ARTICLE IN PRESS

Clinical Nutrition (2007) 26, 400–408

Available at www.sciencedirect.com

http://intl.elsevierhealth.com/journals/clnu

REVIEW

Environmental lead toxicity and nutritional factors

Maqusood Ahamed, Mohd. Kaleem Javed Siddiqui

Analytical Toxicology, Industrial Toxicology Research Centre, P.O. Box 80, M.G. Marg, Lucknow 226 001, India

Received 13 July 2006; accepted 28 March 2007

KEYWORDS Summary
Lead exposure; Environmental lead toxicity is an old but persistent public health problem throughout the
Chelating agents; world and children are more susceptible to lead than adults because of their hand to
Nutritional factors; mouth activity, increased respiratory rates and higher gastrointestinal absorption per unit
Essential elements; body weight. In the last decade children’s blood lead levels have fallen significantly in a
Vitamins; number of countries. Despite this reduction, childhood lead toxicity continues to be a
Treatment major public health problem for certain at-risk groups of children, and concern remains
over the effects of lead on intellectual development. The currently approved clinical
intervention method is to give chelating agents, which bind and removed lead from lead
burdened tissues. Studies indicate, however, that there is a lack of safety and efficacy
when conventional chelating agents are used. Several studies are underway to determine
the beneficial effect of nutrients supplementation following exposure to lead. Data
suggest that nutrients may play an important role in abating some toxic effects of lead. To
explain the importance of using exogenous nutrients in treating environmental lead
toxicity the following topics are addressed: (i) different sources of lead exposure/current
blood lead levels and (ii) protective effects of nutrients supplementation (some essential
elements and vitamins) in lead toxicity.
& 2007 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights
reserved.

Contents

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 401
Sources of lead exposure/current blood lead levels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 401
Nutritional factors and lead toxicity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 402
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 406
Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 406
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 406

Corresponding author. Council of Science and Technology—Uttar Pradesh, Vigyan Bhawan, 9, Nabiullah Road, Suraj Kund Park, Lucknow
227017, India. Tel.: +91 522 2284819, +91 522 2211773; fax: +91 522 2211793.
E-mail address: maq_itrc@rediffmail.com (M.K.J. Siddiqui).

0261-5614/$ - see front matter & 2007 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.
doi:10.1016/j.clnu.2007.03.010
 ARTICLE IN PRESS
Environmental lead toxicity and nutritional factors
Introduction
Exposure to lead at concentrations lower than recognized as
threshold by Centre for Disease Control and Prevention1
adversely affect cognitive, neurobehavioral, and neurophy-
siological development of young children. The preponder-
ance of results from the recently published studies
demonstrate that exposure to quantities of lead typically
present in the environment have adverse health effects.2–4
Children are more vulnerable to lead exposure for mainly
three reasons: young children are more at risk of ingesting
environmental lead through normal mouthing behaviors,5
absorption from the gastrointestinal tract is higher in
children than adults,6 and the developing nervous system
is thought to be far more vulnerable to the toxic effects of
lead than the mature brain.7 Table 1 represents the possible
mechanisms of lead toxicity.
The current therapeutic approach to lead toxicity is to
increase the excretion of lead by chelation. However,
reported adverse health effects of conventional chelators
and the uncertainty in their efficacy in reversing or
preventing the toxic effects of lead caused some clinicians
to ignore pharmacological intervention in children with low
blood lead levels.8,9 These facts present a novel approach to
strategies for treating environmental lead toxicity. Nutri-
tional factors are often mentioned as important modifier of
the metabolism and toxicity of lead. Animal experiments
have demonstrated that essential elements, such as
calcium, zinc, iron, selenium, and various vitamins can
counteract the toxic effects of lead.10–12 In humans,
particularly children low dietary intakes of iron, zinc, and
calcium have been associated with increased blood lead
levels.13,14 Zinc supplementation was overturning the
inhibited activity of blood delta-aminolevulinic acid dehy-
dratase (d-ALAD) (2nd enzyme in heme biosynthetic path-
way).15 Low iron intake enhances the impairment of iron
utilization for heme biosynthesis due to lead.16 Rats raised
on a low-calcium diet have much higher blood lead
concentrations among the calcium-deficient animals,10
although lead ingestion did not differ. Similar differences
have also been observed in tissue lead concentrations.
The extents of understanding how nutritional factors
affect susceptibility to lead vary from nutrient to nutrient.
Techniques used to investigate nutrient/lead interactions
include isolated cells studied in vitro, in situ–in vivo
methods, whole animal studies, cross sectional and long-
Table 1 Possible mechanism for lead toxicity.
Competition with and substitution for calcium
Disruption of calcium homeostasis
Stimulation of release of calcium from mitochondria
Opening of mitochondrial transition pore
Direct damage to mitochondria and mitochondrial
membranes
Generation of reactive oxygen species (ROS)
Disruption of tissue oxidant/antioxidant balance
Alteration of lipid metabolism
Substitution for zinc in various zinc-mediated processes
Sequestration and mobilization of lead from bone stores
401
itudinal studies with humans, and clinical trial with nutrient
therapy. The latter have typically been poorly controlled
with respect to other variables. Adequate nutrition may be a
key factor in reducing the risk of lead exposure. Nutrients
supplementation modifies the process of absorption, trans-
port, storage, and inactivation of lead, thus reducing its
toxicity.17 To explain the importance of using exogenous
nutrients in treating environmental lead toxicity the
following topics are addressed: (i) different sources of lead
exposure influencing the blood lead levels and (ii) possible
protective effects of nutrients supplementation (some
essential metals and vitamins) in lead toxicity.
Sources of lead exposure/current blood lead
levels
The main sources of lead in children’s environments are
diet, lead-based paint in older housing, lead in soil and dust
from contaminated leaded paint and gasoline, or past and
present mining and industrial activity18,19 (Fig. 1). Exposure
from air and waterborne sources has been greatly reduced
with the introduction of unleaded gasoline and the replace-
ment of lead water pipes and water tanks with non-lead
alternatives. However, lead in soil and dust continues to be a
major source of exposure. Indoor floor dust accounts for
approximately 50% of a young child’s total lead intake.20,21
Hand-to-mouth behavior and pica activity (eating sub-
stances not normally eaten, e.g., soil or paint chips) are
significantly associated with elevated blood lead levels.5
Children typically ingest o50 mg/day of soil on average.22
However, in the case of pica, this amount can be X5 g a
day23 and some children have ingested 25–60 g during a
single day.24 Indeed, from the point of view of risk
assessment, Calabrese and colleagues urge that soil pica
be seen ‘‘as an expected, although highly variable, activity
in a normal population of young children, rather than an
unusual activity in a small subset of the population’’. Soil
abatement and paint hazard remediation programs have
attempted to reduce children’s exposures to lead and other
heavy metals, with mixed outcomes.25,26
Children’s blood lead concentrations have fallen substan-
tially in a number of countries in the last few decades,
including the United States, Australia, Mexico, Germany,
Poland, Sweden, United Kingdom, and India.20,27–32 By 1999
the geometric mean blood lead for US children 1–5 years of
age had fallen from 15 mg/dL in the late 1970s to 2.0 mg/dL.
A survey of 774 Swedish children over the period 1995–2001
showed blood lead levels had stabilized at 2 mg/dL at 7–11
years of age.33 In the United Kingdom, blood lead levels of
584 children measured during 1995 in the Avon Longitudinal
Study of Pregnancy and Childhood (ALSPAC) showed mean of
3.44 mg/dL at 2.5 years of age.34 In India, blood lead levels
of 576 children (175 from Hyderabad and 401 from Mumbai,
two metropolitan cities of India) measured during
1996–1998 showed mean of 13.3 and 8.0 mg/dL for Hyder-
abad and Mumbai children, respectively, at 3–6 years of
age.35 Another recent study from Lucknow, northern region
of India showed mean level of blood lead 7.43 mg/dL in
children at 4–12 years of age.31 Despite these falls in blood
lead levels, childhood lead poisoning continues to be a
major public health problem for certain groups of children,
 ARTICLE IN PRESS
402
Figure 1 Sources of lead exposure and its health effects (modified from Fewtrell et al.19).
specifically low-income, urban, African-American children in
the United States,36 children suffering from abuse and
neglect,37 children living in rural mining communities,38 and
children in developing countries.19,31,39,40
Lowering of exposure guideline levels reflects concern
over the growing body of evidence that low levels of lead
exposure have subtle effects on the nervous system of
children. Since 1971 there have been four reductions in the
CDC guideline level above which children are considered to
have an elevated lead level. This level currently stands at
10 mg/dL (0.483 mmol/L).1 In 1997 the CDC estimated that
4.4% of children in the United States 1–5 years of age have
blood lead levels X10 mg/dL.38 In a recent report of blood
lead levels in children 6 months–5 years of age living in New
Orleans, Louisiana, USA, 29% had levels X10 mg/dL.41 In
Wuxi City, China, 27% of children 1–5 years of age had blood
lead levels 410 mg/dL,42 whereas in Johannesburg, South
Africa, the blood lead levels of 78% of schoolchildren
X10 mg/dL40 and in Dhaka, Bangladesh, 87% of children
4–12 years of age had blood lead levels 410 mg/dL.43 In
Mumbai and Delhi, India, 47% children o3 years of age,
whereas in Lucknow, India 29% children 4–12 years of age
had blood lead levels 410 mg/dL.31,32 The proportion of
children with blood lead levels 410 mg/dL ranged from
0.74% to 5% according to recent reports from three different
regions of England.20,44–46 There is growing concern that
significant numbers of children remain at risk from lead
exposure in different parts of the world and low dietary
intake of essential elements is not uncommon among
children.47
Nutritional factors and lead toxicity
Nutrients and their effects on lead toxicity can be viewed
from a number of perspectives. If one is seeking strategies
to reduce the toxicity of lead exposure, followings are very
common nutritional factors that can subside the lead
toxicity (Fig. 2).
M. Ahamed, M.K.J. Siddiqui
Total food intake: Overall patterns of food consumption
and frequency of food intake influence absorption of lead
from the gastrointestinal tract.48 Although the mechanisms
may be complex, the data are relatively straightforward.
Lead that is ingested during fasting is absorbed to a much
greater extent than if ingested food. For example, Rabino-
witz et al.49 reported that among adult male subjects, lead
without food was 35% absorbed; tracer lead ingested with
food was absorbed to the extent of 8.2% and lead in food was
10.3% absorbed. Similar results have been reported by Blake
and Mann50 and Flanagan et al.51 Inter-individual variability
of oral absorption was shown in the study by Heusler-Bitsehy
et al.52 in which gastrointestinal absorption ranged from 10%
to 80% in eight fasted volunteers receiving a single exposure
of 0.007 or 0.002 mg lead/kg/day in drinking water.
Identifying the particular components of food intake that
so dramatically reduce lead absorption largely remains to be
done. However, some data are available. For example,
addition of ferric ion during fasting reduces the percentage
retention of the lead dose to that of non-fasted animals.53
The practical role of this information depends on the
reason people have limited food intake. Frequency of food
intake is controlled by a number of cultural and economic
factors. Certainly, shortages of food exist in many parts of
the world. In addition, there are numerous individuals, who
for various reasons that have little to do with the food
supply or economics have bizarre eating patterns. Many
people reduce their frequency of food intake for weight
reduction. In industrial situations, people may have odd
eating patterns because of lack of food service facilities or
work in irregular shift patterns.
Calcium: Not only do nutritional factors increase overall
lead absorption, nutrients can also have marked effects on
patterns of tissue deposition of lead once absorbed from the
environment. The experimental literature on this topic is
extensive and rather consistently supports the observations
that ingestion of diets low in calcium increases lead
absorption and toxicity. For example, Mahaffey-Six and
Goyer54 observed that lowering dietary calcium from 0.7% to
 ARTICLE IN PRESS
Environmental lead toxicity and nutritional factors
Figure 2 Nutritional factors known to influence susceptibility to lead effects.
0.1% significantly enhanced the body lead burden of rats
exposed for 10 weeks to 200 ppm lead in their drinking
water. Under these conditions, blood, kidney, and femur
levels of lead increased significantly as did urinary excretion
of delta aminolevulinic acid (d-ALA). A significant increase in
renal intra-nuclear lead inclusion bodies also was observed
in lead exposed animals consuming the low calcium diet. In a
similar study, metabolic and morphologic manifestations of
lead exposure were compared in adult rats receiving 2, 13,
48, 96, and 200 ppm lead in their drinking water and either a
0.1% or 0.7% calcium diet.55 Animals consuming the low
calcium diet have increased blood, kidney, and femur lead
levels, urinary excretion of d-ALA, and renal intra-nuclear
lead inclusion bodies at lower doses of lead than those on
the adequate calcium diet. However, interpretation of these
results is confounded by the fact that the animal receiving
the low calcium diet without lead supplementation demon-
strated sign of enhanced lead uptake as evidenced by
increased levels of lead in femur and kidney, as well as
elevated urinary excretion of d-ALA. This may be result of
enhanced uptake of ingested ambient lead that does not
bode well for inadequately nourished children. Also,
exposure to lead resulted in a decline in rate of weight
gain and food consumption in animals receiving the low
calcium diet. Decreased lead absorption with increasing
dietary intake of calcium also has been observed in
humans.56 In 8 adult male subjects fasted overnight, it
was observed that absorption of 100 mg lead as lead chloride
containing 203Pb decreased from 60% to approximately 10%
when followed by a dose of 200 mg calcium (as calcium
carbonate) and 140 mg of phosphate (as sodium bipho-
403
sphate). Calcium alone reduced lead uptake by a factor of
1.3, and phosphate alone by a factor of 1.2 whereas both
together reduced uptake by a factor of 6. The calcium and
vitamin D status of subjects may have influenced these
results; however, they were not determined. A similar result
has been reported by Blake and Mann.50 Recently, Ballew
and Bowman57 critically evaluated the few clinical studies.
An inverse relationship between dietary calcium and lead
absorption was found. Although calcium glycerophosphate
supplement prevented lead absorption,58 another study
concluded that calcium supplementation should not be
routinely prescribing for mild to moderately lead-poisoned
children with adequate calcium intakes.59
Although bone has predominantly been considered a
storage site for sequestering absorbed lead, bone is not
simply an inert storage site. Once deposited in bone, lead
can be remobilized from bone in response to both
physiological (e.g. pregnancy or lactation) and pathological
(e.g. osteoporosis) conditions.60 It has been shown that
during the first few years after onset of menopause, there
can be marked mobilization of calcium from bone matrix.
Analysis of data from the Second National Health and
Nutrition Examination Survey (NHANES II) has demonstrated
a highly significant increase in whole blood lead concentra-
tion after menopause. Mobilization of long-term stores of
lead from the maternal skeleton may be a major determi-
nant in transfer of lead from mother to infant during
pregnancy and lactation. Because of concern that maternal
blood lead concentrations be maintained as low as possible
during pregnancy, this remobilization of lead from bone has
substantial public heath interest.
 ARTICLE IN PRESS
404
Iron: Iron-deficiency is recognized worldwide as one of
the most prevalent nutritional problems.46 The public health
implications for enhanced lead toxicity among iron deficient
persons are substantial. Both iron and lead affect the heme
biosynthetic process. The cellular basis for greater suscept-
ibility of iron deficient animals to lead is that limited iron in
the mitochondria apparently enhances the impairment by
lead of iron utilization for heme synthesis.16 Lead is known
to interfere with mitochondrial energy metabolism that is
necessary to reduce ferric iron to ferrous iron before
insertion of iron into porphyrin ring. Where there is
insufficient ferrous iron for incorporation by ferrochelatase
into heme, protoporphyrin accumulates. Ferrochelatase
activity is sensitive to both lead and iron. Kappor et al.61
have reported that the enzyme kinetics of ferrochelatase in
isolated human erythrocytes change with both iron and lead
concentrations. When iron deficiency is present, ferroche-
latase is more sensitive to lead effects. The cellular basis for
greater susceptibility of iron deficient animals to lead is that
limited iron in the mitochondria apparently enhances the
impairment by lead of iron utilization for heme synthesis.
In an our earlier study, blood lead levels were negatively
correlated with blood iron level14 is in agreement with a
study of preschool children; an increase in blood lead with
decreasing dietary iron intake was found.62 Finding of
Osman et al.13 also supports who has reported that children
with low serum iron level have a tendency to higher blood
lead levels, indicating increased gastrointestinal absorption
of lead at reduced iron stores. However, Flanagan and
coworkers51 found no change in lead absorption with
increasing iron absorption due to iron deficiency and
inconsistent results regarding lead absorption in adults were
observed in a study by Watson and coworkers.63 Therefore,
there is probably not a single pathway for the absorption of
these two elements.
The impairment of cognitive function among iron-defi-
cient children has been recognized.64,65 Behavioral changes
accompanying iron-deficiency are similar to those observed
during prolonged exposure to low levels of lead. Inter-
ference with iron absorption and/or metabolism by lead
exposure could result in a synergism of deleterious effects,
especially in young children where iron deficiency is one of
the most common nutritional deficiencies.46 Lozoff et al.65
using the Bayley Scales of Infant Development, found
significant delays in language development among iron
deficient infants ages 19–24 months. Analysis of the
particular items failed on the Bayley tests showed a pattern;
the items failed were those that are most predictive of
latter intelligence. Additional studies include Oski et al.66
who reported the rapid improvement in the development
scores of infants (as assessed by the Bayley Development
Index) following iron therapy. Re-analyses of their own data
did not suggest to Oski et al.66 that these improvements in
cognitive function were due to changes in any particular
elements of the Bayley test.66 However, the children in this
study were younger (9–12 months of age) than the subjects
(19–24 months of age) for whom an effect on language
development was identified by Lozoff et al.65 In the age
group under study (9–12 months old infants) by Oski et al.66
development of motor skills is a strong component of the
entire testing procedures. At this time, it is unclear what
serve as the biochemical basis that links iron-deficiency to
M. Ahamed, M.K.J. Siddiqui
behavioral alterations. To date there has been very limited
investigation of whether or not neurobehavioral changes and
cognitive impairment are more extreme in iron-deficient,
lead toxic children than in either condition alone. However,
it is known that long-term iron-deficiency, as can be created
in experimental animals fed low-iron diets, increases
absorption and retention of lead. Clearly, the timing and
severity of iron deficiency, as is the case with timing and
severity of lead exposures greatly influence the extent of
the cognitive deficit.
Zinc: Interactions between zinc and lead have been
investigated at absorptive and enzymatic sites.67 Zinc and
lead compete for similar binding sites on the metallothio-
nein-like transport protein in the gastrointestinal tract.68
The competition between zinc and lead might decrease the
absorption of lead, thus reducing lead toxicity. Zinc was able
to prevent and treat lead intoxication in rats either alone or
in combination with methionine or thiamine.69,70 In both
studies, simultaneous dietary supplementation with ‘‘zinc+
methionine/thiamine’’ was found to be most effective in
reducing lead-induced inhibition of d-ALAD activity in the
blood and urinary excretion of d-ALA. These studies suggest
that supplementation of the combination therapy concur-
rently with exposure to lad was more effective than
treatment after lead exposure. Dietary supplementation
with zinc and in combination with vitamin C has been
reported to reduce lead toxicity in lead exposed battery
workers.71 In another study, zinc was administrated to lead-
exposed rats along with chelating agents CaNa2 EDTA,
succimer, and D-penicillamine. Zinc was shown to enhance
the efficacy of lead chelation by reducing the blood, hepatic
and renal lead, and overturning the inhibited activity on
blood d-ALAD.70 Additionally, zinc supplementation was
effective in restoring the zinc levels in tissue, which were
depleted following treatment with chelating agents.
A recent study showed that zinc supplementation prevented
the inhibition of d-ALAD and improved cellular antioxidant
status in the testis of lead-exposed rats.72 Evidence
supported the protective effects of zinc against testicular
damage caused by lead may be due to competition between
lead and zinc.
Selenium: Animal experiments have demonstrated that
selenium can partially reduce toxic effects of lead, such as
nephrotoxicity73 and neurotoxicity.74 Mutual detoxifying
effects of lead and selenium were indicated in a study by
Rastogi and coworkers,75 where growth rate, food consump-
tion, and enzymatic activity of d-ALAD were normal in rats
receiving high doses of both lead and selenium, and
depressed in animals receiving either of the elements. In
humans, a significant negative correlation between blood
lead and plasma selenium was observed in lead exposed
workers.76 Osman et al.13 also found significant negative
correlations of blood lead levels with serum selenium and
selenoprotein P levels in children. The association was
mainly apparent at low blood lead concentrations, which
may indicate an influence of selenium on the kinetics of lead
via possibly forming the complex with lead, influences the
metabolism of lead, or by altering the absorption and tissue
distribution of lead. On the other hand, selenium is a
cofactor of glutathione peroxidase (GPx), which is an
antioxidant enzyme. Selenium enhances the availability of
glutathione (GSH), which is one of the most abundant
 ARTICLE IN PRESS
Environmental lead toxicity and nutritional factors
intrinsic antioxidants that help in preventing lipid peroxida-
tion and the resulting cell damage. After lead exposure,
activity of GPx was decreased due to the interaction of lead
with the essential selenocycteine moiety of the enzyme.77
Protection against liver and kidney damage by selenium was
shown to be a result of enhanced antioxidant capacity of
cells, as evidenced by increased superoxide dismutase (SOD)
and glutathione redutase (GR) activities and elevated GSH
content.78 In animals, the combination of selenium and
other antioxidants has been shown to reduce oxidative
stress. In rats, DNA damage in the liver and spleen induced
by fumonisin B1 was protected by the mixture of antiox-
idants coenzyme Q10, L-carnitine, vitamin E and selenium.79
Combined administration of antioxidants containing sele-
nium, vitamin C, vitamin E, b-carotene, and N-acetyl
cysteine prevented both the diabetes-induced and galacto-
semia-induced elevation of oxidative stress in rats.80
Despite the above findings, the beneficial role of selenium
alone on lead toxicity is still deeds further studies.
Vitamin C: Vitamin C (ascorbic acid) is a low molecular
mass antioxidant that scavenges the aqueous free radicals
by very rapid electron transfer that inhibits lipid peroxida-
tion.81 Administration of vitamin C significantly inhibited the
lipid peroxidation levels of liver and brain, and increased
the catalase levels of kidney in lead-exposed rats.11
Lead-induced free radicals indicated by rat sperm chemilu-
minescence generation were reduced by 40% with supple-
mentation of 500 mg vitamin C/L drinking water.82
Another beneficial role of ascorbic acid supplementation
in lead-exposed rats was associated with serum biochemical
alterations in the haemopoietic system and drug metaboliz-
ing enzymes. Intraperitoneal administration of lead in rats
produced a significant inhibition of heme synthesis in blood
and liver, and reduced drug metabolism in liver. Vitamin C
supplementation in lead-exposed animals significantly re-
duced blood, liver, and renal lead levels. This result
indicated a significant protective action of vitamin C against
toxic effects of lead on heme synthesis and drug metabo-
lism.83 A study found the combination of vitamin C and
thiamine was effective in reducing lead levels in blood,
liver, and kidney. In addition, both lead-induced inhibition in
the activity of blood d-ALAD and elevation in the level of
blood zinc protoporphyrin (ZPP) were reversed by such
combination.84
There has been considerable debate concerning the
relationship between vitamin C nutritional status and heavy
metal body burden in lead-induced toxic effects. Early
reports found that vitamin C might act as a possible chelator
of lead, with similar potency to that of EDTA.85 Vitamin–
mineral supplementation in African-American women
was found to reduce blood lead levels from 5.1 to
1.1 mg/dL, which was negatively correlated with serum
levels of vitamin E and C.86 Dhawan et al.87 found that
ascorbic acid might increase urinary elimination of lead and
reduced the hepatic and renal lead burden in rats. A cross-
sectional study analyzed 4213 young and 15 365 adult
Americans with mean blood lead levels of 2.5–3.5 mg/dL,
respectively, and showed an inverse relationship between
serum vitamin C and blood lead level.88 In another study of
85 volunteers who consumed a lead-containing drink,
vitamin C supplementation produced small reductions in
lead retention.89
405
On the other hand, some studies suggested that vitamin C
supplementation did not significantly lower blood lead
levels. In workers occupationally exposed to lead, and with
blood lead levels ranged from 28.9 to 76.4 mg/dL, supple-
mentation of vitamin C and zinc did not significantly reduce
blood lead levels.90 A recent report stated that rats treated
with ascorbic acid did not reduce lead burden in the liver,
kidney, brain, and blood.11 Although it is biologically
plausible that vitamin C may affect lead absorption and
excretion, the effect is more obvious in low-exposed
subjects with higher vitamin C supplementation.
Vitamin E: Vitamin E is the generic term used to describe
at least eight natural-occurring compounds that possess
the biological activity of a-tocopherol. The group is
comprised of a-, b-, g- and d-tocopherol and a-, b-, g- and
d-tocotrienol. The a-tocopherol has the highest biological
activity,91 the other tocopherols and tocotrienols are less
biologically active but they are at least as abundant as
a-tocopherol in certain foods.92 Vitamin E is nature’s major
lipid soluble chain-breaking nutrient that is known to
protect biological membranes and lipoproteins from oxida-
tive stress.93 The main biological function of vitamin E is its
direct influencing of cellular responses to oxidative stress
through modulation of signal-transduction pathways.94 One
of the protective roles of vitamin E on lead toxicity was
preventing lead’s effects on productions of free radicals in
liver.95
The interaction between vitamin E and other nutrients
might have a more efficient protective action against lead
toxicity. Vitamin E and C jointly protect lipid structures
against peroxidation.96 Although vitamin E is located in
membranes and vitamin C in aqueous phases, vitamin C is
able to recycle oxidized vitamin E.97 Vitamin C repairs the
tocopherol radical, thus recovering the chain-breaking
antioxidant capacity of vitamin E.96 Vitamin E alone or in
combination with conventional chelator, CaNa2EDTA, was
found to decrease the lead-induced lipid peroxide levels of
liver and brain in rats.11
Vitamin B6: Vitamin B6 is a necessary co-factor for several
trans-sulfuration (TSS) pathway enzymes, whose activities
are impaired by B6 deficiency.98 Because TSS pathway and
dietary methionine are thought to be the main source of
cysteine incorporated into mammalian GSH, the lack of B6
may affect the contribution by methionine to GSH biosynth-
esis by limiting the availability of cysteine. An early study
has described the beneficial effect of vitamin B6 on
increasing tissue GSH levels in rats.99 In 1989, McGowan100
studied GSH metabolism of lead-exposed rats fed a vitamin
B6-deficient diet. They found that a lack of vitamin B6
inhibited the involvement of methionine in GSH biosynthesis
by limiting the availability of cysteine. The results indicated
an indirect antioxidant role of vitamin B6 in lead-exposed
rats.100 However, other possible roles of vitamin B6 in lead
toxicity have not been studied extensively.
b-Carotene: The reaction of carotenoids with free
radicals is partly due to the roles of carotenoids in
photosynthesis, thus electron transfer from b-carotene to
P680+, with the b-carotene being oxidized to its radical
cation CAR+.101 It has been accepted from epidemiological
evidence, that dietary b-carotene, mediated by the pre-
vention of lipid peroxidation, can reduce the incidence of
many diseases including cancer, atherosclerosis, age-related
 ARTICLE IN PRESS
406
macular degeneration, and multiple sclerosis.102,103 How-
ever, the generally accepted beneficial roles of carotenoids
as nutrients have been seriously challenged by the results
from clinical trials that suggest deleterious effects of
administered b-carotene in heavy smokers.104
There have been considerable recent investigations in the
interaction of b-carotene and other nutrients.105 The
antioxidant effects against lead toxicity by Spirulina
fusiformis, a blue-green algae containing rich b-carotene
and SOD enzyme, were observed on the testes of Swiss mice.
Once lead was administered and free radicals generated in
mice testes, the Spirulina provided antioxidant nutrients of
b-carotene and SOD to scavenge the free radicals.106
Machartova et al.107 found that supplementation with
multiple antioxidants including vitamin C, vitamin E,
b-carotene, selenium, and zinc resulted in significant
increase of SOD and GPx in 36 workers exposed to lead.
The interaction of carotenoids and carotenoid radicals with
other nutrients is of importance with respect to anti- and
possibly pro-oxidative reactions of carotenoids.
Conclusions
Although CDC released guidelines for the management of
childhood lead toxicity in 1985108 and 1991,1 a nationwide
survey of pediatric lead toxicity treatment programs
indicated that no common approach for the treatment of
low-level lead toxicity appears to exist within the lead
clinics.9,109 The current therapeutic approach to lead
toxicity is to increase the excretion of lead by chelation.
But the safety and efficacy of various chelators may be
questioned as evaluated extensively.8 The present review
suggests that nutritional factors (some essential elements
and vitamins) may be important modifier for the metabolism
and toxicity of lead. Essential elements altered the
biokinetics of lead both at absorptive and enzymatic sites,
whereas vitamins mainly act as antioxidants in preventing
the lead toxicity via rebalancing the impaired oxidant/
antioxidant balance due to lead exposure. However, over-
dose of some nutrients may also cause adverse health
effects. For example, overdose of iron could leads to
hepatotoxicity.110 Consequently, experiments are needed
to show the effects of nutrients on the cells or animals that
are treated concomitantly for lead exposure. Detailed
mechanistic studies are required to understand the mechan-
isms underlying the beneficial effects of nutrients and to
explore the optimum dosage and duration of treatment to
obtain better clinical recoveries in lead intoxication cases.
Acknowledgment
One of the authors (Maqusood Ahamed) gratefully acknowl-
edges the financial support provided by the Council of
Scientific & Industrial Research, New Delhi, India.
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