C H A P T E R
Toxic Metals in Food
BRUCE A. FOWLER, JAN ALEXANDER, AND AGNETA OSKARSSON
ABSTRACT
Ingestion of toxic metals/metalloids in food is
a major route of exposure for the general popula-
tion over the course of a lifetime. Globalization of
food sources, coupled with the application of metal-­
contaminated fertilizers and irrigation water sources,
has increased the importance of foodborne exposures
to metallics in both developed and developing coun-
tries. However, measures taken to reduce metal con-
tamination have also been successful and resulted in
reduced metal exposure, e.g. reduction of lead in fuel
and in food cans, as well as restrictions on cadmium in
fertilizers. This chapter will consider various aspects of
these issues for cadmium, lead, mercury, and arsenic,
which are major toxic elements, and offer unique case
studies on the more general problem of public health
issues related to foodborne exposures to metallics. The
chapter will also briefly discuss issues related to silver
nanoparticles in food packaging as an emerging issue
for future research.
1 INTRODUCTION
Food is the major source of exposure to both essen-
tial and nonessential metals. Sensitive subpopulations
at special risk for metal toxicity are also discussed in
the context of the need for differential guidance fac-
tors that would provide a greater level of protection for
them. Details on mechanisms of toxicity and adverse
health effects at higher exposure levels and from other
exposure routes are presented in chapters on the spe-
cific elements. The issue of toxic metals in foods as part
Handbook on the Toxicology of Metals 4E
http://dx.doi.org/10.1016/B978-0-444-59453-2.00006-8
of general food safety has been recently reviewed by
the U.S. Institute of Medicine and National Research
Council (IOM/NRC, 2010).
The main focus of this chapter is on the three “clas-
sical” toxic metals in food: lead, methylmercury, and
cadmium, but arsenic in food and drinking water is
also included because of growing health concerns.
Even if there are sporadic cases of serious metal poison-
ing originating from contaminated food, the highest
concern is population risk associated with exposures
at levels lower than those causing overt or clinical
signs of toxicity. Exposure is considered throughout
the whole lifetime and includes vulnerable groups of
the population. Contamination of food via soil, air, and
water, as well as via food processing and food pack-
aging, will be discussed. Exposure to metals via food
in developing countries is a growing concern due to,
for example, increased use of cadmium-­ containing
fertilizers, contaminated irrigation water used to
grow staple food crops such as rice, and the location
of metal-recycling facilities in agricultural areas where
metal contamination of food crops may occur from air
and water releases.
In this chapter, metal concentrations in food are
expressed per kg fresh weight, which is generally the
basis for regulation of contaminants in food and thus
the conventional way to present the occurrence of met-
als and metalloids, such as arsenic, in food. It should
be noted that the fresh weight varies widely among
foodstuffs and may also vary among samples of the
same foodstuff.
Risk assessments for metals from food have been
performed by a number of national and interna-
tional bodies. Although there are some differences
123 Copyright © 2015 Elsevier B.V. All rights reserved.
124 Bruce A. Fowler, Jan Alexander, and Agneta Oskarsson
in the established health-based guidance values (tol-
erable intakes), in general the agreement is good
because largely the same scientific database is used
for the assessments. The guidance values are regularly
updated as new scientific evidence become available.
For a number of the major toxic metals/metalloids,
recent studies based on more sensitive measure-
ments have been able to show minor increases in risk
of subtle, but adverse, effects in the population. This
has resulted in a growing concern for exposures at low
levels previously assumed to be safe. Hence, with the
aim to protect the public health of sensitive subpopu-
lations, more stringent health-based guidelines have
been established by risk assessment bodies. On the risk
management side, options of risk reducing measures
are considered based on the risk assessments.
2 CADMIUM
Cadmium is a toxic metal causing renal tubular dys-
function and bone toxicity at low exposure levels, such
as in the general nonsmoking population. Further-
more, recent evidence suggests an association between
elevated cadmium exposure and hormone-related
cancers, e.g. breast cancer (McElroy et al., 2006; Julin
et al., 2012a), as well as effects on neurodevelopment
(Petersson Grawé et al., 2004; Ciesielski et al., 2012).
Cadmium is taken up by plants via the root system,
and grain and vegetable products constitute the major
dietary source of cadmium. Sensitive groups, such as
infants, vegetarians, smokers, fertile women with low
iron status associated with a facilitated gastrointesti-
nal absorption of cadmium, and people with preexist-
ing renal dysfunction are of special concern. There are
several recent reviews and risk assessments on cad-
mium from international expert groups (EFSA, 2009b;
ATSDR, 2012; JECFA, 2011a). Most of the data in this
chapter are from these reviews unless other references
are given, which is mainly the case with more recent
findings.
2.1  Occurrence in the Food Chain
Food, and especially cereal and vegetable products,
is the main source of cadmium exposure in the general
nonsmoking population (Figure 1). Cadmium in plant
foodstuffs is the result of either natural occurrence or con-
tamination of soil with cadmium, which is taken up by
the root system. In general, cadmium tends to accumu-
late in the leaves of plants, including tobacco. The tobacco
plant is of general concern since smoking the leaves con-
stitutes a major source of cadmium exposure in smokers
and in nonsmokers exposed to second-hand smoke.
Coffee,
Miscellaneous tea,
5% Cereals cocoa
Milk 20% 5%
5%
Sugar &
chocolate
6%
Fish & seafood Veg, nuts, &
8% pulses
18%
Alc. beverages
8% Roots &
Meat & offal potatoes
12% 13%
FIGURE 1  Relative contribution of dietary sources to the total
daily intake of cadmium. Source: data compiled from EFSA (2009b).
The average concentration of cadmium in the
Earth’s crust is about 0.1 mg/kg, with higher levels
(0.3-11 mg/kg) in sedimentary rocks. Up to 200 mg
Cd/kg is found in areas with sedimentary black shale
deposits, for example in the United Kingdom and USA,
and in areas with deposits of zinc, lead, and copper.
Soils tend to reflect the chemical composition of the
parent material and may in addition be contaminated
from mining and other sources. Weathering of rocks
results in a flux of cadmium to the oceans, estimated to
give an input of 15,000 tons per year, thus contaminat-
ing the marine food chain. Shellfish such as oysters,
mussels, and other species of filter-feeding marine
invertebrates may contain substantial concentrations
of cadmium (Copes et al., 2008; Bendell, 2010). Hence,
this food source is a particular concern for populations
who consume large quantities of these organisms in
their diet.
Anthropogenic sources add to the natural lev-
els in soil and are derived from phosphate fertilizers
(54-58%), atmospheric deposition (39-41%), and sew-
age sludge (2-5%) (Alloway, 1995). On a local basis,
sewage sludge can be a significant source of cadmium
in the soil. The relative importance of different sources
varies widely and depends on background cadmium
levels and local contamination. In Sweden, Andersson
(1992) calculated mass balance and estimated that the
anthropogenic input had increased the plow-layer cad-
mium concentration by 33% between 1900 and 1990. Of
the increase, 55% was derived from phosphate fertiliz-
ers and 29% from atmospheric deposition; the rest was
mainly due to feed additives (excreted and applied to
soil as manure) and lime. Soil concentrations of cad-
mium were investigated in a Swedish environmental
monitoring program, and 80% of the approximately
3000 agricultural soil samples had concentrations
ranging from 0.11 to 0.37 mg/kg dry weight, with a
 6  Toxic Metals in Food 125

TABLE 1  Mean Cadmium Concentrations (mg/kg) in 140,000 Samples of Foodstuffs from 20 European Countries
Foods with > 0.10 mg Cd/kg Foods with 0.10-0.06 mg Cd/kg Foods with 0.05-0.02 mg Cd/kg

Food mg Cd/kg Food mg Cd/kg Food mg Cd/kg

Bivalve molluscs 0.380 Crustaceans 0.093 Herbs 0.045

Oysters 0.292 Chocolate 0.090 Nuts 0.043
Cephalopods 0.285 Spices 0.074 Wheat grain & flour 0.030
Snails & limpets 0.255 Bran & germ 0.065 Rice 0.025
Supplements 0.236 Swordfish 0.063 Leafy vegetables 0.023
Oil seeds 0.227 Spinach 0.062 Stem & root vegetables 0.021
Fungi 0.209 Potatoes 0.021
Kidney 0.201
Cocoa 0.178
Horsemeat 0.172
Herbal tea, dry 0.140
Celeriac 0.104
Liver 0.116

Source: EFSA (2009b).

median concentration of 0.20 mg/kg (Eriksson et al.,
1997). Recent calculations indicate a balance between
input and output of cadmium in Swedish arable soils,
probably due to the use of phosphate fertilizers with
low cadmium content and decreased atmospheric
deposition of cadmium (Kirchmann et al., 2009). How-
ever, the import of cadmium in feed, for example soy-
based feed, and feed supplements gives a significant
input of cadmium to soil via manure in farms with
animal production (Lindén et al., 2003). Studies in
developing countries where rice is a major dietary
staple have demonstrated that contamination from
metal-recycling activities is of particular concern, such
as reported from Vietnam (Minh et al., 2012). It should
be noted that studies from Bangladesh (Rahman et al.,
2012) also reported elevated exposures to cadmium in
that country from water and the consumption of veg-
etables and rice. Studies from Iran (Chamannejadian
et al., 2013) have reported elevated concentrations of
cadmium in rice grown in calcareous soils, indicat-
ing that this important food crop may be a vehicle for
human exposure in such regions.
Plant uptake of cadmium is dependent on a num-
ber of factors, of which cadmium concentration in soil
and pH are the most important (Olsson et al., 2005).
Decreasing pH and increasing soil cadmium will
increase cadmium uptake in plants. Soil properties
will influence the uptake: a high content of organic
matter and of micronutrients, e.g. zinc, will decrease
the uptake of cadmium. The uptake level varies with
plant species. Among cereals, the concentration gen-
erally decreases in the order winter wheat > oats > bar-
ley. Also, cadmium uptake varies between cultivars of
a certain crop, for example between different strains
of wheat and of potatoes (Olsson et al., 2005). Thus, a
consideration of cadmium uptake should be important
in plant breeding.
Cadmium occurrence data in food from different
regions in the world, including a large dataset from
20 European countries, was compiled by the Joint
Food and Agriculture Organization of the United
Nations (FAO)/World Health Organization (WHO)
Expert Committee on Food Additives (JECFA, 2011a).
The European data, representing about 140,000 sam-
ples and covering the period from 2003 to 2007, were
assessed by the Scientific Panel on Contamination in
the Food Chain (CONTAM) at the European Food
Safety Authority (EFSA, 2009b). Approximately 34%
of the samples had cadmium levels below the limit of
detection and were included in the data with a con-
centration of 50% of the limit of detection. Food with
the highest mean cadmium concentrations are shown
in Table 1 and are generally in good agreement with
data from the U.S. Food and Drug Administration
(FDA) Total Diet Study (Table 2). Please note that food
categories with a mean cadmium concentration below
0.02 mg/kg are not included in Table 1.
Cadmium concentrations in various food catego-
ries published in the Total Diet Study Report (FDA,
2010) are presented in Table 2. The data indicate that
some nuts and grains (such as sunflower seeds) and
leafy green vegetables (such as spinach and lettuce)
may accumulate large quantities of cadmium. Animal
organ meats, such as liver, may also accumulate cad-
mium, presumably as a result of ingesting plant-based
feed.
126 Bruce A. Fowler, Jan Alexander, and Agneta Oskarsson
TABLE 2  Foods with the 10 Highest Mean
Concentrations of Cadmium in the U.S. Food and Drug
Administration Total Diet Study, for the Period Jan. 2006
to April 2008
Food description Mean cadmium (mg/kg)
Sunflower seeds (shelled, roasted, salted) 0.412
Spinach, fresh/frozen, boiled 0.124
Liver, beef/calf, pan-cooked with oil 0.069
Lettuce, leaf, raw 0.064
Potato chips 0.057
Peanuts, dry roasted, salt 0.054
Lettuce, iceberg, raw 0.051
Shredded wheat cereal 0.050
Celery, raw 0.040
Peanut butter, creamy 0.036
Source: FDA (2010).
2.1.1  Exposure from Foodstuffs
The dietary intake of cadmium is dependent on
food consumption patterns, as well as on cadmium
levels in foodstuffs. Many of the food items with high
cadmium levels are rarely consumed or are consumed
in small quantities, such as oil seeds, offal meats, herbs,
and certain seafoods, and thus make a small contribu-
tion to the daily intake of cadmium. In contrast, foods
with a high consumption although with lower cad-
mium concentrations will make a major contribution
to the overall cadmium intake. Cereals, vegetables,
rice, roots, potatoes, and other plant foods, generally
with a mean cadmium concentration of ≤ 0.03 mg/kg,
are the major contributors to dietary cadmium intake.
By using food consumption data for all food catego-
ries from European Union (EU) member states, the
mean intake of cadmium from all food categories was
assessed (EFSA, 2009b). Figure 1 illustrates the impact
of various dietary sources on the total daily intake of
cadmium from EFSA data (EFSA, 2009b). Food catego-
ries that make a major contribution are mainly veg-
etarian foods, e.g. cereals and cereal products, nuts
and pulses (fresh and dry legumes), and starchy roots
and potatoes, but also include food from the category
designated as meat and meat products, i.e. offal. The
weekly mean intake was estimated to be 2.3 μg/kg
body weight (b.w.)/week, using a default value of
60 kg, varying between countries from 1.9 μg/kg b.w./
week in Bulgaria to 3.0 μg/kg b.w./week in Germany.
Vegetarians will have a higher exposure, up to 5.4 μg/
kg b.w./week, due to a high contribution from oil-
seeds, nuts, pulses, and cereals. Tofu consumption
has also recently been shown to have a strong corre-
lation with urinary cadmium (Adams et al., 2011). A
high consumption of bivalve molluscs, specific mush-
rooms, and kidney will also significantly increase
cadmium intake. The intake of cadmium in toddlers
and children, estimated from Italian data, was higher
than in adults, mainly due to a higher food consump-
tion per kg/b.w. at young ages compared to adults.
House dust was also estimated to contribute approxi-
mately 20% of the cadmium exposure in children
(EFSA, 2009b). Similar levels of cadmium intake have
been reported from other parts of the world. Health
Canada reported, from its total diet study in 2007, an
average cadmium intake of 1.5 μg/kg b.w./week for all
ages, with a peak of 4.0 μg/kg b.w./week for the age
group 1-4 years (Health Canada, 2007). FAO/WHO,
who expresses the exposure per month instead of
week, reported exposures of 2.2-9.9 μg/kg b.w./month
(JECFA, 2011a). The dietary intake varied between
countries, e.g. the USA had a monthly mean exposure
of 4.6 μg/kg b.w.; however, foods with levels below the
limit of detection were not included. Certain provinces
of China reported higher intakes of up to 36.5 μg/kg
b.w./month (JECFA, 2011a).
2.2  Biomonitoring of Exposure
Bioavailability of cadmium from food varies with a
number of factors, such as the fiber and mineral con-
tent of food as well as health conditions. Cadmium
absorption from food is low, generally below 5%.
However, iron status has a high impact on cadmium
absorption, which increases at low iron stores. Cad-
mium is absorbed in the gastrointestinal tract by the
same transport pathway as that of iron, which is upreg-
ulated at low iron stores in the body. Thus, women of
fertile age with low or empty iron stores (commonly
occurring due to menstrual bleeding) have a higher
absorption of dietary cadmium and higher blood and
urinary cadmium levels than men or women with ade-
quate iron stores. A similar impact of iron status has
been observed in girls aged 15-17 years of age (Bárány
et al., 2005; Meltzer et al., 2010).
There is a close relationship between cadmium con-
centrations in the urine and kidneys. The cadmium
level in urine is used as a biological indicator of the
cadmium body burden. Adjustment for variations
in urine volume is needed, by either specific gravity
or creatinine. An alternative is to collect 24-h urine
samples if that is feasible. Women have higher cad-
mium levels in urine compared to men, mainly due
to a higher gastrointestinal absorption of cadmium at
low iron status. Because the half-life of cadmium in
the body is very long, urinary cadmium increases with
age. The 95th percentile levels of urinary cadmium are
0.6-1.8 μg cadmium/g creatinine in adults, and lower
levels of approximately 0.3 μg cadmium/g creatinine
are reported in children (EFSA, 2009b; JECFA, 2011a).
 6  Toxic Metals in Food
However, an unusual increase in urinary cadmium
has been observed among 6- to 11-year-olds, followed
by a continuous increase until about 60 years of age
(Ruiz et al., 2010). The geometric mean urinary cad-
mium excretion is higher among females than males
for all age groups. The increase at younger ages may
be a function of anatomical and physiological changes
during this period, as suggested by Chaumont et al.
(2012), and may include low iron stores in younger age
groups (Ruiz et al., 2010).
Cadmium in blood is considered to indicate a recent
exposure of cadmium. Generally, for nonsmoking
adults living in nonpolluted areas the concentration of
cadmium varies between 0.1 and 1.0 μg Cd/L in whole
blood, with a 90th percentile of 0.6 μg Cd/L. Among
smokers the concentration may be up to several times
higher, but is seldom above 3 μg/L. Children have
lower blood concentrations, generally below 0.2 μg/L.
A close correlation between cadmium concentrations
in blood and urine has been demonstrated. Smoking
affects urinary cadmium levels to a lesser extent (1.5
to 2 times higher in smokers) than is the case for blood
cadmium. Use of food supplements may contribute
to cadmium exposure. Olsson et al. (2002) reported
elevated urinary and blood cadmium levels in indi-
viduals taking supplements of vitamins and minerals:
median concentrations for those taking supplements
were 0.26 μg/g creatinine and 0.28 μg/L, respectively,
versus 0.20 μg/g creatinine and 0.19 μg/L, respectively,
for those not taking supplements.
2.3 Toxicity
Acute cadmium poisoning is rare but gastrointes-
tinal symptoms have been described after consum-
ing food or drinks contaminated by cadmium from
cooking utensils, solders in water pipes. or beverage
containers. Chronic cadmium poisoning from the con-
sumption of food occurred in the 1950s in cadmium-
polluted areas in Japan. Almost 200 cases, mainly
postmenopausal women, have been reported with itai-
itai disease, exhibiting symptoms of disturbed calcium
metabolism, osteoporosis, and osteomalacia. Cad-
mium levels in unpolished rice from the contaminated
regions were ≥ 0.3 mg/kg.
The main concern for the risk assessment of cad-
mium is the effects after long-term low-level exposure
in the general population. The kidney is a primary
target organ of toxicity after extended oral exposure
of cadmium. Renal dysfunction has been considered
the critical effect due to cadmium accumulation in the
proximal tubular cells of the kidney cortex. Cadmium
is retained in the kidney and liver with a long biologi-
cal half-life of about 15 years. Several epidemiological
127
studies have reported associations between renal effects
and cadmium exposure. Cadmium in urine is related
to various renal biomarkers, such as β2-microglobulin,
retinol-binding protein and N-acetyl-d-glucosaminidase
(Honda et al., 2010). The health significance of these
biomarkers in relation to renal damage in the gen-
eral population is not certain, although it can indicate
potential health impairment and has been suggested
to potentiate diabetes-induced effects on the kidneys.
The association between urinary low molecular weight
proteins and low cadmium exposure has recently
been questioned, and coexcretion in the urine of cad-
mium and biomarkers has been suggested, rather
than a cause and effect relationship (Chaumont et al.,
2012). After long-term cadmium exposure, damage to
the renal blood vasculature may develop, leading to
decreased glomerular filtration rates and eventually
to renal failure (see Hellström et al., 2001; Messner
et al., 2009; Fowler, 2013 for a review).
A recent focus of cadmium risk assessment is on
bone effects. Epidemiological studies have demon-
strated increased risk of the incidence of fracture and
of reduced bone mineral density at cadmium expo-
sure levels present in the general population. Studies
reported in 1999-2008 from Belgium, Sweden, China,
and the USA were summarized by EFSA (2009b), and
indicated effects on bone at urinary cadmium levels
similar to the levels at which kidney damage occurs.
Engström et al. (2012) reported a 32% increased risk of
osteoporosis and a 31% increased risk of any first inci-
dent fracture in postmenopausal women with a high
median dietary cadmium exposure of ≥ 13 μg/day, cor-
responding to 1.5 μg/kg b.w./week (assuming a b.w.
of 60 kg), compared with lower exposures of < 13 μg/day.
A study in women from a nonpolluted area in Japan
(Osada et al., 2011) reported a positive correlation
between dietary intake from rice, estimated to be
9.1 μg/day (mean cadmium concentration in rice was
71 μg/kg), and bone metabolic disorder. The geometric
mean of urinary cadmium concentration was 1.9 μg/g
creatinine.
Cadmium exposure in the general population
has also been associated with neurodevelopmental
effects in children and with hormone-related cancers.
­Ciesielski et al. (2012) reported an increased risk of
learning disability (odds ratio, 3.21) and special educa-
tion utilization (odds ratio, 3.00) among children aged
6-15 years, with urinary cadmium levels in the highest
quartile, 0.18-14.9 μg/g creatinine, compared to those in
the lowest quartile with urinary levels up to 0.06 μg/g
creatinine. Estimated dietary cadmium exposure has
been associated with an increased risk of cancer in the
endometrium (Åkesson et al., 2008), breast (Julin et al.,
2012a), and prostate (Julin et al., 2012b).
128 Bruce A. Fowler, Jan Alexander, and Agneta Oskarsson
2.4  Risk Assessment
2.4.1  Hazard Characterization
Cadmium risk assessment has been performed
recently by two international expert groups, both of
whom consider renal effects to be the critical effect
endpoint. The CONTAM Panel within EFSA (2009b)
based the tolerable weekly intake (TWI) of 2.5 μg/kg
b.w. on the association between urinary cadmium and
β2-microglobulin. A urinary cadmium level of 4 μg/g
creatinine was derived as a benchmark dose with a
lower confidence limit for a 5% increase of the preva-
lence of elevated β2-microglobulin. An adjustment
factor of 3.9 to account for interindividual variation in
urinary cadmium was applied; in order not to exceed
1 μg/g creatinine in urine in 95% of the population, the
TWI of 2.5 μg/kg b.w. was established.
JECFA (2011a) used the same dose-response data
and established a provisional tolerable monthly intake
(PTMI) of 25 μg/kg b.w., based on no increased risk
of elevated excretion of β2-microglobulin at a urinary
excretion of 5.24 μg/g creatinine (5th to 95th percen-
tiles, 4.94-5.57). The lower 5th percentile dietary cad-
mium exposure that equates to this urinary excretion
was estimated to be 0.8 μg/kg b.w./day or about 25 μg/kg
b.w./month. Owing to cadmium’s exceptionally long
half-life, JECFA considered that a monthly value was
more appropriate.
The JECFA (2011a) PTMI is slightly higher than
the TWI established by EFSA (2009b). In this case,
the established health-based guidance value (HBGV)
has a clear impact on risk characterization. Because
of this, EFSA was requested to explain the reason
and advise on which value to use (EFSA, 2011a,b).
The higher HBGV of JECFA is due to differences in
the statistical approaches used; in particular, the tox-
icodynamic variability function had a major impact
on the HBGV. The CONTAM Panel of EFSA reaf-
firmed its TWI of 2.5 μg/kg b.w. for cadmium (EFSA,
2011a,b).
2.4.2  Risk Characterization
The mean exposure in the general population in
various countries is close to or even exceeds the EFSA
TWI value. According to the EFSA (2009b), vegetar-
ians, children, and people with certain food prefer-
ences may exceed the TWI by about twofold, while the
JECFA (2011a) concluded that the estimates of expo-
sure to cadmium through the diet for all age groups,
including consumers with high exposure and sub-
groups with special dietary habits (e.g. vegetarians),
are below the PTMI.
2.5  Risk Management
To reduce cadmium exposure in the general popula-
tion, measures need to be taken throughout the whole
food chain. Conventional strategies, such as iden-
tifying maximum permitted levels in certain foods,
are already in place, for example maximum limits
established on the global level in the Codex General
Standard For Contaminants And Toxins In Food And
Feed (CODEX STAN 193-1995) and within the EU
(EC, 2006). The regulations are followed up by con-
trol programs. As a consequence of the lowered TWI
established by the EFSA (2009b), the European Com-
mission has reviewed the need for maximum limits in
different foods. As the major exposure originates from
the soil via plant foods, measures should be taken to
reduce the input of cadmium to soils and its uptake
in plants. Atmospheric deposition, phosphate fertiliz-
ers, and sewage sludge are main sources of cadmium
input to soil in the local farm circulation of cadmium,
but also to be considered is cadmium in nonlocal feed
components that are excreted and applied to arable
soils as manure in animal production farms. Certain
plants, e.g. Salix (willows), can take up high amounts
of cadmium and thus reduce the soil levels. To limit
the uptake of cadmium in plants, a low pH could be
adjusted upwards by liming, the organic content of
soil increased, and Zn fertilization could be used in
Zn-deficient soils. The most efficient way to reduce
cadmium exposure from plant foods is probably to use
cultivars with a low cadmium uptake grown on soils
with a low natural cadmium concentration in a non-
polluted area.
For smokers, the main preventive measure to reduce
cadmium exposure is to stop smoking. For nonsmok-
ers, cadmium exposure will be reduced by restricted
intake of certain foodstuffs with high concentrations
of cadmium, such as cephalopods, bivalve molluscs,
kidney and liver (especially from older animals), and
certain seeds and nuts, as noted above. However, the
major part of the population already has a negligible
intake of such foods. Keeping adequate iron stores
will restrict cadmium uptake from the gastrointestinal
tract. This applies particularly to women of fertile age
and growing children and adolescents who are at risk
of iron deficiency, as discussed above.
3 LEAD
Lead is a toxic metal associated with a number of
adverse health effects, such as developmental neu-
rotoxicity in young children, and hypertension and
 6  Toxic Metals in Food 129

kidney disease in adults. It cannot be excluded that TABLE 3  Foods with the 10 Highest Mean
adverse effects may occur at current environmental Concentrations of Lead in the U.S. Food and Drug
Administration Total Diet Study, for the Period Jan. 2006
exposure levels, especially in children. Lead is present
to April 2008
in the soil both from anthropogenic activities and from
natural sources. The main exposure is from food, with Food description Mean lead (mg/kg)
cereals and vegetables being the largest contributors.
Shrimp, boiled 0.022
Dietary exposure has decreased significantly in devel-
Syrup, chocolate 0.019
oped countries since the 1970s, when the uses of lead Baby food: arrowroot cookies 0.017
in gasoline and lead solder in cans and drinking water Baby food: sweet potatoes 0.015
plumbing materials were regulated or banned. How- Apricots, canned in heavy/light syrup 0.015
ever, in other countries, exposure to lead is still wide- Candy bar, milk chocolate, plain 0.014
Pineapple, canned in juice 0.013
spread. Recent risk assessments of lead from JECFA
Sweet potatoes, canned 0.012
(2011b) and EFSA (2010) have concluded that there is Baby food: juice, grape 0.012
no evidence for a threshold for the critical effects and Cake, chocolate w/icing 0.011
thus it is not appropriate to derive a TWI for lead. Fruit cocktail, canned in light syrup 0.011
Dill cucumber pickles 0.011
Peach, canned in light/medium syrup 0.011
3.1  Occurrence in the Food Chain
Source : FDA (2010).
Lead is extensively found in the food chain as a
result of past and present use in batteries, gasoline,
food cans, and paint, as well as from mining, lead- Miscellaneous
10% Veg & fruit
smelting facilities, and natural occurrence in the soil.
20%
Urban agriculture is an important means of obtaining Drinking water
food security in developing countries. However, sites 7%
previously used for waste disposal are sometimes used
for cultivation due to the shortage of land, and this Milk
may result in elevated lead levels in leafy vegetables 7%
(Nabulo et al, 2012). Food is the major source of expo-
sure in adults, while drinking water can be a main Fish
2%
source in infants, in addition to ingestion of soil and
dust (EFSA, 2012a). Lead in drinking water usually Spices
originates from water pipes or lead solder in taps for 6%
drinking water. Table 3 presents data on lead concen- Beverages
trations in food from the U.S. FDA Total Diet Study Meat & offal 26%
for the period 2004-2008 (2010). The data indicate that 6%
some shellfish such as shrimp, chocolate products of
various types, sweet potatoes, and various canned Grains
fruits may have elevated concentrations of lead. One 16%
example of a food item recently reported to have a rela- FIGURE 2  Relative contribution of dietary sources to the total
tively high level of lead comprises hot sauces imported daily intake of lead in adults. Source: data compiled from EFSA
from Mexico (Berger et al., 2013). (2012a).

and vegetables; and 58 μg/kg in fish and seafood. An

3.1.1  Exposure from Foodstuffs
Lead occurrence data in food from different
regions of the world has recently been compiled
by JECFA (2011b) and EFSA (2012a). EFSA exam-
ined 144,000 analytical results for lead in food for
the period from 2003 to 2011. More than half of the
samples, 57%, had levels below the limit of quantifi-
cation. Mean concentrations in foodstuffs were 4 μg/
kg in tap water; 15-21 μg/kg in fruits, meat, pota-
toes, and alcoholic beverages; 29-34 μg/kg in cereals
overall decrease in food lead levels of 23% was esti-
mated for the entire period across all sample results.
The relative contribution of different sources to the
dietary exposure of lead in adults from the European
data is illustrated in Figure 2. The food categories
with major contributions were beverages (includ-
ing fruit and vegetable juices, and nonalcoholic and
alcoholic beverages), vegetables and fruits (includ-
ing vegetable products, starchy roots and tubers, and
legumes, nuts, and oilseeds), and grains and grain
130 Bruce A. Fowler, Jan Alexander, and Agneta Oskarsson
products. All together these foodstuffs contributed
62% of the dietary intake, whereas animal products
contributed less. A considerable variation has been
reported in the sources of lead intake among differ-
ent age groups. In infants, the major contribution to
lead intake is from drinking water and milk/dairy
products, contributing 26 and 22%, respectively.
EFSA (2012a) has estimated that the mean lifetime
dietary exposure to lead is 0.68 μg/kg b.w./day in
the overall European population. Toddlers (2 years
of age) had the highest estimated exposure, with
1.32 μg/kg b.w./day, while adult exposure was
0.50 μg/kg b.w./day. Comparison with data from
other parts of the world is difficult to make due to
different estimations, e.g. concerning foods with
concentrations below the limit of detection or quan-
titation and assumption of body weights. JECFA
(2011b) reported mean daily intakes of lead in adults
in μg/kg b.w.: 0.03 in the USA, 0.11 in Canada, 0.44 in
India (Mombay), 0.9 in China, and 3.0 in Chile
(Santiago). Lead exposure in children ranged from
0.03 to 9 μg/kg b.w./day depending on age, country
and assumptions made in the estimations.
3.2  Biomonitoring of Exposure
Gastrointestinal absorption of ingested lead depends
on physical and physiological parameters, such as
solubility of the lead compound, fasting of the sub-
ject, and age. Gastrointestinal lead absorption appears
to be higher in children than in adults. In the blood,
96-99% of lead is bound to erythrocytes. Lead levels in
whole blood are generally used as a biomarker of lead
exposure and for estimation of relationships to health
effects of lead.
In concordance with the decrease in dietary lead
intake, there has been a significant decrease in blood
lead levels. The percentage of children with blood
lead levels higher than 100 μg/L decreased from 88.2
to 4.4% in less than 20 years (ATSDR, 2007). A declin-
ing trend has also been reported in 7- to 11-year-old
children from two municipalities in Southern Sweden,
in whom yearly measurements of blood lead levels
have been taken since 1978 (­ Strömberg et al., 2008). In
2008, the geometric mean in the children was 13 μg/L.
The mean blood levels of lead vary considerably
worldwide. High mean blood lead levels in 2005 were
reported from South Asia (102 μg/L in urban adults),
the Caribbean (97 μg/L in urban children and adults),
and Sub-Saharan Africa (68 μg/L in urban children)
(JECFA, 2011b). In Kampala, Uganda, where lead in
gasoline was phased out in 2005, 20% of the children
studied had blood lead levels above 100 μg/L, and the
mean blood levels were 7.15 μg/L. The factor most
strongly associated with elevated lead levels in blood
was living closer than 0.5 miles to a landfill site con-
taminated with lead (Graber et al., 2010).
3.3 Toxicity
Lead toxicity has been studied for many years, with
an increasing appreciation of low-dose effects, par-
ticularly in children (EFSA, 2010; JECFA, 2011b). Neu-
robehavioral effects in children have been the primary
focus of many studies. The developing brain is more
vulnerable than the adult brain. Elevated blood lead
levels in children are associated with impaired cogni-
tive function, reduced intelligence quotient (IQ), and
behavioral problems. The association is character-
ized as a nonlinear dose-response relationship, with
a higher impact on IQ at lower than at higher blood
lead levels. Lanphear et al. (2005) pooled data from
seven cohort studies initiated before 1995 in the USA,
Mexico, Australia, and Yugoslavia with the aim of
examining effects at blood lead levels below 100 μg/L.
Using a log-linear model, they found that an increase
in blood lead from 24 to 300 μg/L was associated with
a decrease in IQ of 6.9. At blood lead levels below
100 μg/L, there was a stronger negative impact on IQ
(an increase in blood lead level from 24 to 100 μg/L was
associated with a decrease in IQ of 3.9) than at higher
blood lead levels (an increase in blood lead level from
200 to 300 μg/L and from 300 to 400 μg/L was associ-
ated with decreases in IQ of 1.9 and 1.1, respectively).
Exposure to lead has been associated with a vari-
ety of adverse effects on the cardiovascular system in
adults. The effect associated with the lowest lead expo-
sure is an increase in systolic blood pressure (Alissa
and Ferns, 2011).
Polymorphisms in the aminolevulinic dehydra-
tase gene (ALAD) may play a role in mediating these
effects, as has been examined using data from the U.S.
National Health and Nutrition Examination Survey
program (Scinicariello et al., 2010). Relatively low
exposure to lead has also been associated with func-
tional renal deficits, e.g. a reduction in glomerular
filtration rate, elevated serum creatinine levels, and
decreased creatinine clearance.
3.4  Risk Assessment
3.4.1  Hazard Characterization
Two recent risk assessments of lead have come to sim-
ilar conclusions (EFSA, 2010; JECFA, 2011b). The critical
adverse health effect of lead is developmental neurotox-
icity, which makes fetuses, infants, and children the most
sensitive subgroup. Assessing the risk of intellectual
deficits in children measured by the Full Scale IQ Score,
EFSA determined the 95th percentile lower confidence
 6  Toxic Metals in Food
limit of the Benchmark Dose (Lower Confidence Limit)
of 1% extra risk (BMDL01) of 12 μg/L. For adults, the
critical health effects were cardiovascular effects and
nephrotoxicity. A 1% increase in systolic blood pressure,
corresponding to a 1.2  mmHg increase at an average sys-
tolic blood pressure of 120 mmHg, was considered to be
a public health issue, and the BMDL01 for systolic blood
pressure was 36 μg/L. The 10% change in prevalence
(BMDL10) for chronic kidney disease was 15 μg/L. The
corresponding dietary intakes of lead at the respective
BMDL01 for neurocognitive effects and effect on blood
pressure, and the BMDL10 for chronic kidney disease
were estimated to be 0.50, 1.50, and 0.63 μg/kg b.w./day.
JECFA (2011b) estimated that the previously estab-
lished provisional TWI (PTWI) of 25 μg/kg b.w., cor-
responding to a daily intake of 3.6 μg/kg b.w., is
associated with a decrease of at least 3 IQ points in
children and an increase in systolic blood pressure
of 3 mmHg. In concordance with EFSA (2010), JECFA
concluded that the PTWI can no longer be considered
as health protective and it was therefore withdrawn.
As there was no evidence of a threshold for the critical
effects of lead, it was not possible to establish a new
tolerable intake level of lead.
3.4.2  Risk Characterization
Current exposure to lead in the general population,
based both on lead concentrations in blood and on
dietary intakes, shows very low or almost no margins
to the respective BMDLs established by EFSA (2010).
EFSA (2010) estimated the dietary lead intake values
corresponding to the BMDLs in adults for the cardio-
vascular and kidney effects to be 1.50 μg/kg b.w./day
and 0.63 μg/kg b.w./day, respectively. In children up
to age 7 years, a dietary value of 0.50 μg/kg b.w./day
was estimated to correspond to the BMDL01 for devel-
opmental toxicity. EFSA (2010) concluded that the
margins were such that the possibility of an effect from
lead in some consumers, particularly in children, can-
not be excluded. The risk of clinically important effects
on either the cardiovascular system or kidneys of adult
consumers were considered low or negligible; whereas
there were potential concerns for effects of lead on
neurodevelopment in fetuses, infants, and children.
3.5  Risk Management
Given the above discussion, it is clear that every
effort should be made to reduce lead exposures by all
routes, including food, due to the adverse health find-
ings noted at current environmental exposure levels.
Measures taken to reduce lead exposure have resulted
in a significant decrease in lead levels in food and in
blood. The phase-out of lead in gasoline has been an
131
extremely successful measure to reduce lead exposure,
not only via inhalation but also via dietary intake.
Also, banned or decreased uses of lead in plumbing
systems, lead soldered food cans, and lead in paints
have been very important means to reduce lead
exposure. Atmospheric emissions of lead from point
sources such as coal-fired power plants/smelters or
automobile emissions from countries where leaded
gasoline is still in use are known to move large dis-
tances with the jet stream, with subsequent soil/water
deposition in other countries from rain, snow, or dry
deposition. This means that lead from these sources
can be taken up into food crops from soil or fishery
products in addition to inhalation exposures. Lead-
containing dust from past uses of lead-based paints or
atmospheric deposition is another major route of expo-
sure, particularly for infants or toddlers who engage
in hand-to-mouth activities. Maximum limits of lead
in food are established on the global level in CODEX
STAN 193-1995 and within the EU (EC, 2006).
4 MERCURY
Mercury is released into the environment from
both natural and anthropogenic sources, and it under-
goes complex transformations and cycles between the
atmosphere, oceans, and land. There are three chemi-
cal forms of mercury: (1) elemental or metallic mer-
cury (Hg0); (2) inorganic mercury [mercurous (Hg22+)
and mercuric (Hg2+) cations]; and (3) organic mercury.
Methylmercury is by far the most common form of
organic mercury in the food chain. There is extensive
toxicological information on the effects of methylmer-
cury both in experimental animals and in humans. The
main target is the nervous system, in particular the
developing central nervous system, but the cardiovas-
cular and immune systems can also be affected (EFSA,
2012b). The target organ of inorganic mercury is the
kidney with e.g. tubular toxicity with proteinuria and
immunologically related glomerular disease (ATSDR,
1999; EFSA, 2012b). Methylmercury is biomagnified
and bioaccumulated particularly through the marine
and freshwater food webs, with fish and seafood as
major dietary sources. In other foods, inorganic mer-
cury is the main form of mercury. Most of the data in
this chapter are, unless other references are given, from
reviews and risk assessments of mercury by ATSDR
(1999), EFSA (2012b), and JECFA (2004, 2007, 2011c).
4.1  Occurrence in the Food Chain
The source of mercury in aquatic sediments is a
combined result of local geology, runoff, and atmo-
spheric deposition. The main source is combustion of
132 Bruce A. Fowler, Jan Alexander, and Agneta Oskarsson
fossil fuel. Contamination may be local, transported
long distance, or runoff from mining activity involv-
ing mercury. In aquatic sediments, mercury is mainly
methylated by sulfate- and iron-reducing bacteria, but
inorganic and methylated mercury species may also
occur in the water columns of aquatic environments,
usually bound to particulates, phytoplankton, or zoo-
plankton. Factors that affect methylation (in addition
to availability of mercury and methylating microor-
ganisms) are temperature, pH, redox potential, and
complexing agents. Biomagnification and bioaccumu-
lation of mercury largely as methylmercury take place
in aquatic food webs; there are numerous reports in
the scientific literature regarding this phenomenon.
The highest concentrations are seen in predatory fish
and sea mammals at the top of the food web. Mercury
biomagnification has been a particular problem with
the consumption of large predatory fish (­Bourdineaud
et al., 2012; Kidd et al., 2012) and marine mammals
(Bjerregaard and Mulvad, 2012; Jeppesen et al., 2012).
Recently, a high concentration of mercury was found
in Persian caviar from the southern Caspian Sea
(­Hosseini et al., 2013).
In developing countries, artisanal gold mining tech-
niques use mercury, often with considerable local con-
tamination to soil, waterways, and the atmosphere,
which may result in human exposure to mercury via
fish consumption (Ashe, 2012). Other foods, such
as rice, may also become contaminated with mer-
cury from mining runoff to rice paddies (Krisnayanti
et al., 2012). Another source of inorganic mercury is
certain species of mushrooms (Falandysz et al., 2002;
­Chojnacka et al., 2012; Drewnowska et al., 2012) and
some vegetables (Park and Lee, 2012).
4.1.1  Exposure from Foodstuffs
Several analytical techniques are suitable for the
determination of mercury in foods. In most cases, only
total mercury has been determined. Speciation with the
determination of methylmercury has been performed
in a limited number of food samples. In the recent risk
assessment by EFSA (2012b), the fractions of methylmer-
cury to total mercury in food samples, which had been
analyzed using speciation techniques, was compared
with data from the literature. In general, the majority of
samples found to contain mercury, determined by spe-
ciation of methylmercury, were fish or sometimes other
seafoods such as crustaceans or molluscs.
Generally about 80-100% of total mercury in fish
muscle is methylmercury. Fish lower in the food chain
contain less total mercury, and also the fraction of
methylmercury may be lower, down to about 50% of
total mercury but highly variable (EFSA, 2012b). In line
with this, JECFA stated that in fish, methylmercury
ranged between 30 and 100%, depending on the spe-
cies of fish and its size, age, and diet. But in the major-
ity of samples methylmercury accounted for more
than 80% of total mercury. To avoid underestimation
of dietary exposures, EFSA (2012b) used conservative
approaches in the calculation of dietary exposures to
both methylmercury and inorganic mercury. It was
assumed that 100% of the mercury in fish is in the form
of methylmercury. In calculating the dietary exposure
to inorganic mercury, it was at the same time assumed
that 20% of the total mercury in fish was inorganic mer-
cury. For seafood (other than finfish), in which meth-
ylmercury typically comprises 50-80% of total mercury
and inorganic mercury 20-50%, it was assumed that
80% of the total mercury consisted of methylmercury
and that inorganic mercury in shellfish constituted
50% of total mercury (EFSA, 2012b). This means that
the figures for methylmercury and inorganic mercury
in EFSA’s dietary intake calculations will add up to
more than 100%. In foods other than seafood, all mer-
cury was assumed to be present as inorganic mercury.
The highest total mercury concentrations were gen-
erally found in samples of finfish, varying from 0.001
to 11.4 mg/kg in about 6000 samples, whereas 1900
shellfish samples had total mercury concentrations that
ranged from 0.002 to 0.86 mg/kg. With regard to methyl-
mercury, major contributing species were tuna, sword-
fish, cod, whiting, and pike (EFSA, 2012b). The dietary
exposure to methylmercury was calculated to vary
from 0.06 μg/kg b.w./week in the elderly to 1.57 μg/kg
b.w./week in toddlers. The 95th percentile ranged up
to a maximum of 5.05 μg/kg b.w./week in adolescents
and up to 7.48 μg/kg b.w./week in children with a
high fish consumption. Infants are exposed to mercury
via breast milk from mothers consuming fish, as mea-
sured by total mercury (Okati et al., 2012; Orün et al.,
2012). However, Oskarsson et al. (1996) did not find a
correlation between concentrations of organic mercury
in blood and milk, while there was a significant cor-
relation between inorganic mercury in blood and milk,
indicating an efficient transfer of inorganic mercury
into milk. Based on the mean concentration in breast
milk, the exposure of infants to methylmercury ranged
from 0.09 to 0.94 μg/kg b.w./week and to inorganic
mercury ranged from 0.17 to 1.94 μg/kg b.w./week
(EFSA, 2012b). Intake estimates made by JECFA gener-
ally accords with those of EFSA. With regard to intake
calculations of dietary exposure to inorganic mercury,
these values ranged from 0.13 μg/kg b.w./week in
the elderly to a maximum of 2.16 μg/kg b.w./week
in toddlers (EFSA, 2012b). Exposure to inorganic mer-
cury from breast milk in infants ranged from 0.17 to
1.94 μg/kg b.w./week.
 6  Toxic Metals in Food
As noted above, fish are generally the largest source
of foodborne mercury exposure, predominantly as
methylmercury, for the general populations in most
countries (Jenssen et al., 2012; Miklavčič et al., 2012;
Watanabe et al., 2012; Holloman and Newman, 2012;
Tsuchiya et al., 2012; You et al., 2012; Karjalainen et al.,
2012; Kim et al., 2012). Predatory fish species accu-
mulate methylmercury to a high extent and the type
of water in which the fish are caught, i.e. marine or
fresh, is of major importance for the mercury concen-
tration, with the highest levels in fish from freshwater.
In addition, it has also been reported that farmed fish
generally have lower mercury concentrations than fish
caught in the wild (Kim et al., 2012; Karimi et al., 2012).
Hence, fish of the same species available at the market
may vary greatly in their mercury content.
Whales, seals, and dolphins have been reported
to have a concentration of methylmercury of about
13 mg/kg. The consumption of such meat from small
cetaceans may pose health concerns for both pregnant
women and persons in the general population (Endo
et al., 2005). In this regard, subsistence hunters and
fishers in various Native American groups such as
the American Indians or Eskimos/Inuits may also be
populations at special risks of elevated exposures to
mercury from fish (Burger and Gochfeld, 2007; Burger
et al., 2007; Laird et al., 2013). Similar issues may be
raised for fishers who catch and consume large preda-
tory fish from European rivers such as the Danube
(Subotić et al., 2013).
Data on total mercury concentrations in foodstuffs
from the U.S. FDA Total Diet Study (2010) indicate
that large predatory fish, such as tuna, generally have
the highest concentrations of mercury, usually largely
present as methylmercury.
4.2 Toxicity
The toxic effects seen after exposure to mercury vary
by chemical form. This is in part due to differences in
toxicokinetics. Methylmercury is much more exten-
sively and rapidly absorbed than inorganic mercury.
Methylmercury passes the placenta, crosses the blood-
brain barrier, and enters the cerebrospinal fluid and
hair follicles. This allows accumulation in the brain,
fetus, and hair; measurement in these tissues may
serve as a biomarker. In the blood, methylmercury is
mainly bound to red blood cells. Inside cells and in the
brain, methylmercury may undergo demethylation to
inorganic mercury, which is less able to pass through
cell membranes. Methylmercury is mainly excreted via
bile into the feces and a large fraction is reabsorbed in
the intestine. Inhibition of reabsorption by complex-
ation to a nonabsorbable material has been used in
133
the treatment of methylmercury poisoning. Inorganic
mercury, on the other hand, does not easily pass bio-
logical barriers because of limited lipophilicity; less is
bound to red blood cells and more is found in plasma.
The highest proportion is found in the kidneys, in par-
ticular in the proximal convoluted tubules where it
exerts its toxic effects. Inorganic mercury also binds to
periportal areas in the liver, mucus membrane of the
intestinal tract and the skin, the testes, and the choroid
plexus of the brain. The main route of excretion is via
feces.
There is an extensive scientific literature on the
toxic effects of mercury in experimental animals and
in humans. Briefly, for inorganic mercury, the kidney
is the critical target organ. Other organs or targets
affected are the liver, nervous system, immune system,
and the developing organism. For methylmercury,
effects seen in experimental animals include neuro-
toxicity, cardiovascular toxicity, and reproductive and
developmental toxicity. The latter comprise embryonic
lethality, teratogenicity, neurotoxicity, and immuno-
toxicity (EFSA, 2012b).
There is also a large body of epidemiological stud-
ies focusing on methylmercury. The main focus has
been on various developmental effects, in particular
neurodevelopment and motor and cognitive functions,
but also neurological auditory function. There are also
associations between exposure to methylmercury and
cardiovascular disease, which was addressed by FAO/
WHO in 2006 (JECFA, 2007). These relationships are not
considered conclusive. A complicating factor for epide-
miological studies is that fish and seafood, which are
the main sources of methylmercury exposure, may also
contain other contaminants such as chlorinated persis-
tent organic compounds like polychlorinated biphe-
nyls, as well as important long-chain unsaturated fatty
acids (LCPUFAs), which may be beneficial for health.
4.3  Risk Assessment
4.3.1  Hazard Characterization
In the past, numerous risk assessments have been
conducted for mercury; these also vary as a function of
the particular chemical form involved. Recently, JECFA
reassessed methylmercury in 2006 and inorganic mer-
cury in 2010. EFSA assessed mercury (methylmercury
and inorganic mercury) in 2012 (JECFA, 2007, 2011c;
EFSA, 2012b).
With regard to inorganic mercury, EFSA in 2012
did not identify studies suitable for risk assessment in
addition to those used by JECFA and agreed with the
rationale of JECFA, which set an HBGV using a study
showing changes in kidney weight in male rats as the
134 Bruce A. Fowler, Jan Alexander, and Agneta Oskarsson
pivotal study. A BMDL10 of 0.06 mg/kg b.w. expressed
as mercury was used as the reference point and using
an uncertainty factor of 100 to account for inter- and
intra-species variability a PTWI of 4 μg/kg b.w. was
set. Accordingly, a similar figure was used by EFSA for
their TWI.
Several recent assessments of methylmercury
have been based on its neurodevelopmental effects in
humans (EFSA, 2012b). In 2003, JECFA established a
PTWI of 1.6 μg/kg b.w. based on epidemiological stud-
ies of possible effects of prenatal exposure on child
neurodevelopment (JECFA, 2004). Neurodevelop-
ment was considered to be the most sensitive health
outcome and development in utero the most sensitive
period of exposure. The basis of setting an HBGV was
an average of the benchmark dose for 0.5% increased
incidence (BMDL05; Faroe Islands)/no observed
adverse effect level (NOAEL; Seychelles) of 14 mg/kg
for concentrations of mercury in maternal hair in stud-
ies from the Faroe Islands and the Seychelles. This con-
centration in hair was converted to a methylmercury
concentration in maternal blood of 0.056 mg/L, which
would correspond to a daily intake of 1.5 μg/kg b.w.
Using a combined uncertainty factor of 6.4 based on a
data-derived factor of 2 for the conversion from hair to
blood and 3.2 to account for interindividual variability
in toxicokinetics, a PTWI of 1.6 μg/kg b.w. was set. This
PTWI was confirmed in 2006 (JECFA, 2007). Since 2006,
new data from the two cohorts have been published.
In the Faroese cohort, the association between prenatal
exposure and neurological auditory function was still
present at 14 years of age, although with a slightly less
impact. Reassessment of the data also found beneficial
effects of fish consumption and an underestimation
of the effects of methylmercury. The Seychelles Child
Development Study indicated an association between
prenatal mercury exposure and decreased neurode-
velopment scores at 9 and 30 months when adjusted
for intake of n-3 LCPUFAs. An apparent NOAEL of
approximately 11 mg/kg hair was reported. Based on
these data, EFSA used a mean NOAEL of 11.5 mg/kg
hair (BMDL05, 12 mg/kg and 11 mg/kg hair) in the
Faroese and Seychelles studies and similar conver-
sion factors and uncertainty factor to those used by
JECFA (i.e. corresponding to a blood concentration of
0.046 mg/L and a daily intake of 1.2 μg/kg b.w.) and
established a TWI of 1.3 μg/kg b.w. (EFSA, 2012b).
4.3.2  Risk Characterization
In Europe, EFSA assessed the dietary intake in rela-
tion to the tolerable intakes (EFSA, 2012b). The mean
dietary exposure did not, except for toddlers and other
children in some surveys, exceed the TWI. With regard
to the 95th percentile, dietary exposure to methyl-
mercury was close to or exceeded the TWI for all age
groups. A risk group constitutes those with a high
consumption of fish, which would include pregnant
women. The consumption may exceed the tolerable
intake by 4.7- and 6-fold based on the highest estimated
exposures among adults and children, respectively.
Biomonitoring data on hair and blood confirmed that
the general European population is exposed below the
tolerable intake of 1.3 μg/kg b.w./week. Exception-
ally high concentrations were observed only in some
individuals.
4.4  Risk Management
Risk management for mercury exposures from
food will need to consider the food consumption pat-
tern and mercury content, particularly of the fish con-
sumed in different age groups, as well as gender in the
exposed populations. In practical terms, an important
consideration is the availability of noncontaminated
food sources. This will be an important consideration
for people living in developing countries, as well as
subsistence hunters and fishers. On the basis of data
submitted from France, Japan, the UK, and the USA,
JECFA evaluated the mercury content in fish and the
impact of the Codex Alimentarius guidelines of 0.5
and 1.0 mg/kg for nonpredatory and predatory fish,
respectively (JECFA, 2007). In each of these countries,
the seafood market is dominated by species that do
not contain high concentrations of mercury. Given that
seafood consumers randomly select fishery products
from the total market, their mean level of methylmer-
cury exposure would not be substantially reduced by
excluding fish that exceed the Codex Alimentarius
guidelines (CODEX STAN 193-1995) or maximum
limits from other regulations, such as the EU (EC,
2006); neither would it significantly reduce the num-
ber of individuals exposed to methylmercury above
the PTWI. On the other hand, individuals with a pref-
erence for fish species with a known high content of
mercury would benefit from excluding fish that exceed
the guideline levels because this could lower their
exposure significantly. In this context, it is important
to also consider the potential health benefits of fish
consumption.
5 ARSENIC
Public health issues such as cancer and cardiovas-
cular disease related to arsenic in drinking water and
medicines have been appreciated for many years. The
relative contribution to arsenic exposure of drinking
 6  Toxic Metals in Food
water and food varies. As the concentration of inor-
ganic arsenic in drinking water decreases, the pro-
portion of exposure to inorganic arsenic from food
increases (JECFA, 2011d). Concerns for arsenical con-
tamination of foodstuffs or dietary supplements aris-
ing from use of arsenic-contaminated water for crop
irrigation and cooking practices has only recently
emerged as a public health issue. The uptake of arseni-
cals into food crops, such as rice, from these routes of
exposure is now of high concern due to the use of rice
in baby foods. Another emerging issue is the exposure
of livestock to feed containing ground feathers from
poultry given arsenical dietary supplements contain-
ing organic arsenicals such as roxarsone to stimulate
growth (Nachmann et al, 2013).
5.1  Occurrence in the Food Chain
Arsenic may occur as inorganic arsenic and in a large
variety of organic forms. Arsenic in drinking water is
inorganic, while in plants it is mainly inorganic but
also to some extent organic arsenic. In foods of marine
animal origin, organic arsenic species constitute the
major part. In comparison with marine animals, lower
amounts of arsenic are found in terrestrial animals. In
species used for food, inorganic arsenic and methylated
arsenic species may both be present. In addition, other
organic arsenicals may be present if the feed contains
components of marine origin (Molin et al., 2012a,b). In
the case of plants, arsenic has been shown to be taken
up by edible plants from the soil as a result of irriga-
tion of crops with arsenic-containing groundwater. This
has been a particular problem in developing countries
for crops such as rice (Smith et al., 2006; Rahman and
Hasegawa, 2011; Phan et al., 2012; Spanu et al., 2012)
and vegetables (Rahman et al., 2012; Some et al., 2012).
Arsenic has also been detected in the edible tissues
of animals either treated with roxarsone to stimulate
growth (Conklin et al., 2012) or exposed to arsenic from
contaminated water or animal feeds based on crops irri-
gated with arsenic-containing water (Datta et al., 2012).
5.1.1  Exposure from Foodstuffs
It is important to note that human exposure to
arsenicals in foodstuffs varies widely by country and
region. The presence of arsenic in water used for irri-
gation of crops is the major underlying source of arse-
nic contamination for plant food items. In a number of
countries where rice is a major food staple, irrigation
is conducted using groundwater contaminated with
arsenic via irrigation of rice paddies, causing increased
arsenic rice content. In these areas, arsenic from rice
adds to the arsenic exposure from drinking water. The
135
exposure may be substantial and associated concerns
of arsenic toxicity have been reported. The West Bengal
region of India (Rahman and Hasegawa, 2011; Rahman
et al., 2012), Bangladesh (Smith et al., 2006), and more
recently in the Mekong River Basin of Cambodia (Phan
et al., 2012) are examples of this phenomenon. Stud-
ies in Burkina Faso (Some et al., 2012) have reported
high concentrations of arsenic in tube-well water, but
nondetectable concentrations of arsenic in tomatoes,
cabbages, and potatoes, suggesting plant-specific pat-
terns of arsenic uptake. In addition, elevated intakes
of arsenic have been reported in China (Chen et al.,
2011) from the consumption of fruits and vegetables,
such as tomatoes, spinach, cabbages, celery, and broc-
coli. Differences in soil composition/acidity may be
important factors in determining plant uptake of this
element, and there is an extensive scientific literature
on the impact of genomics on arsenic uptake into vari-
ous plant species (see Tripathi et al., 2012 for a detailed
review of this research area). It should be noted that
rice grown in southeastern USA may also contain ele-
vated concentrations of arsenic, ostensibly as a result
of prior historical use of arsenical pesticides in this
region for cotton production. Recent studies (Jackson
et al., 2012a,b) have documented elevated concentra-
tions of inorganic arsenic in rice-based foods includ-
ing infant formulas and first foods for children. The
issue of arsenicals in food staples such as rice is hence
international in scope for different underlying source
reasons. The importance of food and drinking water
as the major sources of human exposure to arsenic is
highlighted by a number of recent studies from several
countries. Studies from Hong Kong, which recently
published its first total diet study, Hong Kong Total
Diet Study (Wong et al., 2013), showed that for Asian
diets in general, food groups such as rice, nuts, green
vegetables, and shellfish, are major contributors to
inorganic arsenic dietary intakes. Combined modeling
and measurement studies by Kurzius-Spencer et al.
(2013), which used data from the U.S. FDA Total Diet
Study estimated that 93% of the total arsenic exposure
was due to diet in households with drinking water
concentrations at or below 10 μg/L. Cereals and fruits
are relatively small food sources of arsenic compared
to fish and seafood. Beverages, such as some fruit
juices (Wilson et al., 2012) and wine (Lovreglio et al.,
2012), meat/offal, fruits, and vegetables are important
dietary sources of arsenic. Arsenic in these dietary sta-
ples is largely present as inorganic species, which gen-
erally have greater toxic potential than organic species.
Although fish and other seafood products represent a
large percentage of total arsenic intake, it is important
to note that arsenic in fish and seafood is largely pres-
ent as methylated species that are of lower toxicity than
136 Bruce A. Fowler, Jan Alexander, and Agneta Oskarsson
the inorganic arsenic species. A more detailed discus-
sion of the differences between inorganic and organic
arsenical species is presented elsewhere in this book
(see Chapter 28). In addition to commonly consumed
food items, dietary supplements based upon herbs and
botanicals may also make major contributions to over-
all dietary intakes of inorganic arsenic (Hedegaard
et al., 2013). Table 4 presents data on arsenic concentra-
tions in food from the U.S. FDA Total Diet Study (2010).
The data indicate that a number of fishery products
may contain elevated concentrations of arsenic, which
is largely present as stable methylated arsenical spe-
cies and regarded as being of low toxic potential. Some
food, such as raisin bran cereal, rice, and mushrooms,
may also contain elevated concentrations of arsenic,
present largely as inorganic arsenic.
5.2 Toxicity
Inorganic arsenicals have been known to produce cel-
lular toxicity in a number of organ systems, including
cardiovascular effects and cancer, in humans following
oral exposures via drinking water and food. Arsenic-
induced effects on mitochondrial respiration and the
generation of reactive oxygen species (ROS) appear to
be central elements in producing these effects. ROS may
also damage a number of other intracellular macromol-
ecules including DNA and alter epigenetic regulatory
processes, which may lead to the development of carci-
nogenic responses. With regard to organic arsenic spe-
cies, less is known about their biotransformation and
toxicity, although generally they are considered to be
less toxic. Exceptions are the trivalent methylated spe-
cies, which appear to be more toxic than trivalent inor-
ganic arsenic. Some of the organic arsenic species, such
TABLE 4  Foods that had the 10 Highest Mean
Concentrations of Total Arsenic Measurements in the U.S.
Food and Drug Administration Total Diet Study, for the
Period Jan. 2006 to April 2008
Food description Mean arsenic (mg/kg)
Tuna, canned in water, drained 1.000
Fish sticks/patty, frozen, oven cooked 0.527
Fish sandwich on bun, fast-food 0.380
Salmon, steaks/fillets, baked 0.288
Shrimp, boiled 0.265
Tuna noodle casserole, homemade 0.164
Raisin bran cereal 0.135
Clam chowder, New England, canned, 0.128
prepared with whole milk
Mushrooms, raw 0.073
Rice, white, enriched, cooked 0.065
Source: FDA (2010).
as arsenosugars, may be subject to biotransformation
to inorganic arsenic methylated species (Molin et al.,
2012a,b). It is not known whether inorganic arsenic or tri-
valent methylated arsenicals may occur as intermediates
and thus pose a health hazard.
5.3  Risk Assessment
There have been a number of risk assessments con-
ducted over the last 20 years by various agencies and
organizations (see EFSA, 2009a; JECFA, 2011d). Most
of these risk assessments were conducted using stud-
ies on health effects related to (inorganic) arsenic expo-
sures via drinking water and via food (EFSA, 2009a;
JECFA, 2011d).
5.3.1  Hazard Characterization
Data from two recent studies (Chen et al., 2010a,b)
on urinary tract cancer and lung cancer in the same
prospective cohort from northeastern Taiwan, with
average 11.5 years of follow-up, were modeled. These
studies used arsenic in drinking water as the exposure
parameter. Assumptions were made for the volume of
drinking water consumed, the use of water in cooking,
and the level of inorganic arsenic in food. The latter
source had less impact. The lowest BMDL obtained,
based on dietary arsenic exposure, was from the lung
cancer study of Chen and coworkers (Chen et al.,
2010a). The modeling gave ranges for the BMDL0.5
of cancer over background of 4.5-7.3 μg/kg b.w./day
and ranges of BMDL0.5, 95% confidence limit, for the
benchmark dose of 3.0-5.0 μg/kg b.w./day. The lowest
BMDL0.5 of 3.0 μg/kg b.w./day was selected as the ref-
erence point for risk assessment. A sensitivity analysis
showed that this BMDL0.5 could be in the range of 2.0-
7.0 μg/kg b.w./day.
Further uncertainties noted by JECFA in the stud-
ies were a general uncertainty about arsenic in food
commodities and uncertainty in extrapolating to other
populations because of the possible influence of nutri-
tional status, e.g. low protein intake, low folate intake,
low selenium status, and other lifestyle factors that
might have an impact on the effects observed in the
studied population.
Based on the assessment described above, JECFA
(2011d) noted that the old PTWI of 15 μg/kg b.w. was
in the region of the BMDL0.5 and therefore inappropri-
ate. The old PTWI was withdrawn.
5.3.2  Risk Characterization
Because the hazard assessment is related to inor-
ganic arsenic, the risk would be related to dietary expo-
sures, including drinking water, to inorganic arsenic
 6  Toxic Metals in Food 137

species. Because of analytical constraints, there is a
general lack of data on inorganic arsenic in foods. The
proportion of inorganic arsenic in some foods appears
to vary widely. In the estimated exposures made by
JECFA (2011d), information on total arsenic content
of food commodities were used instead of preferable
measurements of inorganic arsenic.
Reported mean dietary exposure to inorganic arsenic
in the USA and various European and Asian countries
ranged from 0.1 to 3.0 μg/kg b.w./day. Hence, the margin
of exposure (MOE) is small because it ranges from 1 to 30.
JECFA (2011d) noted that in regions of the world
where concentrations of inorganic arsenic in drink-
ing water exceed 50-100 μg/L, epidemiological studies
may show evidence of adverse effects. In areas where
arsenic concentrations in water are above the WHO
guideline value of 10 μg/L, but are less than 50 μg/L,
increased incidences of adverse effects as a result of
exposure to inorganic arsenic would be difficult to
detect in epidemiological studies.
5.4  Risk Management
Risk management issues for arsenic are similar to
those outlined above for cadmium and mercury since
arsenic may also contaminate staple foods, such as rice,
which are of major dietary importance in developing
countries in particular (CODEX STAN 193-1995; EC,
2006). A recent paper by Spanu et al. (2012) reported
that arsenic uptake in rice could be greatly reduced
by the use of sprinkler irrigation systems versus con-
tinuous flooding of rice paddies and growing rice
plants under the anaerobic conditions found in pad-
dies. These authors reported that rice grown using
the sprinkler irrigation approach had 50 times lower
arsenic content than rice grown using historical irri-
gation techniques. These findings suggest a practical
approach for managing arsenic accumulation in rice
and hence risks of human exposures to this element
via this important food staple.
6  HEALTH-BASED GUIDANCE VALUES
AND BENCHMARK DOSE (LOWER
CONFIDENCE LIMIT) FOR CADMIUM,
MERCURY, LEAD, AND ARSENIC
On the basis of the types of scientific information
presented above, JECFA and EFSA have developed
international HBGVs (or used BMDLs as reference
points when a MOE approach was taken in the risk
assessments) for arsenic, cadmium, lead, and mer-
cury in foods. This information is presented below in
Table 5.

TABLE 5  Health-Based Guidance Value or Benchmark Dose (Lower Confidence Level)a

JECFA EFSA

Metal HBGV Effect Year HBGV Effect Year

Arsenic BMDL0.5: 3 μg/kg 0.5% increase in lung 2009, 2010 BMDL01: 0.3-8 μg/kg 1% increase in risk of lung, 2009b
b.w./day cancer risk b.w./day skin and bladder cancer,
as well as skin lesions
Cadmium PTMI: 25 μg/kg b.w. Kidney toxicity, renal 2009, 2010 TWI: 2.5 μg/kg b.w. Kidney toxicity, renal pro- 2009, 2011
proteinuria teinuria
Lead Previous PTWI Cognitive deficit: IQ, 2010, 2010 Previous PTWI no Cognitive deficit: IQ 2010
withdrawn no threshold identi- longer appropriate.
fied BMDL01: 0.50 μg/kg
b.w./day
BMDL01: 0.63 μg/kg Systolic blood pressure
b.w./day
BMDL10: 1.50 μg/kg Chronic kidney disease
b.w./day
Mercury: PTWI: 4 μg/kg b.w. Kidney toxicity 2010, 2011 TWI: 4 μg/kg b.w. Kidney toxicity 2012b
inorganic
Mercury: PTWI: 1.6 μg/kg b.w. Neurodevelopment 2003, 2006 TWI: 1.3 μg/kg b.w. Neurodevelopment 2012b
­methylmercury

BMDL, benchmark dose (lower confidence level); EFSA, European Food Safety Authority; HBGV, health-based guidance value; IQ,
i­ ntelligence quotient; JECFA, Joint FAO/WHO Expert Committee on Food Additives; PTMI, provisional tolerable monthly intake; PTWI,
provisional tolerable weekly intake; TWI, tolerable weekly intake.
aBMDLs were given when a margin of exposure approach was used in the risk assessment.
bEFSA (2009a).
138 Bruce A. Fowler, Jan Alexander, and Agneta Oskarsson
7  FOOD CONTAMINATION FROM
PACKAGING
7.1 Tin
Leaching of tin into foodstuffs, such as fruits and
fruit juice, from unlacquered or partially lacquered
cans has been reported to result in elevated concentra-
tions of tin in some of these foods. Human exposure to
tributyltin and triphenyltin compounds has also been
reported from a market basket survey in Japan in the
1990s (see ATSDR, 2005 for a discussion).
7.2 Aluminum
Food is the major source of aluminum exposure for
the general population (EFSA, 2008) and it has been
estimated that the average adult in the USA consumes
7-9 mg aluminum from food each day (ATSDR, 2008).
Aluminum may be present in foods by direct addi-
tion to ingredients, such as flour, baking powder, and
anticaking/coloring agents (ATSDR, 2008). Aluminum
may also leach into acidic foodstuffs from aluminum
packaging or cookware (EFSA, 2008).
7.3  Silver Nanoparticles
There is currently an intense interest in silver
nanoparticles due to their growing use as an antimi-
crobial agent in food packaging (Pinto et al., 2012;
Chaudhry et al., 2008), and there are concerns about
data gaps with regard to chemical safety (Wijnhoven
et al., 2009). Subchronic studies via the oral route
of exposure (Kim et al., 2010) and in vitro studies
(Braydich-Stolle et al., 2005; Li et al., 2011) have dem-
onstrated the high relative toxicity of silver nanoma-
terials. Other in vitro studies (Park et al., 2011) have
reported that the cytotoxicity of silver nanoparticles
is size dependent, with smaller particles (20 nm) dem-
onstrating more cytotoxicity than larger particles (80
or 113 nm) or silver ions. A fibroblast cell line showed
greater sensitivity than a macrophage cell line, and
cytotoxic effects were most pronounced for metabolic
and membrane cellular endpoint markers. These data
indicate that the cytotoxic potential of silver nanopar-
ticles is both size and cell-type dependent. Please see
Chapter 4 on metallic nanomaterials in this volume for
a more complete discussion of these issues.
7.4 Nickel
EFSA evaluated oral exposure to nickel from food
in 2005 (EFSA, 2005). Inhaled nickel is an established
human carcinogen, classified as Group 1 by the
International Agency for Research on Cancer (IARC,
1990). Limited data indicate that orally ingested nickel
salts are not carcinogenic. By the oral route in experi-
mental animals, nickel salts can cause toxic effects on
kidneys, spleen, lungs, and the myeloid system. It also
causes increased perinatal mortality in the offspring of
female rats; this occurred at the lowest dose tested of
1.3 mg nickel/kg b.w./day. In humans, oral intake may
aggravate allergic contact dermatitis in individuals
sensitized to nickel. The prevalence of this condition is
estimated to be up to 15% of women, of whom many
are undiagnosed. In sensitized subjects, the lowest oral
dose of nickel reported to aggravate hand eczema was
about 500 μg/day or 8 μg/kg b.w./day.
The origins of nickel in food are releases from
kitchen utensils and food plants that accumulate
nickel from the soil. The average contribution from
kitchen utensils is not known but could contribute
as much as 1 mg/day. Chocolate is known to contain
high concentrations of nickel. Cocoa contains the high-
est amount of nickel (8.2-12 mg/kg), followed by soy-
beans (4.7-5.9 mg/kg), oatmeal (0.33-4.8 mg/kg), and
hazelnuts (0.66-2.3 mg/kg). Less is found in almonds
and legumes (EFSA, 2005). The average dietary intake
in Danes was estimated to be 150 μg per person per
day, but up to 900 μg per person per day was esti-
mated (Flyvholm et al., 1984). In Sweden, studies have
found average intakes of 82-115 μg/day (Becker and
Kumpulainen, 1991; Jorhem et al., 1998). Other esti-
mates have been in the same magnitude, and ranging
up to 406 μg/day (Pennington and Jones, 1987; Dabeka
and McKenzie, 1995). Maximum levels in drinking
water are usually up to 35 μg/L, but may be much
higher in the first tap when left for 8 h or overnight
(EFSA, 2005; WHO 1996).
8 CONCLUSION
It is clear from this brief overview that foodborne
exposures for a number of the major toxic elements
are well documented and represent an ongoing area of
public health concern, particularly in developing coun-
tries. The ongoing use of metals, such as tin and alumi-
num, in food packaging and the incorporation of new
metallic materials, such as antimicrobial nanosilver
particles, into packaging represent new and challeng-
ing areas of research and risk assessment in order to
protect public health. The risks to human health have
not been sufficiently studied to allow us to understand
them fully, and additional research is needed. It should
be noted that the metals discussed here have been con-
sidered on an individual basis, but it is not uncommon
for them to be present in food and other matrices as
 6  Toxic Metals in Food
mixtures, which further challenges public health risk
assessments in this area. The issue of mixtures of met-
als is taken up elsewhere in this volume.
References
Adams, S.V., Newcomb, P.A., Shafer, M.M., et al., 2011. Sci. Total
­Environ. 409, 1632–1637.
Åkesson, A., Julin, B., Wolk, A., 2008. Cancer Res. 68, 6435–6441.
Alissa, E.M., Ferns, G.A., 2011. J. Toxicol. 2011:870125. http://dx.doi.
org/10.1155/2011/870125.
Alloway, B.J., 1995. In: Alloway, Brian J. (Ed.), Heavy Metals in Soils.
Chapman and Hall, London, pp. 122–151. Chapter 6. Cadmium.
Andersson, A., 1992. Trace Elements in Agricultural Soils—Fluxes,
Balances and Background Values. Swedish Environmental Pro-
tection Agency, Report 4077, Solna, Sweden.
Ashe, K., 2012. PLoS One 7 (3), e33305.
ATSDR (Agency for Toxic Substances and Disease Registry), 2012.
Toxicological Profile for Cadmium. Atlanta GA.
ATSDR, 2005. Toxicological Profile for Tin and Tin Compounds.
Atlanta GA, 11–22.
ATSDR, 2007. Toxicological Profile for Lead. Atlanta GA, 1–582.
ATSDR, 2008. Toxicological Profile for Aluminum. Atlanta GA.
ATSDR, 1999. Toxicological Profile for Mercury. Atlanta GA.
Bárány, E., Bergdahl, I.A., Bratteby, L.-E., et al., 2005. Environ. Res.
98, 215–223.
Becker, W., Kumpulainen, J., 1991. Br. J. Nutr. 66, 151–160.
Bendell, L.I., 2010. Toxicol. Lett. 198, 7–12.
Berger Ritchie, J.A., Gerstenberger, S.L., 2013. J. Environ. Sci. Health
B. 48, 530–538.
Bjerregaard, P., Mulvad, G., 2012. Int. J. Circumpolar Health. 71,
18588. http://dx.doi.org/10.3402/ijch.v71i0.18588.
Bourdineaud, J.-P., Laclau, M., Maury-Brachet, R., et al., 2012. Int. J.
Mol. Sci. 13, 7710–7738.
Braydich-Stolle, L., Hussain, S., Schlager, J.J., et al., 2005. Toxicol. Sci.
88, 412–419.
Burger, J., Gochfeld, M., 2007. Environ. Res. 105, 276–284.
Burger, J., Gochfeld, M., Jeitner, C., et al., 2007. Sci. Total Environ.
384, 93–105.
Chamannejadian, A., Sayyad, G., Moezz, I.A., et al., 2013. Iranian
J. Environ. Health Sci. Eng.10:28.
Chaudhry, Q., Aitken, R., Scotter, M., et al., 2008. Food Addit. Con-
tam. Part A Chem. Anal. Control Expo. Risk Assess 25, 241–258.
Chaumont, A., Nickmilder, M., Dumont, X., et al., 2012. Toxicol. Lett.
210, 345–352.
Chen, C., Qian, Y., Chen, Q., et al., 2011. J. Food Sci. 76, 181–188.
Chen, C.L., Chiou, H.Y., Hsu, L.I., et al., 2010a. Environ. Res. 110,
455–462.
Chen, C.L., Chiou, H.Y., Hsu, L.I., et al., 2010b. Canc. Epidem. Bio-
mark. Preven 19, 101–110.
Chojnacka, A., Drewnowska, M., Jarzynska, G., et al., 2012. J. Environ.
Sci. Health A. Tox. Hazard Subst. Environ. Eng. 47, 2094–2100.
Ciesielski, T., Weuve, J., Bellinger, D.C., et al., 2012. Environ. Hlth.
Perspect. 120, 758–763.
CODEX STAN 193-1995, 1995. Codex General Standard For Con-
taminants And Toxins In Food And Feed. http://www.fao.org
/fileadmin/user_upload/livestockgov/documents/1_CXS_193
e.pdf (accessed 06.11.13).
Conklin, S.D., Shockey, N., Kubachka, K., et al., 2012. J. Agric. Food
Chem. 60, 9394–9404.
Copes, R., Clark, N.A., Rideout, K., et al., 2008. Environ. Res. 107,
160–169.
Dabeka, R.W., McKenzie, A.D., 1995. J. AOAC. Intern. 78, 897–909.
139
Datta, B.K., Bhar, M.K., Patra, P.H., et al., 2012. Toxicol. Int. 29, 59–62.
Drewnowska, M., Sapȯr, A., Jarzynska, G., et al., 2012. J. Environ. Sci.
Health A. Tox. Hazard Subst. Environ. Eng. 47, 1577–1591.
EC (European Commission), 2006. Commission Regulation (EC) No
1881/2006 of 19 December 2006 setting maximum levels for cer-
tain contaminant in foodstuffs. Official Journal. L364/5: 20pp.
EFSA (European Food Safety Authority), 2005. Tolerable Upper
­Intake Level of Nickel. EFSA J. 146, 1–21. http://www.efsa.eu.
int/science/nda/nda_opinions/catindex_en.html.
EFSA, 2008. EFSA J. 754, 1–34.
EFSA, 2009a. EFSA J. 7, 1351–1356.
EFSA, 2009b. EFSA J. 980, 1–139.
EFSA, 2010. EFSA J. 8, 1570–1574.
EFSA, 2011a. EFSA J. 9, 1975–1993.
EFSA, 2011b. EFSA J. 9 (2006), 1–28.
EFSA, 2012a. EFSA J. 10 (2831), 1–59.
EFSA, 2012b. EFSA J. 10 (2985), 1–241.
Endo, T., Haraguchi, K., Hotta, Y., et al., 2005. Environ. Sci. Technol.
39, 5703–5708.
Engström, A., Michaëlsson, K., Vahter, M., et al., 2012. Bone 50,
1372–1378.
Eriksson, J., Andersson, A., Andersson, R., 1997. Current Status of
Swedish Arable Soils. In: Swedish with English Summary. ­Swedish
Environmental Protection Agency. Report 4778, Stockholm,
Sweden, p. 59.
Falandysz, J., Gucia, M., Skwarzec, G., et al., 2002. Arch. Environ.
Contam. Toxicol. 42, 145–154.
FDA (U.S. Food and Drug Administration), 2010. Total Diet Study
Statistics on Element Results. Center for Food Safety and Applied
Nutrition College Park, MD.
Flyvholm, M.A., Nielsen, G.D., Andersen, A., 1984. Z. Lebensm. Unt-
ers. Forsch. 179, 427–431.
Fowler, B.A., 2013. Cadmium and aging. In: Weiss, B. (Ed.), Aging
and Vulnerabilities to Environmental Chemicals. Royal Society
of Chemistry, Cambridge, UK, pp. 376–387.
Graber, L.K., Asker, D., Anandaraja, N., et al., 2010. Environ. Hlth.
Perspect. 118, 884–889.
Canada, Health, 2007. Average Dietary Intakes (ug/kg bw/
day) of trace elements for Canadians in different age/
sex groups for a Total Diet Study in 2007. http://www.­hc-
sc.gc.ca/fn-an/surveill/total-diet/intake-apport/chem_age-
sex_chim_2007-eng.php (accessed 20.10.12).
Hedegaard, R.V., Rokkjær, I., Sloth, J.J., 2013. Anal. Bioana.l Chem.
405, 4429–4435.
Hellström, L., Elinder, C.G., Dahlberg, B., et al., 2001. Am. J. Kidney
Dis. 38, 1001–1008.
Holloman, E.L., Newman, M.C., 2012. Sci. Total Environ. 416, 111–120.
Honda, R., Swaddiwudhipong, W., Nishijo, M., et al., 2010. Toxicol.
Lett. 198, 26–32.
Hosseini, S.V., Hosseini, S.M., Monsef Rad, S.F., et al., 2013. Environ.
Monit. Assess. 185 (12), 9995–9999.
IARC (International Agency for Research on Cancer), 1990. IARC
Monograph on Chromium. Nickel and Welding 49 (677).
pp. Lyon.
IOM/NRC (Institute of Medicine and National Research Coun-
cil), 2010. Enhancing Food Safety: The Role of the Food and
Drug Administration. The National Academies Press, Wash-
ington, DC.
Jackson, B.P., Taylor, V.F., Karagas, M.R., et al., 2012a. Environ.
Health Perspect. 120, 623–626.
Jackson, B.P., Taylor, V.F., Punshon, T., et al., 2012b. Pure Appl. Chem.
84, 215–223.
JECFA (Joint FAO/WHO Expert Committee on Food Additives),
2004. Safety Evaluation of Certain Food Additives and Contami-
nants. WHO Food Additives Series 52, 565–623. Methymercury.
140 Bruce A. Fowler, Jan Alexander, and Agneta Oskarsson
JECFA, 2007. Safety Evaluation of Certain Food Additives and Con-
taminants. WHO Food Additives Series, 58. Methylmercury,
pp. 270–310.
JECFA, 2011a. Safety Evaluation of Certain Food Additives and
­Contaminants. WHO, Geneva. WHO Food Additives Series, 64.
Cadmium, pp. 305–380.
JECFA, 2011b. Safety Evaluation of Certain Food Additives and
Contaminants. WHO, Geneva. WHO Food Additives Series, 64.
Lead, pp. 381–497.
JECFA, 2011c. Safety Evaluation of Certain Food Additives and
Contaminants. WHO Food Additives Series, 63. Mercury, pp.
605–684.
JECFA, 2011d. Safety Evaluation of Certain Food Additives and Con-
taminants. WHO, Geneva. WHO Food Additives Series, 63. Ar-
senic, pp. 153–288.
Jenssen, M.T., Brantsaeter, A.L., Haugen, M., et al., 2012. Sci. Total
Environ. 439C, 220–229.
Jeppesen, C., Jørgensen, M.E., Bjerregaard, P., 2012 May 17. Assess-
ment of consumption of marine food in Greenland by a food
frequency questionnaire and biomarkers. Int. J. Circumpolar
Health. 71, 18361. http://dx.doi.org/10.3402/ijch.v71i0.18361.
Jorhem, L., Becker, W., Slorach, S., 1998. J. Food Comp. Anal. 11, 32–46.
Julin, B., Wolk, A., Bergkvist, L., et al., 2012a. Cancer Res. 72,
1459–1466.
Julin, B., Wolk, A., Johansson, J.-E., et al., 2012b. Br. J. Cancer 107 (5),
895–900.
Karimi, R., Fitzgerald, T.P., Fisher, N.S., 2012. Environ. Health Per-
spect. 120 (11), 1512–1519.
Karjalainen, A.K., Hallikainen, A., Hirvonen, T., et al., 2012. Food
Chem. Toxicol. 54, 70–77.
Kidd, K.A., Muir, D.C., Evans, M.S., et al., 2012. Sci. Total Environ.
438, 135–143.
Kim, C.K., Lee, T.W., Lee, K.T., et al., 2012. Chemosphere 89 (11),
1360–1368.
Kim, Y.S., Song, M.Y., Park, J.D., et al., 2010. Part. Fibre Toxicol. 7, 20.
Kirchmann, H., Mattsson, L., Eriksson, J., 2009. Environ. Geochem.
Health 31, 561–571.
Krisnayanti, B.D., Anderson, C.W., Utomo, W.H., et al., 2012. J. Envi-
ron. Monit. 14 (10), 2598–2607.
Kurzius-Spencer, M., O’Rourke, M.K., Hsu, C.H., et al., 2013. J. Expo.
Sci. Environ. Epidemiol. 23, 442–449.
Laird, B.D., Goncharov, A.B., Chan, H.M., 2013. Environ. Int. 59C,
33–40.
Lanphear, B.P., Hornung, R., Khoury, J., et al., 2005. Environ. Hlth.
Perspect. 113, 894–899.
Li, X., Li, S., Zhang, M., et al., 2011. Rare Metal Mat. Eng. 40,
0209–0214.
Lindén, A., Olsson, I.M., Bensryd, I., et al., 2003. Ecotoxicol. Environ.
Saf. 55, 213–222.
Lovreglio, P., D’Errico, M.N., De Pasquale, P., et al., 2012. Med. Lav.
103, 372–381.
McElroy, J.A., Shafer, M.M., Trentham-Dietz, A., et al., 2006. J. Natl.
Cancer Inst. 98, 869–873.
Meltzer, H.M., Brantsaeter, A.L., Borch-Iohnsen, B., et al., 2010. Envi-
ron. Res. 110, 497–504.
Messner, B., Knoflach, M., Seubert, A., et al., 2009. Arterioscler.
Thromb. Vasc. Biol. 29, 1392–1398.
Miklavčič, A., Casetta, A., Snoj Tratnik, J., et al., 2012. 120:7–17.
Minh, N.D., Hough, R.L., Thuy, L.T., et al., 2012. Sci. Total Environ.
416, 164–171.
Molin, M., Ydersbond, T.A., Ulven, S.M., et al., 2012a. Food Chem.
Toxicol. 50, 2462–2472.
Molin, M., Ulven, S.M., Dahl, L., et al., 2012b. Environ. Res. 112, 28–39.
Nabulo, G., Black, C.R., Craigon, J., et al., 2012. Environ. Pollut. 162,
389–398.
Nachmann, K.E., Baron, P.A., Raber, G., et al., 2013. Environ. Hlth.
Perspect. 121, 818–824.
Okati, N., Sari, A.E., Ghasempouri, S.M., 2012. Biol. Trace Elem. Res.
149, 155–162.
Olsson, I.M., Bensryd, I., Lundh, T., et al., 2002. Environ. Hlth. Per-
spect. 110, 1185–1190.
Olsson, I.M., Eriksson, J., Öborn, I., et al., 2005. Ambio 34, 344–351.
Orün, E., Yalçin, S.S., Aykut, O., Orhan, G., Koç-Mor-
gil, G., Yurdakök, K., Uzun, R., 2012 Mar-Apr. Turk.
J. Pediatr. 54 (2), 136–143.
Osada, M., Izuno, T., Kobayashi, M., 2011. Environ. Health Prev.
Med. 16, 341–349.
Oskarsson, A., Schutz, A., Skerfving, S., et al., 1996. Arch. Environ.
Health 51, 234–241.
Park, M.V., Neigh, A.M., Vermeulen, J.P., et al., 2011. Biomaterials
32, 9810–9817.
Park, S., Lee, B.K., 2012. Arch. Environ. Contam. Toxicol. 64 (1),
160–170.
Pennington, J.A.T., Jones, J.W., 1987. J. American. Dietetic Assoc. 87,
1644–1650.
Petersson Grawé, K., Teiling-Gårdlund, A., Jalkesten, E., et al., 2004.
Toxicol. Pharmacol. 17, 35–43.
Phan, K., Sthiannopkao, S., Heng, S., et al., 2012. J. Hazard Mater. http://
dx.doi.org/10.1016/j.jhazmat.2012.07.005 (accessed 06.11.13).
Pinto, R.J., Fernandes, S.C., Freire, C.S., et al., 2012. Carbohydr. Res.
348, 77–83.
Rahman, M.M., Asaduzzaman, M., Naidu, R., 2012. J. Hazard Mater.
[Epub June 30].
Rahman, M.A., Hasegawa, H., 2011. Sci. Total Environ. 409, 4645–
4655.
Ruiz, P., Mumtaz, M., Osterloh, J., et al., 2010. Toxicol. Lett. 198,
44–48.
Scinicariello, F., Yesupriya, A., Chang, M.-H., et al., 2010. Environ.
Health Perspec. 118, 259–264.
Smith, N.M., Lee, R., Heitkemper, D.T., et al., 2006. Sci. Total Environ.
370, 294–301.
Some, I.T., Sakira, A.K., Ouedraogo, M., et al., 2012. Interdiscip. Toxi-
col. 5, 38–41.
Spanu, A., Daga, L., Orlandoni, A.M., et al., 2012. Environ. Sci. Tech-
nol. 46, 8333–8340.
Strömberg, U., Lundh, T., Skerfving, S., 2008. Environ. Res. 107,
332–335.
Subotić, S., Višnjić Jeftić, Z., Spasić, S., et al., 2013. Environ. Sci. Pol-
lut. Res. Int. 20 (8), 5309–5317.
Tripathi, R.D., Tripathi, P., Dwivedi, S., et al., 2012. Front. Physiol.
3, 275–288.
Tsuchiya, A., Duff, R., Stern,.AH., et al., 2012. Environ. Health 11, 37.
Watanabe, N., Tayama, M., Inouye, M., et al., 2012. J. Toxicol. Sci. 37,
853–861.
WHO (World Health Organisation), 1996. Guidelines for drinking
water quality. Health criteria and other supporting information,
vol. 2, Geneva.
Wijnhoven, S.W., Peijnenburg, W.J., Herberts, C.A., et al., 2009.
Nanotoxicology 3, 109–138.
Wilson, D., Hooper, R.C., Shi, X., 2012. J. Environ. Health 75, 14–20.
Wong, W.W., Chung, S.W., Chan, B.T., et al., 2013. Food Chem. Toxi-
col. 51, 379–385.
You, C.H., Kim, B.G., Jo, E.M., et al., 2012. Neurotoxicology 33,
676–682.