United States
Environmental Protection
Agency
Health Effects Research
Laboratory
Research Triangle Park NC 2771 1
Research and Development
EPA-600/S1-83-007 Sept. 1983
&EPA Project Summary
Fetotoxic Effects of Nickel in
Drinking Water in Mice
Ezra Berman and Blair Rehnberg
Nickel chloride was administered in
drinking water to pregnant mice from
the 2nd through the 17th day of ges-
tation at nickel doses of 0, 500, or
1000 ppm. Fetal or maternal toxicity
was not seen after administration of
500 ppm of nickel. However, the higher
dose caused spontaneous abortions,
loss of fetal mass in survivors, and loss
of maternal mass. The oral route of
administration via drinking water was
at least 2.7 times less effective than
parenteral routes in producing fetal
effects.
This Project Summary was developed
by EPA's Health Effects Research Lab-
oratory, Research Triangle Park, NC, to
announce key findings of the research
project that is fully documented in a
separate report of the same title (see
Project Report ordering information at
back).
Introduction
This report summarizes the work done
to examine a soluble nickel salt for its
efficacy to cause fetotoxic effects in mice.
Administering the compound in drinking
Off
dam was killed by suffocation with C02
gas and weighed. The uterus was removed
and counts were made of dead (resorbed
and newly dead) and live fetuses. The live
fetuses were removed, examined for gross
abnormalities, blotted dry, and weighed.
Two of every three fetuses were fixed in
Bourn's solution, and the third fetus was
preserved in alcohol.
Pregnancy rates and other incidental
data were analyzed using contingency
tables. Unless stated otherwise, all data
were analyzed using the litter as the ex-
perimental unit.
The rate of water consumption in mice
was 1 60 ml/kg body mass/24 h esti-
mated by observations of bred mice gang-
caged from the 14th through the 1 8th day
of gestation. During 24 h of this study, the
consu mption of nickel at concentrations of
500 and 1000 ppm in water was esti-
mated to be 80 and 1 60 mg/kg body
mass, respectively. For the period of
administration (2nd through 1 7th day of
gestation), the total consumption of nickel
at concentrations of 500 and 1000 ppm
was estimated to be 1280 and 2560
mg/kg body mass, respectively.
-------
live for producing nickel toxicity A wide
range and high incidence of terata in
fetuses of mice administered 4.6 mg of
NiCli/kg body mass IP once between the
7th and 1 1 th day of gestation has been
observed. On the basis of the ratio of
effectiveness of an oral vs. an injected
dose, a 4.6 mg IP dose would be equiva-
lent to a 60 mg oral dose.
In our study, we could not induce a wide
range and incidence of terata after we
administered nickel in 1 650 mg/kg orally
daily (1 000 ppm in drinking water). Only
decreased fetal body mass was observed.
Any higher dose was so toxic for both dam
and conceptuses that the frequency did
not continue Therefore, our 1 60 mg/kg
dose is the closest response to a 4.6
mg/kg IP dose that we could achieve. As
the calculated oral equivalent of 4.6 mg/kg
IP is 60 mg/kg, our 1000 ppm dose is 2.7
times less effective. Therefore, such cal-
culations do not adequately account for
the observed differences.
The variation in results may depend on
some other factor in the route of adminis-
tration which decreases the effectiveness
of low but continuous oral intake com-
pared to high single parenteral route. It
appears, therefore, that the fetal effects of
nickel poisoning may be overestimated by
experiments using parenteral methods.
Conclusions
The oral dosage of nickel required to
produce fetal toxicity or teratology may
have been overestimated when based on
studies using parenteral administration. A
factor as large as 2.7 times may be needed
to correlate the effects of parenterally
administered nickel with those of orally
administered nickel.
The EPA authors Ezra Berman (also the EPA contact) and Blair Rehnberg are with
the Health Effects Research Laboratory, Research Triangle Park, NC 27711.
The complete report, entitled "Fetotoxic Effects of Nickel in Drinking Water in
Mice." (Order No. PB 83-225 383; Cost: $7.00. subject to change) will be
available only from:
National Technical Information Service
5285 Port Royal Road
Springfield, VA 22161
Telephone: 703-487-4650
Ezra Berman can be contacted at.
Health Effects Research Laboratory
U. S. Environmental Protection Agency
Research Triangle Park, NC 27711
US GOVERNMENT PRINTING OFFICE 1983-659-017/7176
-659-017/7
------- |