Assessing the health risks of rice cadmium content standards in China

Abstract

With increasing understanding of cadmium (Cd) exposure levels and toxicity mechanisms, the adequacy of current Cd limit standards for protecting public health requires comprehensive evaluation. Here, we found that 39.04% of rice Cd content surpassed the fifth percentile of benchmark dose lower limit (BMDL₅; 17.100 micrograms per day) threshold for dietary Cd associated with chronic kidney disease in Jiangsu Province. Moreover, more than 90% of rice Cd levels posed potential health hazards, with some samples presenting lifetime carcinogenic risks. Blood and urinary Cd levels demonstrated age-dependent increases, with 48.40 and 20.61% of participants exceeding BMDL₅ levels for blood Cd (0.640 micrograms per liter) and urinary Cd (0.120 micrograms per liter), respectively. The derived reference values for dietary Cd were 0.149 and 0.018 micrograms per kilogram of body weight per day for adults and children, respectively. The lowest concentrations of Cd in rice consumed by adults and children were also observed, which indicated that current Cd limit standards appear insufficient to protect public health, indicating a need for more stringent safety thresholds.

The current rice cadmium limit is insufficient to safeguard human health, warranting stricter thresholds.

INTRODUCTION

Heavy metal pollution has emerged as a critical global environmental concern, contributing to ~12.6 million deaths worldwide through soil contamination (1, 2). Cadmium (Cd) is a pervasive environmental toxicant characterized by a biological half-life spanning 10 to 30 years in the human body. Chronic Cd exposure can induce multisystemic damage, impair embryonic development, and exhibit carcinogenic properties, with particular toxicity to the kidneys as its primary target organ (2). The International Agency for Research on Cancer has classified Cd as a group 1 carcinogen, and the World Health Organization (WHO) has designated it as a priority food contaminant. Despite widespread implementation of mitigation measures across various nations to address Cd-related health risks, global Cd pollution remains severe due to ongoing industrial activities. A nationwide survey (2005 to 2013) by China’s Ministry of Environmental Protection revealed that more than 7% of the country’s farmland soils were severely contaminated with Cd. Cd has the highest exceedance rate in soil (exceedance rate, Cd > Hg > As > Pb > Cr) in Jiangsu Province (3). Similarly, in India and Bangladesh, Cd concentrations in groundwater and surface water have exceeded local drinking water safety standards (4). Therefore, a comprehensive assessment of Cd exposure levels and their impact on human health risks is essential to establish a scientific foundation for prevention strategies and targeted interventions.

Cd enters animals and humans mainly through the digestive and respiratory tracts (5). Inhalation exposure leads to Cd accumulation in the lungs, resulting in pulmonary diseases (6–9). Following oral exposure, Cd is transported via the bloodstream and gradually accumulates in the kidneys, liver, and bones, with the kidneys serving as the primary target organ of Cd toxicity (10). Blood Cd (BCd) and urinary Cd (UCd) are commonly used as biomarkers to assess internal Cd exposure levels in populations. BCd primarily reflects recent Cd exposure (11), while UCd may be associated with long-term Cd exposure or renal Cd burden (9). In addition, some epidemiological studies have used dietary Cd intake as a surrogate indicator of Cd exposure to analyze the association between Cd exposure levels and chronic kidney disease (CKD) (9, 12).

Dietary exposure represents the primary route of environmental Cd intake, accounting for ~90% of total Cd exposure in nonsmoking populations (13). Rice consumption constitutes the predominant dietary source of Cd (14). However, surveillance data indicate that a portion of rice samples in China continues to exceed the maximum allowable Cd levels established by the Ministry of Health. In Cd-affected regions, ~56 to 87% of rice samples surpass China’s food safety standards (15), raising concerns about the health implications of Cd contamination in rice.

While China’s current rice Cd content standards, established in 2022 (GB 2762-2022; Cd limit standards in rice, 0.2 mg/kg), were based on international guidelines and standards from other countries, their adequacy in protecting public health requires reassessment given rapid economic development and evolving dietary patterns. Of particular concern are infants and children, who exhibit heightened sensitivity to Cd toxicity. Although both the European Union and China have established specific limits for Cd content in infant cereal products, the current standard system lacks comprehensive considerations for children’s exposure. Moreover, potential variations in Cd metabolism among different populations necessitate validation of these health guidance values for the Chinese population. These factors underscore the critical need to investigate both internal and external Cd exposure levels and calculate population-specific health guidance values for human Cd exposure.

The benchmark dose (BMD) method is a statistical approach that determines the lower 95% confidence limit of the dose causing a specified positive response in experimental participants, typically at effective dose 1 (ED1), ED5, or ED10 levels. This methodology has gained widespread acceptance as a robust tool for toxicological data analysis, offering comprehensive assessment capabilities through the integration of multiple toxicological endpoints. Its extensive validation and broad application in risk assessment have established it as a cornerstone technique in the field (16, 17). Physiologically based pharmacokinetic (PBPK) models, grounded in physiological principles, enable the simulation and prediction of exogenous substance distribution and metabolism within organisms, proving invaluable in health risk investigations across various toxic compounds (18–20).

This investigation analyzes both external Cd exposure levels across environmental matrices and internal Cd exposure levels in biological samples. We evaluate the population health impacts resulting from both external and internal Cd exposure pathways and calculate safety thresholds for dietary Cd exposure and internal Cd biomarkers in blood and urine. These findings will provide crucial scientific and theoretical foundations for the development and potential modification of Cd-related regulatory policies.

RESULTS

The association between PM_2.5-bound Cd concentration and rice Cd concentration

Analysis of particulate matter less than 2.5 μm in aerodynamicdiameter (PM_2.5) exposure levels and associated Cd concentrations (PM_2.5-Cd) in Jiangsu Province revealed an annual average PM_2.5 mass concentration of 0.046 mg/m³, which exceeded China’s annual average limit (tables S1 and S2 and fig. S1A). PM_2.5 concentrations exhibited clear seasonal variation, with peak levels in winter and minimum levels in summer (Fig. 1A and table S2). A positive correlation was observed between atmospheric PM_2.5 mass concentration and PM_2.5-bound Cd concentration (fig. S1B). The concentration of Cd bound to PM_2.5 was concurrent with seasonal PM_2.5 fluctuations (Fig. 1B). The annual average Cd content was 0.695 ng/m³ (table S2), remaining below China’s national standard of 5 ng/m³ (GB3095-2012). To analyze the correlation between PM_2.5-bound Cd and Cd in rice, we calculated quarterly average air quality data from the cities where the sampling areas were located, along with average Cd content in rice. The results demonstrate that no correlation existed between Cd in PM_2.5 and Cd in rice for the entire year (fig. S1C). These findings indicate that, while annual average atmospheric PM_2.5 levels exceeded safety limits, PM_2.5-bound Cd concentrations remained within acceptable ranges.

Fig. 1. Seasonal distribution of PM2.5 and PM2.5-bound Cd.

Satellite cloud images to analyze the concentration distribution of PM_2.5 (A) and PM_2.5-bound Cd (B) in seasons.

The evaluation of Cd concentration levels in soil and rice

Cd concentrations in farmland soils ranged from 0.001 to 12.000 mg/kg, with mean and median values of 0.203 and 0.150 mg/kg, respectively (table S3). Analysis of soils with varying pH values revealed that average Cd concentrations did not exceed regulatory limits across all pH categories (Fig. 2A). The geoaccumulation index (Igeo) analysis identified eight samples (1.54%) exhibiting grade II or higher Cd pollution, indicating light to moderate contamination (Fig. 2B). Rice samples demonstrated mean Cd concentrations below regulatory thresholds (Fig. 2C), with values ranging from 0.002 to 0.820 mg/kg. Eight samples exceeded the national food safety standard, with mean and median concentrations of 0.046 and 0.027 mg/kg, respectively (table S3). The generalized linear model (GLM) correlation analysis indicated that a 1% increase in soil Cd content led to a significant 1.60% rise in rice Cd levels at pH ≤ 5.5 (β = 1.60, P = 0.004). In addition, similar result was observed at pH levels between 5.5 and 6.5 (β = 0.40, P = 0.011) (Fig. 2D). These findings indicate that Cd concentrations in the majority of Jiangsu Province’s farmland soils and rice comply with national safety standards.

Fig. 2. The evaluation of Cd concentration levels in soil and rice.

(A) Cd concentration in soils with different pH values. (B) Cd pollution status in soil [geoaccumulation index (Igeo)]. (C) Comparison of Cd concentration in rice. China (0.2 mg/kg), European Union (EU; 0.15 mg/kg), and Codex Alimentarius Commission (CAC; 0.4 mg/kg) standards. (D) The correlation between soil Cd concentration and rice Cd concentration under different soil pH conditions. Generalized linear model (GLM) was used to examine the correlation between soil and rice Cd concentrations across various pH conditions. Grade 0, Igeo < 0 indicates uncontaminated soil; grade I, 0 ≤ Igeo < 1 suggests uncontaminated to moderately contaminated conditions; grade II, 1 ≤ Igeo < 2 indicates moderate contamination; and grade VI, Igeo ≥ 5 denotes extreme contamination.

Assessing the bioaccumulation factors of soil Cd in rice Cd

To comprehensively evaluate Cd bioaccumulation from soil to rice, we analyzed samples from surface and deep soil layers alongside rice roots, stems, and mature grains. Mean Cd concentrations were 0.036, 0.264, and 0.535 mg/kg in rice grains, stems, and roots, respectively, with corresponding median values of 0.023, 0.140, and 0.440 mg/kg (table S4). Bioconcentration factors (BCFs) were calculated for soil-to-rice, soil-to-stem, and soil-to-root transfers (Table 1). The proportion of samples with BCF values exceeding 1 was 2.5% for soil-to-rice, 52.5% for soil-to-rice stem, and 72.5% for soil-to-rice root transfers, indicating Cd accumulation from soil to plant tissues (Table 1). These results establish rice Cd concentration as a reliable indicator of soil Cd contamination, highlighting the remarkable relationship between soil and rice Cd levels.

Table 1. The bioaccumulation factors of Cd from soil to rice, rice stem, and rice root.

Variables	Range	Mean	Median	Number (%) of BCF > 1
Soil - rice	0.032–1.538	0.242	0.156	1 (2.50)
Soil - rice stem	0.177–11.230	1.865	1.107	21 (52.50)
Soil - rice root	0.340–11.540	3.729	3.017	29 (72.50)

The health risk assessment of rice Cd intake

Rice consumption represents the primary dietary staple in Jiangsu Province. We calculated rice Cd intake based on heavy metal concentrations from multiple cities across Jiangsu (Fig. 3A). The average daily dietary Cd intake from rice for adults was 0.175 μg/kg of body weight (bw) per day, which was below both the provisional tolerable daily intake (PTDI) value [Calculated intake quantity based on provisional tolerance monthly intake (PTMI, 25 μg/kg of bw per month); 0.83 μg/kg of bw per day] and the average dietary Cd intake (0.275 μg/kg of bw per day, calculated based on 8.26 µg/kg bw per month) reported in China’s sixth total diet study (TDS) conducted during 2016 to 2019 (21). Given that rice-derived Cd exposure accounts for 55.80% of total dietary Cd exposure (12), we calculated the daily dietary Cd intake (Cd intake) for adults (Fig. 3B), and the average Cd intake was 20.340 μg/day. One hundred four samples (20%) exceeded the average Cd intake (32.7 μg/day) reported in China’s fifth TDS (22).

Fig. 3. The health risk assessment of rice Cd intake.

(A) The daily dietary intake of Cd from rice and compare it with the daily dietary Cd intake standards set by the provisional tolerable daily intake (PTDI; 0.83 μg/kg of bw per day) and sixth total diet study (TDS; 0.275 μg/kg of bw per day). (B) The daily dietary intake of Cd for adults and compare it with the values of fifth TDS (32.7 μg/day), and the values of the BMDL₅ (17.100 μg/day) for dietary Cd that could lead to CKD. Assess the noncarcinogenic (C) and carcinogenic (D) risk of Cd intake in the diet. HQ, hazard quotient (HQ≥1 and HQ<1); ILCR, Incremental lifetime cancer risk (1.0E-6 ≤ ILCR ≤ 1.0E-4, 1.0E-4 < ILCR ≤ 1.0E-3 and ILCR > 1.0E-3).

Because the kidney is the primary target organ for Cd toxicity and dietary patterns are strongly associated with CKD in Chinese adults (12, 23), we conducted a comprehensive literature analysis to determine the threshold for dietary Cd exposure causing CKD. Among the included studies, two specifically identified dietary Cd exposure as an important risk factor for CKD in large population samples. One study provided data suitable for calculating the BMD lower limit (BMDL) for CKD induced by dietary Cd exposure. Table 2 revealed that the dietary Cd intake threshold BMDL₅ (fifth percentile of BMDL) that may have CKD risk in 5% of the population was 17.100 μg/day (Table 2). In our study, 39.04% of samples exceeded this threshold of 17.100 μg/day (Fig. 3B), indicating a potential CKD risk for Jiangsu populations.

Table 2. The BMDL₅ values for dietary Cd, UCd, and BCd.

Classification	Sample sizes	Outcome	BMDL5	References	Proportion*
Dietary Cd (μg/day)	8,429	CKD	17.100	(12)	39.04%
UCd (μg/liter)	9,821	CKD	0.120	(23)	48.40%
BCd (μg/liter)	9,821	CKD	0.640		20.61%

^*Exceeding the proportion compared to the study samples.

We further assessed the health impacts of dietary Cd intake across different age groups. The proportion of cases where rice consumption resulted in hazard quotient (HQ) values exceeding 1 was 99.04% for children, 98.85% for adolescents, and 93.08% for adults (Fig. 3C). Carcinogenic risk assessment revealed that 54.81% for children had incremental lifetime cancer risk (ILCR) values exceeding 1.0 × 10⁻⁴, with 0.96% cases surpassing 1.0 × 10⁻³. Among adolescents, 28.46% cases exceeded 1.0 × 10⁻⁴, with 0.19% case exceeding 1.0 × 10⁻³. For adults, 9.23% cases exceeded the 1.0 × 10⁻⁴ threshold (Fig. 3D). These findings indicate remarkable carcinogenic risk associated with Cd content in regional rice samples, particularly concerning for children as a vulnerable population.

Analysis of Cd exposure levels in populations

We analyzed internal Cd exposure levels in 626 residents from soil and rice sampling sites through blood and urine samples. The study population comprised 311 females (mean age, 29.70 ± 23.32 years) and 315 males (mean age, 29.37 ± 23.29 years). Table S5 revealed that mean/median BCd levels were 0.483/0.268 μg/liter in females and 0.973/0.250 μg/liter in males, while UCd levels were 0.443/0.300 μg/liter in females and 0.550/0.355 μg/liter in males, respectively. After creatinine adjustment, mean/median UCd values were 0.503/0.343 μg/g of creatinine in females and 0.432/0.318 μg/g of creatinine in males. Table S5 demonstrated significant positive correlations between both UCd and BCd levels with age (P < 0.001). Using the literature on Cd exposure levels and CKD, we calculated the BMDL₅ thresholds for UCd and BCd associated with CKD risk. Table 2 indicated BMDL₅ values of 0.120 μg/liter for UCd and 0.640 μg/liter for BCd. In our study population, 48.4% exceeded the UCd BMDL₅ threshold, while 20.61% exceeded the BCd BMDL₅ threshold associated with CKD risk (Fig. 4, A and B). These findings suggest that Cd exposure in this population poses potential health risks, particularly for CKD.

Fig. 4. Cd exposure levels in populations.

(A) The UCd concentrations across different age groups. BMDL₅ for CKD-related UCd (0.120 μg/liter). (B) The BCd concentrations of the BMDL₅ levels related to CKD (0.640 μg/liter).

Calculation of Cd exposure levels by PBPK model

Using the previously calculated daily rice intake values, we used PBPK modeling to extrapolate internal exposure levels across age groups, including concentrations in kidney tissue, renal cortex, blood, and urine. The results demonstrated that Cd accumulation in above tissues and body fluids increased with age in both female and male populations (Fig. 5 and fig. S2). BCd concentrations exceeded the literature-derived BMDL₅ at relatively young ages, while UCd concentrations approached the urinary BMDL₅ around age 20, both indicating potential health risks at current converted intake doses.

Fig. 5. Calculation of Cd exposure levels by PBPK model.

The PBPK model uses the rice Cd intake to calculate the Cd internal exposure levels in human blood and urine (A) and organs (including kidney and renal cortex) (B).

Furthermore, we used measured BCd concentrations from biological samples to estimate daily dietary rice intake. Table 3 revealed lower Cd exposure concentrations in females compared to those in males, although neither group exceeded Joint Food and Agriculture Organization of the United Nations (FAO)/WHO Expert Committee on Food Additives (JECFA)–recommended thresholds for dietary intake control (25 μg/kg of bw per month). The derived reference values for dietary Cd intake were 0.018 μg/kg of bw per day for children and 0.149 μg/kg of bw per day for adults. On the basis of age-specific rice consumption patterns and the proportion of dietary Cd derived from rice (24), our analysis indicated the Cd content in rice. According to a previous study, the average weight for a 6-year-old child was 21 kg, with a staple food intake of 248.3 g, and the staple food accounts for 40.4% of dietary Cd intake (25). Meanwhile, adult body weight was set to 65 kg, with staple food intake at 310 g, of which 55.8% of dietary Cd originated from rice. Results showed that the lowest Cd concentrations in rice were 0.0006 mg/kg for children and 0.017 mg/kg for adult. These findings emphasize the importance of considering population characteristics and vulnerable groups when revising health guidance values for dietary Cd exposure.

Table 3. The predicted concentration of daily dietary intake Cd and the Cd concentration in rice.

DDI, daily dietary intake; Con_Cd, concentration of Cd; Bw, body weight.

Age	Predicted DDI from blood (μg/kg of bw per day)		Predicted ConCd in rice (mg/kg)
	Female	Male	Female	Male
6	0.018	0.035	0.0006	0.001
18	0.232	0.481	0.027	0.056
45	0.149	0.304	0.017	0.036
60	0.155	0.312	0.018	0.036

DISCUSSION

In this study, while only a small percentage of samples exceeded national limit standards, health risk assessments revealed that the majority of samples could pose noncarcinogenic health risks to the Chinese population, with particularly concerning carcinogenic risks for children. Our findings suggest that current health guidance values for dietary Cd are insufficiently protective, indicating the need to establish dietary Cd health guidance values that account for population characteristics, gender differences, and age-specific vulnerabilities.

Dietary Cd represents the primary exposure pathway for the general population, with rice being a staple food for Chinese consumers. A national-level assessment reveals a close relationship between the concentration of UCd and the Cd level in rice, suggesting the significance of assessing Cd content in rice for preventing region-specific health risks (26). Previous research has documented a concerning trend in rice Cd contamination, with average Cd content in rice grains increasing from 0.116 mg/kg in 2011 to 0.229 mg/kg in 2016 (27). While regional variations exist in rice Cd content, our study found levels of 0.046 mg/kg, substantially below the threshold of 0.2 mg/kg. However, even at relatively low soil Cd concentrations, this heavy metal can bioaccumulate through the food chain via rice consumption, potentially causing toxic effects in humans (28, 29).

The extent of rice Cd contamination is modulated by multiple factors, including soil pH, organic matter content, microbial activity, climate conditions, and water safety (30). Studies demonstrate that Cd levels in raw, uncooked rice differ from those in the cooked form, and cooked rice is more suitable for human health risk studies. Furthermore, washing, soaking, steaming, the volume of cooking water, drinking water quality, and Cd content in cooking water all affect the Cd content in cooked rice. In addition, long-term monitored data showed that Cd concentrations in drinking water and various drinking water sources were significantly lower than the national limit [based on the GB5749-2002 (China) standard, with a Cd limit of 0.005 mg/liter]. Therefore, given the complexity of collecting cooked rice samples, this study has not yet tested the Cd content in the cooked rice consumed by participants. In addition, soil Cd level is the primary source of Cd in grains (30), and only 16.5% of the increase in soil Cd originated from irrigation (31). This study mainly focused on the correlation between soil Cd levels and Cd in rice. Implementing comprehensive strategies, particularly bioremediation techniques, to reduce soil Cd content and subsequent rice accumulation represents a crucial intervention to mitigate Cd pollution in the soil-rice ecosystem and minimize its threat to human health.

Health risk assessments of rice-derived Cd indicate that HQ values and cancer risk index for rice produced across many provinces exceed safety thresholds (32, 33). Our findings reveal that the majority of samples pose potential noncarcinogenic health risks across age groups, with 54.81% of samples potentially increasing lifetime carcinogenic risk for children, 28.46% for adolescents, and 9.23% for adults. Previous research has demonstrated both carcinogenic and noncarcinogenic risks from dietary Cd intake in young children (34, 35), with risk decreasing with age in both Chinese and Iranian populations (36, 37). Children are particularly vulnerable to heavy metal exposure due to their higher metabolic rates, greater food intake per unit body weight, and frequent hand-to-mouth contact (38, 39). Given the potential developmental damage from chronic Cd exposure in young children, many nations have established specific Cd limits for infant and toddler foods. However, current standard systems appear to inadequately address children’s unique susceptibilities.

Environmental health risk assessment encompasses four primary steps: hazard identification, dose-response assessment, exposure assessment, and risk characterization. The BMD and PBPK models serve different functions within this framework. The BMDL is primarily used in the second step of dose-response assessment, serving as a safety threshold in chemical risk assessment and replacing the traditional no-observed-adverse-effect level. PBPK modeling is predominantly used in the third step of exposure assessment, estimating target organ doses across various exposure routes and populations. These two approaches complement each other effectively in comprehensive risk assessment.

A comparison was conducted between the Cd internal exposure levels in the study population and the international standard. Data showed that 210 of the 626 participants had Cd levels in their blood exceeding the safe levels recommended by Agency for Toxic Substances and Disease Registry (ATSDR; 0.38 μg/liter), but the UCd concentrations were all below the safety limits of JECFA (5.24 μg/g of creatinine). While existing PBPK models primarily assess population-level Cd exposure risks through exposure pathway evaluation (40), we applied the model specifically to assess risks associated with rice-derived Cd consumption. Our analysis of average dietary Cd intake from rice revealed that UCd and BCd concentrations, as well as kidney tissue concentrations, increased with age in both males and females, with females showing higher internal exposure levels. Both UCd and BCd levels in the study population exceeded the BMDL₅ concentration associated with CKD, supporting the elevated risk of CKD from rice-derived Cd exposure. These findings align with previous research (40) and may be attributed to females’ higher gastrointestinal Cd absorption rates compared to males (41).

On the basis of the BCd levels of this population, we used the PBPK model to estimate dietary Cd exposure levels and further deduced the concentration of Cd in rice. Our results revealed that females achieve equivalent internal exposure levels at lower intake doses, indicating enhanced sensitivity to Cd intake. Notably, daily dietary Cd exposure levels for adults (0.149 μg/kg of bw per day) in this study are significantly higher than ATSDR stated that the chronic durational oral minimal risk level (MRL) for Cd is 0.1 μg/kg per day based on its renal effect (42). Furthermore, we estimated that the lowest Cd concentrations in rice were 0.017 mg/kg for adults and 0.0006 mg/kg for children’s rice consumption based on the aforementioned calculations. Similarly, Wang et al. (43) also estimated that the Cd content in rice should be lower than 0.09 mg/kg based on the value of JECFA and China’s rice consumption levels. Based on the above calculations, the reference concentrations of Cd in rice were all lower than the current national standards. These data indicated that, although 66.45% of the BCd concentrations were within the recommended limits by ATSDR, both the health guidance values for dietary Cd exposure and the Cd content in rice were significantly lower than the current standards. In situations where it is necessary to protect the health of 95% of the population, the standard values calculated could be even lower. Therefore, the necessity to reevaluate the impact of current standards on public health is evident, and we need to establish a health standard that is more in line with our national conditions.

This study has several limitations: First, due to its cross-sectional design, we were unable to obtain specific indicators of health effects, including kidney damage markers, preventing direct correlation analysis between internal Cd exposure and health outcomes. To address this limitation, we conducted a comprehensive literature analysis incorporating 9812 cases to estimate internal Cd exposure levels and assess associated health risks using BMDL₅ levels for CKD. Second, the lack of detailed individual rice consumption data precluded precise determination of relationships between rice-specific or total dietary Cd intake and internal Cd exposure levels. Third, the genotypes and retention coefficient of various rice varieties had not yet been obtained, making it impossible to analyze the impact of genetic differences on Cd accumulation in rice. Fourth, β2-M serves as a suboptimal biomarker for early kidney injury due to its limited specificity and instability; this study uses CKD as a health biomarker for assessing the risk of Cd exposure through rice consumption. It is important to identify more sensitive and specific biomarkers for early kidney injury in the future. Last, due to lack of smoking information, thus, it is not applicable for evaluation of Cd health guidance values in smoking and nonsmoking populations, respectively.

In conclusion, our comprehensive analysis of environmental Cd exposure, assessment of rice-associated health risks, and integration of BMD calculations with PBPK modeling reveals concerning findings. While most soil and rice samples contain Cd levels below national safety standards, our results demonstrate persistent noncancer health risks and potential carcinogenic risks. These findings raise fundamental questions about the adequacy of current Cd safety limits in preventing Cd-associated diseases and protecting public health. The health guidance values proposed in this study provide robust scientific evidence supporting the revision of Cd safety thresholds.

MATERIALS AND METHODS

Study area and field location

Jiangsu Province, renowned as the “Land of Fish and Rice,” represents one of China’s principal rice-growing regions. Its fertile soil, abundant water resources, and favorable climate make it an ideal location for rice cultivation. Consequently, assessing the dietary risk of rice Cd in Jiangsu Province holds particular significance.

In 2022, we collected 2313 environmental samples from various cities across Jiangsu Province, comprising air (n = 1273), soil (n = 520), and rice (n = 520) samples. PM_2.5 filter pretreatment, metal analysis, and quality assurance are available in previously published studies (44, 45). The details of rice cultivar types were shown in table S6. To comprehensively investigate the Cd content and its interrelationships within the soil-rice system, we established eight sampling points in each of five project counties: Jiangyin, Yixing, Wujiang, Kunshan, and Yizheng. Considering the practical constraint of obtaining complete sample sets during the rice harvest period, we established 40 sampling points. At these locations, we collected 40 comprehensive sample sets, each including soil, rice roots, rice stems, and rice grains. Detailed analytical and testing methodologies for all sample types are provided in the Supplementary Materials.

Because BCd is considered the most valid marker of recent exposure, we collected whole blood to detect BCd level (46). In addition, we obtained 1252 human biological samples, consisting of 626 blood samples and 626 urine samples during the period of collecting above rice and soil samples. Inclusion criteria: (i) living in the area and primarily consuming locally produced rice as staple food and (ii) donating the biological samples including at least 50 ml of morning fasting random midstream urine and 5 ml of blood sample. Exclusion criteria: those with occupational exposure from industries such as metallurgy, chemical, and mining; and pregnant and lactating females who have taken complex trace element drugs and supplements within the 3 months before the survey. The concentration of Cd in urine and blood was detected according to the reported studies (47–49). The limit of detection for BCd was 0.002 μg/liter and that of UCd was 0.001 μg/liter.

Ethics approval statement

The collection and analysis of human biological samples were conducted with approval from the Human Ethics Committee of Jiangsu CDC (201814). The donors consented for the use of the samples for research.

Bioconcentration factor of Cd

The transfer of Cd from soil to rice components is quantified using the dimensionless BCF, expressed by Eq. 1

$$\mathit{\text{BCF}}=\frac{\mathit{Ci}}{\mathit{Cei}}$$ (1)

In this equation, Ci (milligrams per kilogram) represents the concentration of Cd within the plant tissue, while Cei denotes the Cd concentration in surface soil. The BCF serves as a crucial metric for evaluating plants’ capacity to accumulate Cd from soil. Higher BCF values indicate greater accumulation potential, with values exceeding 1 specifically identifying plants as Cd accumulators from soil.

Geoaccumulation index

The Igeo is a widely accepted metric for evaluating pollution levels in sediments and soils. Originally developed for bottom sediments, its application has since expanded to comprehensive soil pollution assessment (Eq. 2)

$$\mathit{\text{Igeo}}={\text{Log}}_2\left(\frac{C\text{sample}}{\mathit{Bn}\ast 1.5}\right)$$ (2)

In this equation, $C\text{sample}$ represents the measured Cd concentration in soil samples, while $\mathit{Bn}$ denotes the geochemical background Cd content in shale. The factor of 1.5 is incorporated to account for potential variations in background content due to lithogenic effects. The interpretation of Igeo values follows a standardized scale: Grade 0, Igeo < 0 indicates uncontaminated soil; grade I, 0 ≤ Igeo < 1 suggests uncontaminated to moderately contaminated conditions; grade II, 1 ≤ Igeo < 2 indicates moderate contamination; grade III, 2 ≤ Igeo < 3 represents moderate to heavy contamination; grade IV, 3 ≤ Igeo < 4 signifies heavy contamination; grade V, 4 ≤ Igeo < 5 indicates heavy to extreme contamination; and grade VI, Igeo ≥ 5 denotes extreme contamination.

Dietary daily intake of Cd assessment

The estimate dietary intake (EDI; micrograms per kilogram of bw per day) represents the average daily intake of Cd from rice consumption in adult populations, calculated using Eq. 3

$$\mathit{\text{EDI}}\mathit{=}\frac{C\mathit{\times }\mathit{\text{IR}}}{\mathit{\text{BW}}}$$ (3)

where C represents the Cd concentration in rice (milligrams per kilogram dry weight); IR represents the daily rice ingestion rate, which averages 310 g/day in China (50); and BW represents the average body weight of an exposed individual in China, established as 65 kg for adults. Previous research has demonstrated that rice processing reduces Cd content by ~19% (51). Therefore, when assessing Cd content in polished rice, we applied a retention factor of 80% in our calculations (52).

Subsequently, the daily dietary Cd intake (Cd intake; micrograms per day) is calculated using Eq. 4

$$\mathit{\text{Cd intake}}=\mathit{\text{EDI}}/55.8\%\times \mathit{\text{BW}}$$ (4)

Health risk assessment

To quantitatively evaluate the health risks associated with rice consumption under varying natural deposition conditions, we calculated the HQ using Eq. 5 (48)

$$\mathit{\text{HQ}}\mathit{=}\mathit{\text{CDI}}\mathit{/}\mathit{\text{Rfd}}$$ (5)

where CDI represents the chronic daily intake. The CDI is calculated using Eq. 6

$$\mathit{\text{CDI}}\mathit{=}\mathit{(}C\mathit{\times }\mathit{\text{IR}}\mathit{\times }\mathit{\text{EF}}\mathit{\times }\mathit{\text{ED}}\mathit{)}\mathit{/}\mathit{(}\mathit{\text{BW}}\mathit{\times }\mathit{\text{AT}}\mathit{)}$$ (6)

where C represents the metal concentration in food, IR is the ingestion rate, EF denotes the exposure frequency, ED represents the exposure duration, BW indicates body weight, and AT signifies the average time for cancer risk assessment (calculated as ED × 365). The reference dose (Rfd) represents the acceptable daily intake, with the specific value for Cd established at 1 μg/kg per day (JECFA, 2011). An HQ value greater than or equal to 1 indicates potential increased health risks, while a value below 1 suggests the exposed population is within safe limits. All parameters used in the calculations were derived from existing literature (25).

Cancer risk assessment

The ILCR quantifies the additional probability of developing cancer over a lifetime due to exposure to a specific contaminant. The ILCR is calculated using Eq. 7

$$\mathit{\text{ILCR}}\mathit{=}\mathit{\text{CDI}}\mathit{\times }\mathit{\text{CSF}}$$ (7)

The cancer slope factor (CSF) represents the upper-bound estimate of the probability of cancer response per unit intake over a lifetime, with an established value of 0.38 mg/kg per day (24). According to the “China Nutrition and Chronic Disease Survey Report” (2020), the reference body weights in China are 65 kg for adults, 21 kg for 6-year-old children, and 49 kg for 14-year-old adolescents. An ILCR exceeding 1.0 × 10⁻⁴ is considered to necessitate intervention, an ILCR below 1.0 × 10⁻⁶ implies no significant hazard, and a risk between 1.0 × 10⁻⁶ and 1.0 × 10⁻⁴ is deemed acceptable.

Article retrieval

Using the keywords “Cd and disease” and “dietary Cd and CKD,” we conducted a systematic search of articles published between December 2000 and December 2024 in PubMed and Web of Science (English language) and CNKI and Wanfang (Chinese language) databases. The search yielded 2667 articles. Studies were included if they met the following criteria: (i) peer-reviewed publication, (ii) clear documentation of dietary and human body Cd concentrations, and (iii) investigation of associations between Cd exposure and disease outcomes. Studies were excluded if they (i) focused on non-Chinese populations, (ii) were systematic reviews or meta-analyses, (iii) were in vitro or in vivo studies, (iv) were not published in English or Chinese, (v) lacked full-text availability, or (vi) did not report clear odds ratio (OR) values. Following these criteria, nine articles were selected for further analysis. In accordance with the BMD derivation requirements, the literature containing both the internal exposure levels of Cd and the prevalence data of CKD was selected to derive the BMDL₅ levels for BCd and UCd (23). Moreover, the literature with dietary Cd exposure levels and CKD prevalence data was chosen to derive the BMDL₅ levels for dietary Cd (12).

PBPK model

In PBPK modeling, this study used the Kjellstrom-Nordberg (K&N) modified PBPK model, following the methodology of a previous study (53). The K&N Cd toxicokinetics model is a nonlinear framework that divides the body into distinct compartments, each containing biologically based saturation kinetics processes (54–56). The model incorporated age- and gender-specific parameters for both forward and reverse dosimetry applications. Sex-specific absorption rates were implemented, with 10% absorption for women and 5% for men (53). The model’s physiological and chemical parameters, along with ordinary differential equations for each compartment, were executed using Berkeley Madonna software (https://berkeley-madonna.myshopify.com/). Monte Carlo simulations revealed high normalized sensitivity coefficients for four parameters (fraction of dietary intake Cd retained in gastrointestinal tract, rate of transfer of Cd in liver to metallothionein, rate of transfer of Cd in metallothionein to kidney, and age-specific rate constant for transfer of Cd in kidney to urine), which are directly linked to renal Cd uptake and urinary excretion. Subsequent analysis demonstrated strong linear correlations between oral doses and measured maximum steady-state concentration (C_max,ss), further validating the model’s consistency and reliability. The kinetic equations and parameters for these compartments are detailed in the aforementioned reference (53).

BMD method

To estimate toxicological response thresholds at which population effects manifest, we performed BMD calculations. We systematically reviewed epidemiological studies examining Cd exposure and adverse health outcomes in China, using ORs to quantify significant relationships. The analysis used a consensus-based approach using the BMD online platform (https://benchmarkdose.com). A 5% relative change from the control group was selected as the BMD response. The analysis incorporated standard models including exponential 2-5, Hill, power, Michaelis-Menten, and linear models. The optimal BMD value was selected on the basis of three criteria: (i) goodness-of-fit threshold with a P value exceeding 0.10, (ii) lowest Akaike information criterion, and (iii) a BMD-to-BMDL ratio below 3. Following established risk assessment practices, we selected BMDL₅ as conservative points of departure (57–59).

Statistical analysis

GLM was used to explore the relationship between the concentration of rice Cd and soil Cd after regions adjustment (60). Spearman’s correlation was used to analysis the correlation between the concentration of PM_2.5-bound Cd and PM_2.5. t test and one-way analysis of variance (ANOVA) were used to explore differences in the concentration of BCd, UCd, and creatinine-corrected UCd across different genders and age groups. All statistical analyses were conducted using SPSS 25.0 software. A two-sided P of <0.05 was considered statistically significant.

Supplementary Materials

This PDF file includes:

Supplementary Notes 1 and 2

Figs. S1 and S2

Tables S1 to S6