Comparison of Blood, Semen and
Testes Boron Levels in Human and Rat
R. Wayne Ball, Ph.D., DABT
Rio Tinto Minerals
Greenwood Village, CO, USA
Workshop on the New Toxicological Evidence of Borate Substances
Warsaw, Poland
October 9-10, 2012
Introduction
In contrast to the laboratory animal data, studies in
humans have not demonstrated adverse reproductive
effects of high boron exposures.
No adverse effects on semen parameters (the most
sensitive test for testicular toxicity in humans) were
seen in the most highly exposed groups of Turkish
and Chinese boron-industry workers.
Purpose
Conduct a comparison of the boron absorbed dose in
laboratory animals and boron industry workers.
A comparison to blood levels (the effective dose) in
animal and human studies avoids uncertainties of
extrapolating from external exposures by providing a
direct measure of internal exposure.
Methods
• A literature search using online resources was
conducted,
– National Library of Medicine’s PubMed
(http://www.ncbi.nlm.nih.gov/pubmed/)
– TOXLINE (http://toxnet.nlm.nih.gov/cgibin/sis/htmlgen?TOXLINE) databases, to identify
relevant studies for the analysis.
• Review blood and target organ boron levels reported
in the studies of laboratory animals and human
studies.
Results
How do Human & Laboratory Animal Exposures Compare?
• Basal animal diets are significantly higher in boron than human diets, so
total boron exposure is higher than suggested by traditional
NOAEL/LOAEL endpoints.
• Blood plasma levels reflect differences in boron content of diets, so typical
human diet contains fraction of control animal diets.
• Human response to boric acid indicates vomiting likely at fraction of
concentrations that are the animal NOAEL values, so chronic exposures
of humans likely to be self-limiting (rodents unable to vomit).
• Human exposures studied in workers at borate mines and processing
operations, who are likely more exposed than workers in other industries,
and several times more exposed than non-worker populations.
• Studies of workers in the USA, China, and Turkey consistently show no
adverse effects on reproductive endpoints at even the highest exposures.
Comparison of Human and Pregnant Rat Blood Boron Levels
•
Blood boron levels in pregnant female control rats is about 0.23 µg B/g, approximately equal to blood levels in boron
industry workers in China, Turkey and U.S. of 0.25, 0.22 and 0.26 µg B/g.
•
Blood level at the LOAEL (13 mg B/kg) was 1.53 µg B/g, about 6 x greater than typical boron industry workers.
•
GFR primary determinant in elimination of boric acid. GFR increased in pregnant rats by 40-50%.
Comparison of Human and Rat Blood, Semen and Testes Boron Levels
• Blood and semen boron levels in highly exposed Chinese and Turkish workers were lower than control rats.
• Boron levels in testes of rats dosed at the rat fertility LOAEL was over 3x the blood boron levels in highest
exposure group of Chinese boron industry workers.
Tissue Levels of Zinc
Background levels of zinc in humans may interact with boron to reduce hazard of toxic effects.
•Zinc levels in soft tissue in humans are over 2 times greater than in comparative tissues in laboratory animals
(King et al. 2000; Ranjan et al. 2011; Yamaguchi et al. 1996).
•Zinc has been shown to protect against testicular toxicity of cobalt and cadmium (Anderson et al. 1993), and
developmental toxicity of cadmium (Fernandez et al. 2003). A similar interaction with boron could explain in
part the absence of fertility and developmental effects in humans.
• The interaction of Zn and boric acid
was demonstrated by the low acute
toxicity of zinc borate (ZB) with a
LD50 value greater than 10 g/kg-bw
in rats (Daniels 1969) compared to
disodium tetraborate pentahydrate
with a LD50 value of 3.3 g/kg-bw (ZB
and disodium tetraborate pentahydrate
have equivalent boron concentrations).
• No toxic effects in the testes of males
administered 1000 mg ZB/kg/day in a
28-day repeated dose oral gavage
toxicity study, equivalent dose of 50
mg B/kg bw (Wragg et al. 1996). The
LOAEL for testicular effects is 26 mg
B/kg body weight.
Summary
• Workers in boron mining and processing industries represent the
maximum possible human exposure however a comparison of blood,
semen and target organ boron levels in studies of laboratory animals
and human studies shows that boron industry worker exposures are
lower than untreated control rats.
• Only under extreme conditions do human blood boron concentrations
reach those of the animal LOAEL: the subgroup of Chinese boron
workers who also drank boron contaminated water.
• No adverse effects on sperm were seen in Turkish boron industry
workers or in the most highly exposed subgroup of Chinese boron
industry workers drinking boron contaminated water (mean blood
level 1.52 µg B/g).
• Normal background levels of zinc in humans are 2x that found in
laboratory animals. The excess zinc interact with boron to reduce
hazard of toxic effects.
Conclusion
•These studies provide an explanation why studies of highly exposed
boron industry workers have shown no adverse effects and
demonstrate that potential human exposures are not sufficient to
cause reproductive toxicity effects.
•Normal levels of zinc in humans are 2 times that found in laboratory
animals. Zinc interacts with boron reducing the toxic effects of boric
acid, providing a possible mechanism explaining in part the absence
of reproductive and developmental effects in humans.
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