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Methods
Seven animal studies were summarized, and are presented in Table 1. Although exposure protocols varied slightly, all animals in these studies were dosed through drinking water. Four studies in Table 1 were conducted on adult animals: 14-day rat study (Caldwell et al., 1996), 90-day rat study (Siglin 1998) and 90-day mouse studies (Keil et al., 1999; BRT-Burleson Res. Inc. 2000). Three studies were conducted either on pregnant rabbits during gestation (York 1998) or on pregnant rats from pre-mating through gestation and lactation (York 1999; York 2000). Our study comparisons were grouped into short-term studies, sub-chronic studies, and responses in dams and pups in developmental studies.
Five
human studies were also summarized (Table 2).
For all of the human studies, the daily exposure doses were expressed as
mg/kg-day. A default adult body
weight of 70 kg was used to estimate dose when actual body weight was not
available from the original report. In
two studies (Brabant et al., 1992; Li et al., 1999), humans were exposed to
perchlorate through the oral route. In
Li (1999), the neonates were only exposed to perchlorate through the mother
during gestation. Therefore, only
the exposure dose for mother was estimated using an assumption of a daily water
consumption of two liters.
In the three remaining studies, one in Lamm et al. (1998) and two in Gibbs et al. (1998), humans were exposed to perchlorate through inhalation of perchlorate-containing particles. In the Gibbs et al. studies, the perchlorate absorbed following inhalation was used as the equivalent daily perchlorate dose (mg/kg-day). Since chronic exposure was our main concern, we used the data on working-lifetime exposure from the two reported exposure data sets in Gibbs et al. (1998). Furthermore, in Lamm et al. (1998), exposure values were reported as respirable (particle) dose and total dose. As a conservative estimation, we used the respirable dose in our data summary.
To
ease comparison of data among studies and species, we converted all the hormone
measurements into percentages of the corresponding control values (mean% =
exposure mean/control mean x 100). The
data presented in all figures are expressed as means and standard deviations
(mean ±
SD). Thus, the background value,
the control value, equals 100%. In
addition, to facilitate direct dose comparisons among animal and human studies,
all the experimental oral doses in the animal studies were converted to relative
human doses by scaling daily-applied doses in proportion to body weight raised
to the 0.75 power. In all the
figures, an asterisk indicates that the data point significantly differs from
the control based on the results reported in original documents or the published
papers.
Both
the lowest observed effect level (LOEL) and the benchmark dose (BMD) approaches
were used for the dose-response comparison.
The LOEL method compares the lowest effective doses in each study at
which a statistically significant response was observed.
This method is limited by the sample variation because the greater the
sample variation, the less the statistical power.
Thus, a poor experiment will result in a higher LOEL.
To better compare the results, in addition to the LOEL method, we also
used a BMD approach. Using U.S. EPA benchmark dose software version 1.20, the
benchmark dose in the observable range was estimated by modeling the means and
the standard deviations of hormone levels reported in the original documents.
The software provided many available models for analysis of continuous
data. We used power model, hill
model and polynomial model to analyze the data.
The BMD results from the best fitting model in the three model runs are
presented in Table 3, Table
4, and Table 5. The central estimate of the dose that yielded 10% or 20%
change from the control level was estimated and compared with those from the
other studies. Since the central
estimate is less affected by data variation than the lower 95% confidence limit
for the central estimate, we only compared benchmark doses based on the central
estimates.
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