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EC number: 215-572-9
CAS number: 1332-65-6
A total of 269 individuals completed the study (Santiago = 70, Grand
Forks = 68, Coleraine = 58, Shanghai = 73). The screened respondents
were healthy before and throughout the study.
Nausea was the earliest and most prevalent symptom observed within 15
mins of the dose (24.3, 41.1, 25.9 and 50.0% of the subjects at the 4
sites; Santiago, Shanghai, Coleraine and Grand Forks respectively
reported at least one occurrence of nausea at any dose. The average
prevalence of nausea among all subjects of 35.7% at 15 mins. The overall
prevalence for subjects reporting nausea decreased from 15.6% at 15 mins
to 6.3% at 60 mins in the 6 mg Cu/l (1.2 mg Cu in 200 ml) group (see
Table 2). Similarly for those consuming 8 mg Cu/l (1.6 mg Cu in 200 ml),
the overall prevalence decreased from 26.0% at 15 mins to 7.8% at 60
The difference in the occurrence of nausea at 15 and 60 mins is also
illustrated by the difference in the probability of a
positive response at the 2 highest bolus doses using the 200 ml volume,
as estimated using the linear regression model. The probability of
nausea was elevated over control at both time points, but the incidence
rates at 60 mins were considerably lower than at 15 mins (see Table 3).
The results obtained for the analysis of all 4 GI symptoms (nausea,
abdominal pain, vomiting and diarrhoea) were similar to the analysis for
nausea alone. Fig 1. Presents the incidence of nausea at each copper
dose at 15 and 60 mins, for the 300 ml volume.
Table 2 also presents the total number of subjects reporting nausea (at
either 15 or 60 min time points). The total number reporting nausea is
close to the number of those reporting nausea at 15 mins. This means
that most of the subjects reporting nausea at 60 mins had also reported
nausea at 15 mins but some new respondents were reported.
Using the statistical significant increased incidence compared with
control as the criterion to ascertain an adverse effect level and the
200 ml linear dose-response data at 15 mins for nausea effects at all
sites; the generalised linear model analysis data indicated that for
this dosing volume the LOAEL occurred at 1.2 mg Cu (6 mg Cu/l; p =
0.0004) and the NOAEL occurred at 0.8 mg Cu (4 mg Cu/l; p = 0.06). These
results are comparable with those in Araya et al,. (2001) which was a 3
site, mixed sex study.
In addition a benchmark dose (BMD) was calculated for the 200 ml bolus
linear dose-response data at 15 min for nausea effects at a benchmark
response (BMR) of 0.10. The US EPA BMD software version 1.3 was used to
evaluate these dichotomous data, using a multistage model with extra
risk. The goodness of fit p-value was p = 0.94 with a BMD of 0.94 mg
copper (4.8 mg Cu/l). The corresponding 95% lower confidence limit on
the BMD (BMDL) was 0.84 mg copper (4.2 mg Cu/l).
As found with the 200 ml bolus, nausea was also the earliest and most
prevalent symptom recorded following exposure to copper in a 150 and 100
ml bolus solution. Estimates of NOAEL/LOAEL volumes were made for
comparison purposes as the study was not designed for this purpose
having no control groups. The NOAEL/LOAEL for these volumes was
estimated by comparison of the responses to those seen in the 200 ml
control group. For 150 ml volume; the LOAEL occurred at a dose of 1.2 mg
Cu (8 mg Cu/l) and a NOAEL of 0.8 mg Cu (5.3 mg/l). For the 100 ml
volume; the LOAEL occurred at a dose of 0.8 mg Cu and a NOAEL of 0.4 mg
Cu corresponding to concentrations of 8 and 4 mg Cu/l. These data are
only approximations but show a consistent picture with the NOAEL
consistently in the range of 4-5 mg Cu/l over a 2-fold range of total
dose (100 – 200 ml doses).
Table 5 summarises the probability outcome of the 3 x 3 dosing for
nausea at both 15 and 60 min by test site, water volume, copper dose and
water volume x copper interaction. The 3 x 3 factorial ANOVA
demonstrated that at 15 mins there was a significant effect of water
volume (p = 0.032) and copper dose (p = 0.0001). As copper dose
increases or as water volume decreases (thereby increasing the
concentration) there was an increased probability of a female
experiencing nausea (Figure 2). Likewise the highest incidence of
symptoms was reported within the first 15 min. As with the linear 200 ml
dose-response analysis, inclusion of all GI symptoms did not appreciably
change the response incidence from nausea alone.
The interaction of volume by dose was not statistically significant (p =
0.97). This means that the effects of volume and dose were additive i.e.
volume and dose acted independently, not synergistically or
antagonistically. The probability of a positive response increased
significantly as the copper dose increased, regardless of water volume.
Similarly, the probability of a positive response decreased
significantly as the water volume increased, regardless of copper dose.
The lack of interaction of these terms is not informative regarding
whether concentration is an appropriate explanatory variable. This study
was designed to investigate dose-response and not
concentration-response; so formal analyses based on concentration are
not possible. However, as shown in Figure 3, there is a visually
apparent concentration-response, overlaid on top of the dose-response.
Nonetheless, based on the results of Figs 2 and 3, neither dose nor
concentration fully predicts the response; both units of exposure are
relevant in determining the response.
Materials and Methods:
In a double blind, 3x3 factorial (volume x dose) study, 70 adult females
(18-60 yrs of age) at 4 different international sites (total pooledn=
269) were given 100, 150 or 200 ml of bottled drinking water with 0.4,
0.8 or 1.2 mg of Cu as the sulphate salt once a week. Two additional
doses (0 and 1.6 mg Cu) were added at the 200 ml to determine a
dose-response relationship and corroborate previously reported results.
All subjects completed a questionnaire ay 0, 0.25 and 1 h post-dosing
that screened for positive GI effects (nausea, abdominal pain, vomiting
Results and Discussion:
Nausea was the most prevalent symptom reported and was generally
reported within the first 15 min (water volume, p<0.032; copper dose
p<0.0001; and water volume x copper interaction p<0.97). As the volume
was increased, the effects of Cu-induced nausea decreased; as Cu dose
increased, the incidence of nausea increased. At 200 ml, a significant
increase in reported incidence of nausea at 0.25 h occurred at 1.2 mg Cu
(6 mg Cu/l), indicating a NOAEL of 0.8 mg Cu (4 mg Cu/l) for adult
females. These data confirm previously determined human acute NOAEL
study for Cu added to distilled water, and provide additional,
controlled human data for determining safe concentrations of Cu in
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