Environmental Pollution 249 (2019) 1038e1048

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Environmental Pollution
journal homepage: www.elsevier.com/locate/envpol

Cadmium contamination in agricultural soils of China and the impact

on food safety*
Peng Wang a, *, Hongping Chen a, Peter M. Kopittke b, Fang-Jie Zhao a
a
State Key Laboratory of Crop Genetics and Germplasm Enhancement, College of Resources and Environmental Sciences, Nanjing Agricultural University,
Nanjing, 210095, China
b
School of Agriculture and Food Sciences, The University of Queensland, St Lucia, Queensland, 4072, Australia

a r t i c l e i n f o a b s t r a c t

Article history: Rapid industrialization in China during the last three decades has resulted in widespread contamination
Received 15 February 2019 of Cd in agricultural soils. A considerable proportion of the rice grain grown in some areas of southern
Received in revised form China has Cd concentrations exceeding the Chinese food limit, raising widespread concern regarding
15 March 2019
food safety. In this review, we summarize rice grain Cd concentrations in national Chinese markets and in
Accepted 16 March 2019
Available online 19 March 2019
field surveys from contaminated areas, and analyze the potential health risk associated with increased
dietary Cd intake. For subsistence rice farmers living in some contaminated areas of southern China who
mainly consume locally-produced Cd-contaminated rice, their estimated dietary Cd intake is now
Keywords:
Cadmium
comparable to that for the population in the region of Japan where the Itai-Itai disease was first reported.
Food safety Interventions must be taken urgently to reduce Cd intake for these farmers. We also analyze i) the main
Intervention reasons causing elevated grain Cd concentrations in southern China, ii) the dominant biogeochemical
Mitigation strategies processes controlling the solubility of Cd in paddy soils, and iii) molecular mechanisms for the uptake
Soil contamination and translocation of Cd in rice plants. Based on these analyses, we propose a number of countermeasures
to address soil Cd contamination, including i) mitigation of Cd transfer from paddy soils to rice grain, and
ii) intervention in those farmers who consume home-grown Cd-contaminated rice. Liming to increase
soil pH to 6.5 and gene editing biotechnology are effective strategies to decrease Cd accumulation in rice
grain. For these local farmers with high-Cd exposure risk, local governments should monitor the Cd
concentration in their home-grown rice and exchange those high-Cd rice with low-Cd rice in order to
reduce their dietary Cd intake.
© 2019 Elsevier Ltd. All rights reserved.

1. Introduction
Cadmium (Cd) is classified as a Group 1 human carcinogen
(IARC, 2018) and is easily transferred from soil to the food chain
(Chaney, 1980; Clemens et al., 2013). Compared with most other
toxic elements, Cd readily accumulates in edible portions of plants
to levels which are harmful in diets without adversely affecting
plant growth. The long-term dietary intake of Cd at elevated levels
can lead to serious health problems (EFSA, 2012; Jin et al., 2004;
Nordberg et al., 2002; Nordberg et al., 2007; Zhang et al., 2014).
Among the various human diets, grains of rice (Oryza sativa) are the
largest contributor to dietary Cd intake for the general non-
*
This paper has been recommended for acceptance by Prof. Wen-Xiong Wang.
* Corresponding author.
E-mail address: p.wang3@njau.edu.cn (P. Wang).
smoking population (Clemens et al., 2013; Song et al., 2017), lead-
ing to a higher dietary Cd intake for population with subsistence
rice diets (typically in Asian countries) compared to those in the
USA and European countries (Wang et al., 2017). As the staple food
feeding approximately half of the global population, rice has rela-
tively low levels of bioavailable Zn and Fe, which may give rise to
higher absorptive efficiency of Cd in the human body compared to
other foods (Chaney, 2015). Therefore, contamination of paddy soils
with Cd, and the subsequent production of Cd-contaminated rice
grain present a widespread risk to the food chain globally.
In China, rapid industrialization over the last 30 years, together
with inadequate environmental protection, has led to serious issues
due to the contamination of soil with heavy metals and metalloids
(MEE and MNR, 2014). As a result, market basket and field surveys
have found that a considerable proportion of rice grain now has
Cd concentrations exceeding the Chinese food limit
(0.2 mg kg
1)(MHPRC, 2012), especially in some areas of southern

https://doi.org/10.1016/j.envpol.2019.03.063
0269-7491/© 2019 Elsevier Ltd. All rights reserved.
 P. Wang et al. / Environmental Pollution 249 (2019) 1038e1048 1039

China (Chen et al., 2018a; Du et al., 2013; Williams et al., 2009; Zhu
et al., 2016). These surveys have raised widespread concern
regarding food safety and the associated health risk. In this review,
we summarize the i) current status of Cd contamination in rice
grain based upon market and field surveys, and ii) potential health
risk resulting from this elevated dietary Cd intake. In addition, we
analyze the i) reasons responsible for elevated grain Cd concen-
trations in some areas of southern China, ii) factors that are
important in paddy soils for controlling Cd biogeochemistry and
solubility, and iii) molecular mechanisms by which Cd is taken up
and subsequently translocated in rice plants. Finally, we propose
countermeasures to tackle soil Cd contamination, including i)
strategies to mitigate Cd transfer from soil to the food chain, and ii)
intervention measures, especially for those local farmers who
consume locally-produced Cd-contaminated rice and are particu-
larly prone to Cd-induced diseases.
2. China enacts new standards for soil contamination
Soil Environmental Quality e Risk Control Standards for Soil
Contamination of Agricultural Land (GB 15618e2018) and Devel-
opment Land (GB 3660e2018), effective from August 1, 2018. The
new standards introduce screening and intervention values for soil
contamination, with the aim of ensuring safer agricultural products
and a healthier environment. According to the new standard for
agricultural soils (Table 1) (MEE, 2018), if the concentration of the
soil contaminant is less than the risk screening value, the risk is
generally considered to be negligible. If the concentration of the soil
contaminant is between the risk screening value and the inter-
vention value, detailed monitoring and risk evaluation are required.
In such situations, some actions are required to ensure food safety,
including the use of agronomic measures and alternative crops.
However, if the concentration of the soil contaminant exceeds the
intervention value and the concentration of the contaminant in the
agricultural products exceeds the food limit, more stringent mea-
surements must be taken, with the soil being removed from the
production of edible crops or being converted for forestry.

According to the latest nationwide survey on the status of soil
contamination in China (MEE and MNR, 2014), the overall status of
the country's soil environment was suboptimal, with contamina-
tion being particularly severe in central and southwest China. An
estimated 19.4% of the surveyed agricultural soil samples exceeded
the limits based upon the previous environmental quality stan-
dards set by the Ministry of Ecology and Environment (MEE) in
1995 (GB 15618e1995). Of all contaminated samples, heavy metals
and metalloids accounted for the majority of contaminants (82.4%),
with the remaining (17.6%) being organic contaminants. Among the
heavy metals and metalloids, Cd ranked the highest (7%), followed
by nickel (4.8%), arsenic (2.7%), copper (2.1%), mercury (1.6%), lead
(1.1%), and chromium (0.9%).
In order to address the issues associated with soil contamina-
tion, China's State Council issued the Action Plan on Soil Pollution
and Control (‘Soil Action Plan’) in 2016. The Action Plan sets up a
policy framework for all levels of government authorities to reduce
contamination and remediate existing contaminated sites. The
overall target is to make 95% of the contaminated agricultural soils
safe for use by the year 2030 (SCC, 2016). Under this background,
the National People's Congress enacted the Soil Pollution Preven-
tion and Control Law, which took effect on January 1, 2019. In
addition, as part of a national campaign to address soil contami-
nation, the MEE abolished the previous Soil Environmental Quality
Standard (i.e. GB 15618e1995) and issued two new standards of
3. Elevated grain Cd concentrations in Chinese diets and the
potential health risk
Given that Cd is readily taken up by plants, the contamination of
soil with Cd can lead to an increase in the Cd concentration in plant-
derived foodstuffs (McLaughlin and Singh, 1999; Smolders and
Mertens, 2013). For the general non-smoking population, dietary
Cd intake contributes approximately 90% of the total Cd exposure
(Clemens et al., 2013). Among the various diets worldwide, rice is
the largest contributor to dietary Cd intake, although the magni-
tude of its contribution depends upon the country. For example,
rice grain accounts for less than 27% of the total dietary Cd intake
for the general population in Europe (EFSA, 2012), ca. 44% in Japan
(Watanabe et al., 2000), and 56% in China (Song et al., 2017). The
reason that rice contributes such a large proportion of the total
dietary intake is because rice grain: i) forms a large proportion of
the diet (especially in Asian countries) and ii) has a comparatively
high Cd concentration compared to other cereal foods (Song et al.,
2017).
In China, several market basket surveys (Table 2) have shown
mean Cd concentrations of 0.05e0.12 mg kg
1 in rice samples
across the country, with 2.2e10% of the surveyed rice samples
exceeding the maximum permissible level of Cd in rice
(0.2 mg kg
1) established by the Chinese Ministry of Health
(MHPRC, 2012). However, for field-surveyed rice samples from

Table 1
New risk control standard of Chinese soil environmental quality for agricultural land (GB15618-2018, effective on August 1st, 2018) in which risk screening and intervention
values are defined for heavy metals and metalloids on the basis of their total concentration in soil.

Metal(loid)s Risk screening values (mg kg
1) Risk intervention values (mg kg
1)

pH  5.5 5.5 < pH  6.5 6.5<pH7.5 pH>7.5 pH  5.5 5.5 < pH  6.5 6.5<pH7.5 pH>7.5
b
Cd Paddy 0.3 0.4 0.6 0.8 1.5 2.0 3.0 4.0
Other a 0.3 0.3 0.3 0.6
Hg Paddy 0.5 0.5 0.6 1.0 2.0 2.5 4.0 6.0
Other 1.3 1.8 2.4 3.4
As Paddy 30 30 25 20 200 150 120 100
Other 40 40 30 25
Pb Paddy 80 100 140 240 400 500 700 1000
Other 70 90 120 170
Cr Paddy 250 250 300 350 800 985 1000 1300
Other 150 150 200 250
Cu Paddy 150 150 200 200 e e e e
Other 50 50 100 100
Ni 60 70 100 190 e e e e
Zn 200 200 250 300 e e e e
a
Other includes upland, orchard, and meadow. For paddy-upland rotation fields, more stringent values are applied.
b
The intervention values applied to all soil types.
1040 P. Wang et al. / Environmental Pollution 249 (2019) 1038e1048

Table 2
Rice grain Cd concentrations (mg kg
1), the proportion of samples exceeding the allowable limit (%),the estimated dietary Cd intake for an adult of 60 kg body weight, and the
estimated time prior to the onset of a mild Cd disease (Itai-Itai) through the consumption of rice alone.

Rice Region Range Mean Median n Exceeding Dietary Cd intake (mg Estimated time to the onset
(mg (mg (mg kg
1) the limit (%) kg
1 BW month
1) b of Itai-Itai disease (y) e
kg
1) kg
1) a

Market survey (polished) (Song Nationwide market e 0.06 e 19,786 e 3.6e9.6 >100
et al., 2017)
Market survey (polished) (Qian Nationwide market e 0.05 e 712 2.2 2.9e7.7 >100
et al., 2010)
Market survey (polished) (Zeng Nationwide market 0.003 0.12 e 91 10 7.0e18.7 >100
et al., 2008) e1.24
Market survey (polished) (Chen Nationwide market 0.002 0.09 0.05 160 10 5.4e14.4 >100
et al., 2018b) e0.77
c
Field survey (unpolished) (Zhu Changsha, Zhuzhou, and 0.005 0.43 0.34 39,642 76 46.7 76
et al., 2016) Xiangtan cites, Hunan e4.80
province
c
Field survey (unpolished) Xiangtan county, Hunan 0.02 0.69 0.54 200 87 74.9 47
(Chen et al., 2018a) province e1.28
c
Field survey (unpolished) (Du Yiyang county, Hunan 0.01 0.46 e 146 56 50.0 71
et al., 2013) province e2.77
c
Field survey (unpolished) Youxian county, Hunan 0.05 0.57 53 74 61.9 57
(Wang et al., 2016) province e1.83
Field and market survey Mine impacted areas in Hunan 0.002 0.33 e 222 80 51.2 69
(polished) (Williams et al., province e3.71
2009)
d
Field survey (Nogawa et al., Jinzu River basin of Japan (Itai- 0.02 0.38 e 2446 e 58.9 60
2017) Itai disease reported) e0.95
a
Based on the maximum permissible limit of Cd in rice established by Chinese National Health Commission (MHPRC, 2012).
b
The dietary Cd intake is calculated for an adult of 60 kg body weight based on the mean Cd concentrations and the rice consumption rates of 116 g per day and 310 g per
day, with the rates reflecting the typical amounts of northern and southern populations in China.
c
The calculation is based on the polished rice, with an assumption that milling can on average decrease Cd concentration of unpolished rice by 30% (Meharg et al., 2013).
d
The dietary Cd intake is based on the mean Cd concentration in rice and a daily rice consumption of 310 g.
e
The time required to a cumulative accumulation of 2.6 g in a human body, the dose which can cause a mild disease onset of 5% the Itai-Itai disease patients (Inaba et al.,
2005).

some contaminated areas of southern China, mean grain Cd con-

centrations range from 0.33 to 0.69 mg kg
1, with ca. 56e87% of the
surveyed samples exceeding the Chinese food limit (Table 2).
Furthermore, grain Cd concentrations in these contaminated areas
are comparable or even higher than those in the Jinzu River basin of
Japan where the Itai-Itai disease (the most severe stage of chronic
Cd poisoning in humans) was reported (i.e. a mean of 0.38 mg kg
1
of 2446 surveyed rice samples, Table 2), demonstrating the seri-
ousness of the current situation in China. For comparison, a recent
study in Japan showed that the lower limits of the benchmark dose
of the Cd concentrations in rice for Itai-Itai disease or suspected
disease were 0.27e0.56 mg kg
1 for women and
0.62e0.76 mg kg
1 for men (Nogawa et al., 2017).
Dietary Cd intake for the general population of China has
doubled from 6.9 to 15.3 mg kg
1 BW month
1 over the last 25 years
(from 1990 to 2015) (Song et al., 2017; Wang et al., 2017). The
current dietary Cd intake (i.e. 15.3 mg kg
1 BW month
1) exceeds
the Provisional Tolerable Monthly Intake (PTMI) values recom-
mended by the Agency for Toxic Substances and Disease Registry of
the USA (3 mg kg
1 BW month
1) (ATSDR, 2008) and the European Fig. 1. Boxplots of dietary Cd intake for adults of the general population in China and in
some Cd-contaminated areas, with solid lines showing the average Cd intake (data
Food Safety Authority (10.8 mg kg
1 BW month
1) (EFSA, 2012), and
based on Table 2). For comparison, the dietary Cd intake for the population of the Jinzu
is equivalent to 61.2% of the PTMI of the Joint FAO/WHO Expert River basin (Japan) where the Itai-Itai disease was first reported is also presented. The
Committee on Food Additives (25 mg kg
1 BW month
1) (JECFA, dietary Cd intake is calculated for an adult of 60 kg body weight based on rice grain Cd
2011) (Fig. 1). If the increase in dietary intake of Cd continues, it concentrations and rice consumption rates. The daily rice consumption was 310 g and
116 g for typical southern and northern populations in China. International thresholds
is expected to exceed the PTMI of the JECFA in the next 30e35
for Cd intake are also presented, including ATSDR (3.0 mg kg
1 BW month
1), EFSA
years. Clearly, the situation is alarming. (10.7 mg kg
1 BW month
1), and JEFCA (25 mg kg
1 BW month
1).
It is important to note that there is a significant variation in
dietary Cd intake between southern and northern populations in
China. Specially, rice contributes 65% of the total dietary Cd intake primarily a reflection of the difference in daily rice consumption
for the southern population and only 38% for the northern popu- between southern (typically 310 g per day) and northern (116 g per
lation (Song et al., 2017). In a contaminated county of Hunan day) populations (NHC, 2002). Based on the mean Cd concentra-
province, China, rice contributes up to 81% of the total dietary tions in rice grain (Table 2) and rice consumption rates, for an adult
intake for subsistence rice farmers (Chen et al., 2018b). This is of 60 kg body weight, the dietary Cd intake for the general Chinese
 P. Wang et al. / Environmental Pollution 249 (2019) 1038e1048
population from rice alone varies from 2.9 to 7.0 mg kg
1 BW
month
1 (116 g rice per day, northern) to 7.7e18.7 mg kg
1 BW
month
1 (316 g rice per day, southern) - (Table 2 and Fig. 1).
However, for the subsistence rice farmers living in the contami-
nated areas of southern China (assuming a typical rice consumption
rate of 310 g per day), rice contributes a Cd intake of
46.7e74.9 mg kg
1 BW month
1, which are 1.9e3.0 times higher
than the PTMI of the JECFA (Table 2 and Fig. 1). It should be noted
that the estimated dietary Cd intake for subsistence rice farmers in
some contaminated regions is comparable or even higher than the
calculated Cd intake for the population in the region of Japan where
the Itai-Itai disease occurred (Table 2 and Fig. 1). Among different
sub-groups, children (4e11 years) have a Cd exposure 43e46%
higher than adults (Chen et al., 2018a; Song et al., 2017) because
children consume more food per unit of body weight.
Cadmium has a long biological half-life (10e30 years) in the
human body and consequently the Cd concentration in the body
generally increases with age, with the kidney and liver being the
two main accumulating organs (JECFA, 2011). Long-term con-
sumption of Cd-contaminated rice can cause serious health prob-
lems including irreversible renal damage (resulting in chronic
kidney disease), low bone density, osteoporosis, bone demineral-
ization, and increased risk of cancers in the lung, endometrium,
bladder, and breast (EFSA, 2012; Jin et al., 2004; Nordberg et al.,
2002; Nordberg et al., 2007; Zhang et al., 2014). The extreme case
of chronic Cd poisoning in humans is Itai-Itai disease (a bone dis-
ease causing fractures and severe pain) which was first discovered
in the 1950s along Jinzu River basin in Japan. In this region, long-
term consumption of local Cd-contaminated rice and other agri-
cultural products led to the occurrence of Itai-Itai disease. At the
time when mild disease onset was recognized in 5% of Itai-Itai
disease patients, the cumulative lifetime Cd intake was estimated at
2.6 g, and with severe disease onset being estimated at 3.3 g Cd
(Inaba et al., 2005). At the current rate of dietary Cd intake in China,
on average it would take >100 years for the general population to
reach a cumulative Cd intake of 2.6 g, but only 47e76 years for
Fig. 2. Reasons responsible for elevated grain Cd concentration in China.
1041
subsistence rice farmers in contaminated areas to reach this level.
This compares to 60 years for the population in the Jinzu basin of
Japan based on the reported grain Cd concentration (Table 2). This
is a conservative estimation as it does not consider the dietary Cd
intake from vegetables and other foods (Table 2).
4. Reasons for elevated grain Cd concentrations
There are various reasons for the elevated grain Cd concentra-
tions found in some regions of southern China (Fig. 2). First, ac-
cording to the latest national survey of soil contamination (MEE
and MNR, 2014), since the early 1980s, China's soil Cd concentra-
tions have increased by an average of 10e40% in the northern,
northeast, and western China, and by over 50% in the coastal region
and in southern China. This is particularly severe in Hunan prov-
ince, southern China, where average soil Cd concentrations
increased to 0.5e0.6 mg kg
1, being 6e8 times higher than the
background concentration of 0.08 mg kg
1 determined from the
1980s survey (CNEMC, 1990). This increase in soil Cd is due to local
mining and smelting activities and irrigation of paddy soils with
contaminated water. In some regions of southern China which
typically have double-rice cropping systems, irrigation could add
1e400 g Cd ha
1 yr
1 to the soil, whilst atmospheric deposition
(0.4e25 g Cd ha
1 yr
1) and applications of organic manures
(0e10 g Cd ha
1 yr
1) and phosphate fertilizers (0.04e2 g Cd ha
1
yr
1) could also add Cd to the soil (Zhao et al., 2015). By compari-
son, removal of Cd by uptake of double rice crops is estimated to
range from 5 to 55 g Cd ha
1 yr
1 (Zhao et al., 2015).
Soil acidification is the second reason for the increasing grain
concentrations of Cd. It has been estimated that approximately
80e90% of the total area of the paddy fields are within the red soil
region in China (Yu et al., 2016b). The soils of the red soil region are
naturally acidic, but anthropogenic acidification is also occurring
due to the excessive use of nitrogen fertilizers and intensification of
agricultural production. The average pH of Chinese agricultural
soils has decreased by 0.13e0.80 units since the 1980s (Guo et al.,
1042 P. Wang et al. / Environmental Pollution 249 (2019) 1038e1048
2010). In double-rice cropping areas (typically in southern China),
excessive nitrogen fertilizer applications have accelerated soil
acidification, with a reduction of soil pH by almost one unit in the
past 30 years (Zhu et al., 2016). This soil acidification can markedly
increase Cd solubility in soil; a decrease in soil pH by one unit can
increase Cd solubility by 4e5 fold (Wang et al., 2019a). When soil
pH is higher than 6.5, the solubility of Cd is generally less than
0.05% of the total soil Cd.
The third reason for increasing grain concentrations of Cd is that
rice cultivars differ substantially in their ability to accumulate Cd in
the grain (Duan et al., 2017; Sun et al., 2016). There is genotypic
diversity among rice cultivars, which is the underlying reason
causing large variations in grain Cd among various cultivars. Spe-
cifically, the rice cultivars widely grown in southern China belong to
the Indica subspecies, which in general tend to accumulate more Cd
in the grain than Japonica cultivars (Sun et al., 2016; Yang et al.,
2018).
Another important factor influencing grain Cd concentration is
the redox status of the soil, with the paddy water regime having a
remarkable impact on rice grain Cd (Arao et al., 2009; Honma et al.,
2016; Inahara et al., 2007). Paddy fields are characterized by
episodic flooding and drainage processes, and are drained prior to
harvest because continuous flooding can reduce grain yield (Hu
et al., 2013) and also is inconvenient for machine harvesting. The
pre-harvest drainage, typically two-three weeks before plant
maturity, coincides with grain filling stage. This drainage can also
result in a marked increase in the mobilization of soil Cd and
consequently elevated grain Cd concentrations. Keeping paddy
fields flooded as long as possible, especially during the grain filling
stage, has been proposed as an effective strategy to decrease grain
Cd (Zhu et al., 2016; Hu et al., 2013). For example, in a field
experiment, grain Cd concentrations decreased from 0.40 mg kg
1
in a soil drained after heading to 0.08 mg kg
1 in a continuously
flooded soil (Inahara et al., 2007). However, it should be noted that
this strategy often increases grain As concentration (Arao et al.,
2009; Honma et al., 2016; Xu et al., 2008). So far, few strategies
have been proposed to be able to simultaneously mitigate accu-
mulation of Cd and As in rice grain, including combined applica-
tions of woody peat and Fe(NO3)3 (Wang et al., 2019b) or zero-
valent iron and biochar (Qiao et al., 2018). Mn oxides may pro-
vide another ‘silver bullet’ in this regard given that i) addition of Mn
oxides can reduce grain As through enhancing anaerobic oxidation
of As(III) to As(V) in paddy soils (Xu et al., 2017) and ii) Mn2þ can
compete for Cd2þ uptake in rice roots by OsNramp5 transporter
(see later).
5. Paddy Cd biogeochemistry for reducing Cd solubility in the
soil
Periodic changes in redox status have a substantial impact upon
the solubility and speciation of Cd in paddy soils. During soil
flooding, the solubility of Cd decreases rapidly, with concentrations
of soluble Cd typically being less than 0.1 mg L
1 (Smolders and
Mertens, 2013). Some studies, therefore, have used prolonged
flooding to immobilize soil Cd and decrease grain Cd (Arao et al.,
2009; Bingham et al., 1976; Hu et al., 2013). The decrease in Cd
solubility upon flooding has been attributed to the formation of Cd
sulfides (Cornu et al., 2007; Fulda et al., 2013; Furuya et al., 2016;
Hashimoto and Yamaguchi, 2013; Huang et al., 2013), although
direct evidence is still lacking in field-contaminated soils. Pure Cd
sulfide is generally not expected to form in flooded soils given that
Cd concentrations are typically at least two orders of magnitude
lower than those of Zn and Fe (Barrett and McBride, 2007; Smolders
and Mertens, 2013). Instead, Cd is more likely to be co-precipitated
with Zn and Fe sulfides during soil flooding. Once soils are drained,
there is substantial variation in Cd release among soils (Wang et al.,
2019a). Whether the extent of Cd sulfide formation during the
reducing (flooded) phase can influence Cd mobilization in the
subsequent oxidation (drained) phase remains unclear. Interest-
ingly, it has been reported that synthetic pure CdS can be oxidized
more rapidly than co-precipitated (Cd, Zn) sulfides in pure-mineral
systems (Barrett and McBride, 2007; de Livera et al., 2011). This
could have important implications for Cd mobilization in paddy
soils once drained, because there are large variations in the Zn/Cd
ratio among paddy soils.
Soil pH also plays an important role in influencing Cd solubility
in soils, with pH generally being the primary factor controlling Cd
concentrations in the soil solution (Smolders and Mertens, 2013; Yu
et al., 2016a). An increase in soil pH can decrease Cd solubility by
increasing the density of adsorptive sites on the surface of soil
minerals and organic matter (Smolders and Mertens, 2013).
Coupled with soil pH, iron oxides and ‘secondary’ pedogenic iron
minerals that form in flooded soils including Fe(III) (hydro)oxides,
have been suggested to play an important role in immobilizing
metals (Yu et al., 2016b). When soils are flooded, Fe(III) minerals are
reduced and solubilized, releasing substantial Fe(II) into the soil
porewater. This Fe(II) can be re-oxidized to Fe(III) to form ‘sec-
ondary’ Fe (hydro)oxides (Yu et al., 2016b). The newly-formed
Fe(III) (hydro)oxides can remove metal ions from the solution
phase through stabilization and adsorption. There is some evidence
for this mechanism from studies with anions (e.g. AsO3
3

4 , AsO3 ,
2

and CrO4 ) in simplified model systems containing only mineral
phases (Kappler and Straub, 2005) and for Cd2þ in groundwater
systems with bacteriogenic iron oxides (Martinez et al., 2004). Few
studies, however, have investigated the implications of ‘secondary’
Fe (hydro)oxides in field-contaminated soils. For example, using six
paddy soils, Huang et al. (2013) found that an increase in the Cd
bound to Fe oxides resulted in a decrease in the exchangeable
fraction upon flooding of paddy soils. Similarly, Buanuam et al.
(2005) examined the spatial distribution of Cd, finding that the
Cd was co-located with Fe in 79 contaminated soils, with most Cd
sorbed to iron oxides. Therefore, whether the newly-formed ‘sec-
ondary’ iron (hydro)oxides in flooded paddy soils can influence Cd
solubility remains to be elucidated. Our recent studies with 12
field-contaminated paddy soils have demonstrated that iron oxides
play a critical role in controlling Cd solubility during the flooding
and drainage processes through a pH-dependent adsorption and
desorption mechanism (Wang et al., 2019a). The concomitant
decrease in pH in acidic paddy soils once drained is the key factor
resulting in the elevated Cd solubility. This explains why agronomic
practices that are able to increase soil pH, such as liming, are
amongst the most effective strategies for reducing concentrations
of Cd in rice grain (Chen et al., 2018c; Zhu et al., 2016). Indeed, in
our field trials, a one-time application of lime (CaCO3) is highly
effective in reducing grain Cd for at least three years (Fig. 3).
Application of 7.5 t ha
1 CaCO3 with a target soil pH 6.5 can
decrease grain Cd concentrations by 70e80%, to levels below the
Chinese food limit (0.2 mg kg
1). Importantly, liming has no
adverse effect on grain yield (Fig. 3). This field trial has demon-
strated that liming provides an easy and cost-effective approach to
tackle the issue of elevated grain Cd concentration in southern
China.
6. Molecular mechanisms of Cd for breeding low-Cd rice
plants
There is substantial variation in grain Cd concentrations among
rice cultivars, providing a prospect for engineering or breeding low-
Cd accumulating rice cultivars. Several important genes have been
identified for influencing the uptake, translocation, and
 P. Wang et al. / Environmental Pollution 249 (2019) 1038e1048 1043

Fig. 3. Effect of a one-time CaCO3 applications (only in 2016) on soil pH (a), grain Cd concentrations (b), and grain yield (c) in continuous three-year field trials. The field experiment
was carried out in sixteen randomized plots (5  6 m), located in Xiangtan, Hunan province, in southern China, with four levels of lime applied (0, 2.25, 4.5, and 7.5 t ha
1) and two
widely-grown rice cultivars (SY957 and ZLY168). The soil had an initial soil pH of 5.5 and a total Cd concentration of 0.67 mg kg
1. The first two year results have been reported in
Chen et al. (2018c).

accumulation of Cd in rice plants. When Cd2þ reaches the root
surface, it is mainly taken into the root cells as a ‘hitchhiker’
through the manganese (Mn) transporter OsNramp5 (natural
resistance-associated macrophage protein 5) (Ishikawa et al., 2012;
Sasaki et al., 2012a). This protein is located at the distal side of the
plasma membrane of the exodermis and endodermis cells (Sasaki
et al., 2012b) (Fig. 4a). Rice roots have a much higher expression
level of Nramp5 than other cereal plants (Sui et al., 2018; Wu et al.,
2016), and OsNramp5 appears to have a higher transport activity
for Cd than the orthologues from wheat and maize (Sui et al., 2018).
These differences may explain a higher root uptake of Cd in rice
than other cereal crops (Sui et al., 2018). Once Cd2þ is taken into the
root cells, its subsequent radial movement to the xylem is restricted
by OsHMA3, a P1B-type ATPase with transport activity of Cd
(Miyadate et al., 2011; Ueno et al., 2010). The transporter is located
at the tonoplast and is capable of sequestrating Cd into the vacu-
oles, thus limiting Cd loading into the xylem (Miyadate et al., 2011;
Ueno et al., 2010) (Fig. 4a). Some rice cultivars possess weak or loss-
of-function alleles of OsHMA3 and have low abilities to sequester Cd
into the vacuoles, resulting in elevated Cd translocation to the
shoots and grain (Miyadate et al., 2011; Ueno et al., 2010; Yan et al.,
2016). OsHMA2 is another transporter responsible for Cd trans-
location from roots to shoots (Satoh-Nagasawa et al., 2012;
Takahashi et al., 2012; Yamaji et al., 2013). Recently, a new protein
CAL1 (Cd accumulation in leaf 1), preferentially located in the root
exodermis and the xylem parenchyma cells, can lower cytosolic Cd
concentration while promoting the long-distance transport of Cd
via the xylem vessels, although this transporter does not appear to
affect Cd accumulation in the grain (Luo et al., 2018). Finally, Cd can
be transported via the phloem to the grain through the transporter
OsLCT1, which is mainly located in the diffuse vascular bundles
(connected to panicles) in the upper-most node (Uraguchi et al.,
2011).
The recent progress in understanding the molecular mecha-
nisms of Cd uptake and translocation has provided important
knowledge for engineering rice plants or breeding rice cultivars to
produce low-Cd grains. For example, a knockout or knockdown of
the OsNramp5 can cause a marked decrease in the contents of both
Cd and Mn in the shoots and grain (Ishikawa et al., 2012; Sasaki
et al., 2012b). Field trials with osnramp5 mutants produced
extremely low-Cd grain without adverse effects on grain yield
(Ishikawa et al., 2012). However, some studies have indicated that a
decrease in Mn uptake can cause Mn deficiency in plants when
available concentrations of Mn in the growing medium are low
(Sasaki et al., 2012b; Yang et al., 2014). Because Mn is mobilized
when soil is flooded, the availability of Mn is likely to be sufficiently
1044 P. Wang et al. / Environmental Pollution 249 (2019) 1038e1048

Fig. 4. Molecular mechanisms and implications in engineering low-Cd accumulating rice plants. Transporters involved in uptake, vacuolar sequestration, and xylem loading in rice
roots (a), and transgenic rice plants with low Cd including the knockout of OsNramp5 (b) and overexpression of OsHMA3 (c). OsNramp5, located at the distal side of both the
exodermis and endodermis, is responsible for the uptake of Cd (also Mn) into the root cells. OsHMA3, located tonoplast plasm membrane, is responsible for the sequestration of Cd
into the vacuoles of rice roots. Panels (b) and (c) were redrawn of data from Tang et al. (2017) and Ueno et al. (2010). The dashed lines in (b) and (c) represent the level of the Chinese
national food standard (0.2 mg kg
1).

high in most paddy soils under flooded conditions. Recently, trials
in a Cd-contaminated paddy field demonstrated that a knockout of
OsNramp5 in both parents using the CRISPR/Cas9 system can
generate a low Cd hybrid rice (grain Cd being less than
0.05 mg kg
1) without compromising yield (Tang et al., 2017)
(Fig. 4b). Similarly, overexpressing OsHMA3 can produce low levels
of Cd in rice grain (Ueno et al., 2010) (Fig. 4c). The effectiveness was
further confirmed recently in three field trials, almost producing
Cd-free rice, with grain Cd ranging from 0.01 to 0.04 mg kg
1 (Lu
et al., 2019). Moreover, manipulating the expression and tissue
localization of OsHMA3 under the control of the OsHMA2 promoter
can effectively decrease Cd accumulation in rice grain by seques-
tering more Cd in the vacuoles of various tissues (Shao et al., 2018).
A knockdown of OsLCT1 can also substantially decrease grain Cd
concentrations (Uraguchi et al., 2011). These molecular manipula-
tions of genes to engineer low-Cd accumulating rice plants could
give benefit to those subsistence rice farmers with a high-Cd
exposed risk in contaminated regions of southern China. Given
the importance and urgency of reducing grain Cd concentration for
food safety, we believe that genome editing and transgenic ap-
proaches should be seriously considered.
In the medium to long term, breeding low-Cd rice cultivars is
also desirable. Breeding can be facilitated through identifying the
germplasms with low-Cd traits and the quantitative trait loci (QTLs)
controlling Cd accumulation in rice grain. Multiple QTLs for low Cd
accumulation can be pyramided using molecular marker-assisted
breeding. Allelic variation in OsHMA3 can have a profound effect
on Cd accumulation in the grain, although weak or loss-of-function
alleles are not useful for breeding low Cd cultivars (Ueno et al.,
2010; Yan et al., 2016). Strong alleles of OsHMA3, either with a
high Cd transport activity or with a high expression level, would be
particularly useful. Allelic variation in the OsNramp5 promoter re-
gion affecting its expression has been found to affect Mn accumu-
lation in rice, but surprisingly no effect on Cd accumulation (Liu
et al., 2017). It remains unclear whether there exist alleles of OsN-
ramp5 that confer a low transport activity for Cd without affecting
Mn transport; such alleles would be ideal for breeding low Cd rice.
It is also possible to modify the coding region of OsNramp5 to
enhance the protein selectivity for Mn over Cd, although this
approach would require genetic manipulations. The casual genes
for a number of Cd QTLs remain to be identified, which could
provide useful alleles for breeding low Cd rice.
Exogenous-regulation of these genes without editing plant ge-
nomes may provide an alternative strategy to reduce the uptake
and translocation of Cd in rice plants. For example, supplying sili-
con (Si) can decrease shoot Cd concentrations markedly, with this
being attributed to the downregulation of OsNramp5 and OsHMA2
caused by Si (Shao et al., 2017; Shi et al., 2005). Similarly, it has been
shown that foliar application of silica or selenium can reduce Cd
accumulation by regulating the expression of Cd uptake- and
translocation-related genes in rice (Cui et al., 2018; Li et al., 2018).
7. Prediction of rice grain Cd from soil analyses is difficult at
large regional scales
An accurate model to predict rice grain Cd based on suitable soil
tests would be helpful to assess the risk of rice grain Cd accumu-
lation. This may be particularly important for evaluating whether
the quality of a soil is suitable for rice cropping. Numerous studies
have attempted to develop such predictive model (Brus et al., 2009;
Romkens et al., 2009; Ro €mkens et al., 2011; Simmons et al., 2008).
Generally, although rice grain Cd concentrations could be predicted
 P. Wang et al. / Environmental Pollution 249 (2019) 1038e1048
well at the small scale (e.g. in a valley) (Brus et al., 2009) or in
managed field experiments (Romkens et al., 2009; Ro €mkens et al.,
2011), it is difficult to establish such predictive models at the large
field scale (Simmons et al., 2008; Zhang et al., 2011). For example,
field surveys with 308 soil and rice grain samples showed that the
rice grain Cd was poorly correlated with total soil Cd (R2 ¼ 0.117) or
extractable Cd (using 0.005 M DTPA) (R2 ¼ 0.165) of air-dried soils
(Simmons et al., 2008). Similarly, our recent surveys with 200
paired soil and rice grain samples across a county of Hunan prov-
ince found the same poor relationship between rice grain Cd and
soil total Cd (R2 ¼ 0.169)(Chen et al., 2018a). Even including soil pH
in multiple regression analyses did not significantly improve the
predictive ability. The poor relationships are likely due to two
reasons. First, paddy water status has a substantial impact on Cd
accumulation in the rice grain and fluctuation in the water status
during the grain filling stage can significantly affect grain Cd. This
also explains why extractable Cd of air-dried soils is often corre-
lated with soil total Cd, but when soils are incubated under
anaerobic conditions to mimic the flooded conditions in paddy
fields, there is an only poor correlation between extractable Cd
(0.1 M CaCl2 here) and total Cd (Fig. 5). The status of paddy water
largely depends on the farmer's management and weather. For the
purpose of developing a predictive model, measurement of the
extractable Cd concentration of field-moist soil samples, along with
soil pH during the grain filling growth stage, may allow a more
reliable prediction of grain Cd accumulation (Simmons et al., 2008).
Significant differences in grain Cd accumulation among rice
cultivars are the second important factor limiting the prediction. A
recent field study with 471 locally-adapted and high-yielding rice
cultivars grown at three contaminated sites in southern China
showed a 10e32 fold variation in grain Cd concentration (Duan
et al., 2017). The variation in grain Cd concentrations among cul-
tivars even exceeded that due to the variation in soil Cd levels.
Therefore, paddy water status, especially during the grain filling
stage, and rice cultivars should be considered as important pa-
rameters when developing a predictive model.
Fig. 5. The effect of paddy water status on CaCl2-extractable Cd of 41 soils varying
widely in soil properties. Exchangeable Cd was extracted using 0.1 M CaCl2 for either
air-dried soils or wet soils after two-week incubation under anaerobic conditions.
1045
8. Increasing dietary nutrients and human nutrition can
decrease human Cd absorption
Polished rice grains are low in Zn and Fe concentrations
compared to other foods, leading to elevated bioavailability of Cd in
subsistence rice diets (Chaney, 2015). This is because low Zn and Fe
in diets can upregulate Fe2þ transporters (DMT1 and ZIP8) in
mammalian cells, with these two transporters mediating Cd2þ
uptake by the human body (Dalton et al., 2005; Gunshin et al., 1997;
Ryu et al., 2004). It should be noted that women are particularly
vulnerable to Cd-induced diseases. For example, among the 405
patients who had Itai-Itai disease (or were suspected of having the
disease) in Japan, 360 (89%) of the patients were women who had
given birth to multiple children (Nogawa et al., 2017). This high
incidence of Cd-induced diseases in women is due to the low Fe
status of their bodies (Nordberg et al., 2007). Animal intestine ex-
periments have clearly demonstrated the role of the nutrient de-
ficiencies of rice subsistence diets in causing elevated Cd absorption
in the human body (Reeves and Chaney, 2001, 2002; 2004; Ryu
et al., 2004). The absorption of Cd can be decreased by high Zn in
the diet but increased by Fe deficiency (Fox et al., 1979; McKenna
et al., 1992; Ryu et al., 2004). A rat toxicological study using 109Cd
showed that the absorption of Cd into the enterocytes and kidney
was 10-fold higher in Zn-Fe-Ca marginal diets compared to diets
that contained adequate levels of Zn-Fe-Ca (Reeves and Chaney,
2004). Therefore, an increase in nutrients (mainly Zn, Fe and Ca)
in the diet, or alleviation of nutritional stress (Zn, Fe and Ca de-
ficiencies) in humans consuming subsistence rice diets, can reduce
human Cd accumulation and the associated Cd-induced health
risks. Biofortification efforts aimed at increasing concentrations of
these nutrients in rice grain are likely to lower the absorption of Cd
by humans.
9. Intervention strategies to reduce exposure to cd
The dietary Cd intake for some subsistence rice farmers in some
regions of southern China has been comparable to the values for the
population in the area of Japan where Itai-Itai disease was reported
(Table 2). The fact that no Itai-Itai disease patients have been
diagnosed in the regions so far may be a matter of exposure time.
The problem of high Cd concentrations in rice grains has arisen only
during the last two to three decades due to soil contamination and
acidification. Itai-Itai disease may occur after exposure to the cur-
rent levels of Cd intake for 47e76 years in some contaminated areas
(Table 2). Excessive Cd intake can also result in other adverse health
problems before the onset of Itai-Itai disease. Urgent actions are
now needed to prevent the occurrence of Cd-induced disease.
Whilst rice sold on the markets can be regulated strictly, farmers
consuming their home-grown rice are more vulnerable. It is
therefore important that regular monitoring is taken to identify
home-grown rice and paddy fields where grain Cd concentrations
often exceed the food limit. High Cd home-grown rice should be
exchanged with low-Cd rice from the local authorities. A recent
study has shown that a 3-month intervention by supplying low-Cd
rice to farmers who previously consumed home-grown rice can
significantly decrease urinary Cd (Huang et al., 2019). In addition to
the replacement of high-Cd rice, other intervention measures are
also needed to ensure the production of low-Cd rice, including
supplies of low-Cd rice cultivars and lime materials to farmers.
Finally, information about Cd contamination, possible adverse ef-
fects on health, and prevention strategies should be given to local
farmers to raise public awareness.
Without an adequate understanding of the likely harm caused
by chronic exposure to Cd, local farmers may be reluctant to
participate in the intervention and other Cd-reducing strategies.
1046 P. Wang et al. / Environmental Pollution 249 (2019) 1038e1048
10. Concluding remarks and future perspectives
The contamination of agricultural soil with Cd, coupled with soil
acidification, has led to increases in the concentration of Cd in rice
grain, particularly in some areas of southern China. This has caused
widespread concern regarding food safety. These increases in grain
Cd concentrations have inevitably increased dietary Cd exposure to
some populations in southern China, with serious implications for
human health. The situation is alarming. There are several scientific
perspectives to be further studied. First, epidemiologic studies are
required to estimate the health risks associated with elevated di-
etary Cd intake in these contaminated regions and establish the
benchmark doses of urinary Cd and dietary Cd intake for the pur-
poses of risk estimation and regulation. Second, effective inter-
vention measurements are desirable to alleviate the further
accumulation of Cd in the body of high-Cd exposed local farmers.
Third, an effective mitigation program is required to produce Cd-
safe rice through incorporating water management, regulation of
biogeochemical processes, and use of low-Cd rice cultivars. For local
government, a series of urgent actions should be taken to reduce Cd
exposure to the local population, including i) strict monitoring of
rice sold on the markets; ii) monitoring and intervention in the
local farmers who mainly consume home-grown rice with elevated
Cd concentrations; iii) implementing agronomic methods to reduce
Cd accumulation in rice grown in Cd-contaminated paddy soils;
and iv) banning more heavily contaminated soils for the production
of edible crops. Liming acidic paddy soils to pH 6.5 is an effective
agronomic method to reduce Cd accumulation in rice. Biotech-
nology, such as - editing of OsNramp5 or overexpression of OsHMA3
gene, is the most effective method to produce low Cd rice. Growing
of transgenic rice is not permitted in China at present, but there
should be a debate on whether this technology should be consid-
ered in some serious Cd-contaminated regions where a danger of
Cd-induced diseases is likely to happen.
Acknowledgments
The study was supported by the Natural Science Foundation of
China (grant No. 41671309, 21661132001), the National Key
Research and Development Program of China (2016YFD08004002),
the Natural Science Fund for Jiangsu Distinguished Young Scholar
(BK20180025), the fundamental research funds for the Central
Universities (Grant No. KJJQ201902), and the Innovative Research
Team Development Plan of the Ministry of Education of China
(Grant No. IRT_17R56).
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.envpol.2019.03.063.
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