (Table 1). Although there were no overall
age effects, there was a trend for a higher heart rate and
motor activity in the youngest animals during the early
morning that merits comment. Between 6:00 AM and 8:00 AM,
motor activity of the 4-month-old animals was more than
double that of the 24-month-old animals; heart rate of the
younger animals was 20 beats/min higher than that of the
oldest animals during the same time period. A post hoc
ANOVA indicated statistical significance for motor activity
(F ¼ 5.0, p ¼ .024) but not heart rate (F ¼ 3.75, p ¼ .052).
Motor activity of the 4- and 12-month-old rats was
slightly elevated in the morning and then decreased to ;1
count/min in the middle of the day. Activity of all age
groups increased through the later part of the day and
exhibited an approximate doubling during the night. All age
groups showed a peak in heart rate occurring in the first
2 hours of the dark phase that was associated with a transient
increase in motor activity. It is also worth noting that the
coefficient of variation of heart rate and motor activity and
the day versus night amplitudes were elevated in the aged
animals (Tables 1 and 2).
Age had a significant effect on core temperature. The
daytime core temperature of the 24-month-old rats was
significantly elevated through most of the daytime compared
to the 4- and 12-month-old animals (Figure 1). Core temperature of all three ages was ;37.58C during the first
2 hours of the light phase. As the day progressed, temperatures of the 4- and 12-month-old animals decreased to
below 378C, whereas temperature of the oldest animals
remained at ;37.58C. At the onset of the dark phase, the
core temperature of the oldest animals increased to about
the same level as that of the 4- and 12-month-old animals.
The 24-hour average of core temperature of the 24-monthold rats was significantly greater than those of the 4- and
12-month-old groups (Table 1).
Periodogram
The periodograms illustrate the effect of age on the
robustness and variability of the cyclic changes in the telemetry data (Figure 2). The strongest peak for all telemetry
data occurred at 24 hours, indicative of the primary influence of the circadian rhythm. There were no significant
Table 2. Difference Between Day and Night Values of
Heart Rate, Core Temperature, and Motor Activity
From Day to Night in the Three Age Groups
Parameter
Heart rate
Heart rate
Heart rate
Core temperature
Core temperature
Core temperature
Motor activity
Motor activity
Motor activity
Age (Months)
Night–Day Difference
SD
%CV
4
12
24
4
12
24
4
12
24
14.8 beats/min
13.7 beats/min
16.0 beats/min
0.688C
0.598C
0.478C
0.93 counts/min
1.19 counts/min
1.85 counts/min
8.6
4.5
15.6
0.11
0.12
0.21
0.62
0.62
2.41
58.1
32.8
97.5
16.1
25.5
44.6
66.6
52.1
130.2
Note: SD ¼ standard deviation; %CV ¼ percent coefficient of variation.
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Figure 2. Periodogram analysis of core temperature (A), heart rate (B), and motor activity (C) for 5 days of telemetry data. The peak power at a period of 24 hours is
indicative of the amplitude of the circadian rhythm. To enhance clarity, maximum value of power for motor activity varies by age. Data plotted as mean 6 standard
error.
effects of age on the peak 24-hour power for the telemetry
parameters. The core temperature periodogram was the least
variable, and the power at 24 hours for the 4-month-old
animals was nearly double that of the 24-month-old animals.
This reduction in the peak power is partially reflected by
the overall difference between the night and day for the
telemetry parameters (Table 2). There was no overall effect
of age on the day-night difference in core temperature, heart
rate, and activity (Table 2).
Longitudinal Study
Measuring core temperature and motor activity in the
same animals from 3 to 24 months of age corroborated
the finding that aging is associated with an increase in core
temperature (Figure 3A). At 3 months of age, the mean
24-hour core temperature was 37.28C. Core temperature
changed little over the next 5 months with mean 24-hour
temperature decreasing an insignificant 0.18C. When measured at 10 months, core temperature had increased sharply
from the 8-month point. There was a slight decrease at
14 months, then a steady increase over the next 8 months of
age. The elevation in 24-hour core temperature is attributed
to the increase in daytime core temperature in aged animals
(Figure 3B). It is interesting to note that motor activity did
not change appreciably during the same time. There was
a notable increase in activity in the remaining animals at
22 months of age, but the variability at this point was
marked (only two animals survived to this point).
Heart Rate Variability
There was a significant increase in IBI variability in the
24-month-old group at 12:00 PM and 12:00 AM (Figure 4A).
Overall, the coefficient of variation of the IBI in the
24-month-old rats was approximately 12% higher than that
of the 4-month-old animals. The increase in coefficient of
variation in the aged animals is reflected by the marked
increase in SD of the IBI but with little change in mean IBI.
A sample of the ECG wave form of a 12- and 24-month-old
rat exemplifies the increased variability in heartbeat rhythm
in the older animals (Figure 4B). The IBI variability of the
12-month-old animals showed a slight but insignificant
increase compared to the 4-month-old animals.
DISCUSSION
Analyzing several days of telemetry data is an ideal
means of discerning subtle changes in the physiology of
aging animals. The stress from the use of conventional
methods to monitor temperature and heart rate or the simple
presence of personnel near the animals may mask any subtle
effects of aging. There was surprisingly little difference in
the 24-hour mean heart rate and motor activity of 4-, 12-,
and 24-month-old animals. Heart rate of the 4-month-old
rats was noticeably higher at 6:00–8:00 AM compared to
that in the 12- and 24-month-old animals. Likewise, motor
activity of the 4-month-old animals was double that of the
24-month-old animals during this same period. There were
CORE TEMPERATURE IN THE AGING RAT
significant differences in core temperature among the three
age groups. The results of the cross-sectional study suggest
that the 24-month-old rats maintained a significantly
elevated core temperature throughout the daylight hours
compared to the 4- and 12-month-old animals. The longitudinal study of core temperature and motor activity in the
same group of rats corroborates the daytime elevation in
core temperature and suggests that the phenomenon is
initiated at approximately 8 months of age. Core temperature may be an important physiological biomarker of aging
in this strain of rat.
This study is apparently the first to use radiotelemetry to
assess the effect of age on cardiac and thermal rhythms of
young and aged BN rats. Using arterial catheters to monitor
heart rate and blood pressure in Wistar rats at 10 weeks and
24 months of age, Irigoyen and colleagues (4) reported no
effects of age on baseline heart rate or blood pressure. Using
telemetry to monitor 6- and 24-month-old Wistar rats,
Zhang and Sannajust (5) found a significant reduction in
nocturnal heart rate as well as reduced amplitude of the day
versus night difference in both heart rate and blood pressure
in the aged animals. The current study found no evidence of
reduced day versus night amplitude in heart rate or motor
activity in the aged animals (Table 2).
It is well established that hypothermia is a common
thermoregulatory deficit in senescent rodents (11,16). The
marked drop in core temperature coincides with sharp
declines in food consumption and body weight. In contrast,
the gradual elevation of core temperature persists in healthy,
aged BN rats. Is the elevation in core temperature unique to
the BN strain? This question cannot be resolved completely
in this study because the method of averaging days of core
temperature in telemetered animals (i.e., foldagram) has not
been previously used in aging studies. Nonetheless, there is
some evidence in rodent studies that core temperature does
increase with age, but other studies support no change or
a decrease. A few studies using colonic probes to measure
temperature suggest that aged rats may undergo an increase
in baseline core temperature. Kiang-Ulrich and Horvath (17)
measured basal colonic temperature and metabolic rate in
young (3–4 months), adult (12 months), and old (20–24
months) male F344 rats when tested in a calorimeter at
a near thermoneutral temperature of 288C but were normally
housed at 238C. They reported aged-related increases in
colonic temperature, with the old rats having a temperature
0.78C higher than that of the young animals. In contrast,
Horan and colleagues (18) measured colonic temperature in
female BN rats at ages of 3, 5, 23, and 36 months while
housed at 248C. Temperature of the 23-month-old animals
was 0.58C less than that of the 3-month-old animals. Core
temperature was apparently only measured once, and the
time of the measurement was not specified.
The change in mean core temperature could also be
attributed to dysfunction of the circadian pacemaker. Radiotelemetry was used to monitor the changes in circadian
temperature rhythms in young adult and aged Long-Evans
(LE) and F344 rats (15,19). Aging in the male and female
LE rat was associated with a disruption in the circadian
temperature rhythm (15). There is a critical age, approximately 20 months of age, during which the rat displays
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Figure 3. A, Relationship between age and the mean 24-hour core
temperature and motor activity of Brown Norway rats from an age of 3 to 24
months. Numbers indicate sample size. N ¼ 8 for all other points. B, Time course
(24 hours) of core temperature of the same rats monitored at 3, 8, and 24 months
of age. N ¼ 8 for 3- and 8-month-old rats; N ¼ 3 for 24-month-old rats. Each data
set represents a foldagram of 6–7 days of telemetry data. Data plotted as mean 6
standard error. Repeated-measures analysis of variance for effect of age:
Temperature, F ¼ 5.8, p , .001; motor activity, F ¼ 2.9, p ¼ .01.
disruption in the rhythm characterized by attenuation in the
amplitude of the day versus night core temperature. It was
suspected that the disruption in the circadian rhythm was
a result of dysfunction in the circadian pacemaker and not
a failure in thermoregulatory effectors for heat gain and heat
conservation. Although they did not use a multiday analysis
of data (i.e., foldagram) as in the present study, Li and
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Figure 4. A, Mean interval, standard deviation, and coefficient of variation of the interbeat interval of the three age groups measured at 12:00 AM and 12:00 PM for
six consecutive days. *Significant difference from 4-month-old group. B, Examples of electrocardiogram (ECG) wave forms collected from a 12-month-old and
24-month-old animal. Note the variability in the R-R interval of the aged rat.
Satinoff (15) did find a ;0.258C decrease in core temperature of aged rats regardless of whether they had a normal
or disrupted circadian rhythm. The authors did not quantify
the overall relationship between age and the mean core
temperature, but there was no obvious trend for increase
in core temperature with aging as was observed in the
current study. The amplitude of the periodogram in the aged
LE rats with disrupted circadian rhythms was reduced. The
periodograms of temperature in aged rats in the current
study were also reduced and were more variable (cf. Figure
2A). McDonald and colleagues (16) monitored core
temperature in young and aged F344 rats by radiotelemetry
but saw no remarkable changes in core temperature until
senescence. It is important to note that their studies were
carried out under constant dark conditions to evaluate the
function of the circadian pacemaker with aging. In
summary, the gradual increase in core temperature of aging
BN rats could be unique to this strain. Using telemetry and
averaging of multiple days of data will elucidate if there are
subtle changes in the core temperature in other strains and
species of healthy aging animals.
It is interesting to note in the current study that the
elevated daytime core temperature in the aged rats seemed
to have no direct effects on heart rate. That is, the daytime
heart rate of the oldest animals was slightly lower than that
of the younger animals despite a significantly warmer core
CORE TEMPERATURE IN THE AGING RAT
temperature. Based solely on thermal kinetics, one would
expect the pacemaker of the heart to be directly influenced
by temperature and heart rate of the aged animals to be
slightly higher than that of the younger animals with lower
core temperatures. Clearly, there are factors that govern
baseline heart rate other than temperature.
Implanting a transmitter in a young rat for the longitudinal study (cf. Figure 3) and following its core temperature
and motor activity throughout most of its life span is
apparently not a routine technique. It was not clear how well
the transmitter would be tolerated when left in the
abdominal cavity for such a long time. In fact, the mortality
in this group seemed unusually high. Only 2/8 rats survived
to 24 months. Several of the aged rats were killed because of
ascites, weight loss, and/or lack of appetite. At necropsy,
many of these animals were found to be inundated with
tumors on the lining the abdominal wall and many of the
abdominal organs. At this time, there is no explanation, but
it is possible that there was a chronic inflammatory condition in these animals that could have affected temperature
regulation. One should question if an inflammatory reaction
to the long-term implantation of the telemetry unit has a role
in the elevated core temperature in the aged animals. In
contrast, in the cross-sectional study during which physiological measurements were made following a brief period of
implantation, a similar trend for elevated core temperature in
aged rats was observed. This finding would suggest that the
temperature elevation in aged animals is not an artifact of an
inflammatory response to the transmitter.
Conclusion
Application of telemetry and analysis of days of data in
undisturbed animals is proposed to be an ideal means to
study the physiological response to aging in rodents. The
thermoregulatory system of mice and rats typically responds
to handling stress with a prolonged hyperthermic response
(11). Remote monitoring with telemetry eliminates many of
the stress-induced changes in temperature and other homeostatic processes. Telemetry is thus an ideal means of
assessing the role of caloric restriction-induced hypothermia
and increased life span. A mild reduction in core temperature is thought to be a contributing factor in the increase in
life span in animals maintained on calorically restricted diets
(12). A cooler core temperature has been hypothesized to
suppress the effects of aging and attenuate neurodegenerative disorders (20). Core temperature of ad libitum fed
animals is generally assumed to remain relatively stable with
aging and decrease in morbid animals in which death is
imminent. In contrast, the current study indicates a small but
steady increase in core temperature, beginning around
midlife in the male BN rat. This increase in temperature
would be expected to accelerate aging processes. Although
the temperature elevation is ,18C, with sufficient time,
a small temperature elevation could be a significant factor in
the development of pathological effects in aged animals.
ACKNOWLEDGMENTS
I thank Drs. Robert MacPhail and Aimen Farraj for their review of the
manuscript. The technical assistance of C. Mack and P. Becker is
appreciated.
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This article has been reviewed by the National Health and Environmental
Effects Research Laboratory, U.S. Environmental Protection Agency, and
approved for publication. Mention of trade names or commercial products
does not constitute endorsement or recommendation for use.
CORRESPONDENCE
Address correspondence to Christopher J. Gordon, PhD, B105-04,
Neurotoxicology Division, NHEERL, U.S. EPA, 109 T. W. Alexander Dr.,
Research Triangle Park, NC 27711. E-mail: [email protected]
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Received March 31, 2008
Accepted July 28, 2008
Decision Editor: Huber R. Warner, PhD