Benchmark dose modeling to define permissible exposure levels for environmental cadmium

Abstract

Kidney and bone destruction in patients with itai-itai disease is caused by consuming rice contaminated with the heavy metal cadmium (Cd). Based on a lifetime intake of 2 g of Cd, and an elevation of β₂-microglobulin (β₂M) excretion rate, a tolerable Cd intake level was 0.83 µg/kg body weight per day (58 µg/day for a 70 kg person), with a threshold of 5.24 µg/g creatinine. However, current evidence suggests that these guidelines are inadequate to protect public health. Using experimental dosing and human population data, this review highlights the imprecision in determining exposure, internal doses, and adverse effects, leading to erroneous conclusions that Cd exposure did not diminish the estimated glomerular filtration rate (eGFR) nor did it accelerate progressive eGFR decline toward kidney failure among Cd-exposed people. It discusses the principles and application of the benchmark dose (BMD) modeling to human exposure-effect relationships from which the critical Cd exposure levels can be identified reliably, with kidney effect indicators other than the β₂M excretion. It offers insights into the utility of multiple mathematical dose-response models to define the benchmark dose limit (BMDL) value for Cd exposure, which carries discernible health risk. From BMD modeling studies, Cd excretion benchmarks for early kidney effects, reflected by excretion of total proteins, N-acetyl-β-D-glucosaminidase, and eGFR decline, were 0.95, 1.34, and 3.24% of the current threshold, respectively. These Cd excretion levels are ideal for the derivation of safe Cd exposure guidelines because they are equivalent to no-observed-adverse-effect levels (NOAELs).

Keywords

Benchmark dose, cadmium exposure / cadmium nephrotoxicity / NOAEL equivalent / threshold

References

[1] Aoshima K.Epidemiology of renal tubular dysfunction in the inhabitants of a cadmium-polluted area in the Jinzu River basin in Toyama prefecture.Tohoku J Exp Med1987;152:151-72

[2] Cai Y,Katoh T,Kasuya M.Renal tubular dysfunction in male inhabitants of a cadmium-polluted area in Toyama, Japan - an eleven-year follow-up study.J Epidemiol2001;11:180-9 PMCID:PMC11735076

[3] Sasaki T,Matsukawa T.A suspected case of “itai-itai disease” in a cadmium-polluted area in Akita prefecture, Japan.Environ Health Prev Med2024;29:40 PMCID:PMC11310559

[4] Horiguchi H,Sasaki S.Exposure assessment of cadmium in female farmers in cadmium-polluted areas in northern Japan.Toxics2020;8:44 PMCID:PMC7356160

[5] Verbeeck M,Smolders E.Trace element concentrations in mineral phosphate fertilizers used in Europe: a balanced survey.Sci Total Environ2020;712:136419

[6] Zou M,Zhou Y,Guo T.Cadmium pollution of soil-rice ecosystems in rice cultivation dominated regions in China: a review.Environ Pollut2021;280:116965

[7] McDowell RW.Do soil cadmium concentrations decline after phosphate fertiliser application is stopped: a comparison of long-term pasture trials in New Zealand?.Sci Total Environ2022;804:150047

[8] Hou D,Wang L.Global soil pollution by toxic metals threatens agriculture and human health.Science2025;388:316-21

[9] Eklund G,Oskarsson A.A piglet model for studies of gastrointestinal uptake of cadmium in neonates.Toxicol Lett2004;146:237-47

[10] Olsson IM,Lundh T,Skerfving S.Cadmium in blood and urine - impact of sex, age, dietary intake, iron status, and former smoking - association of renal effects.Environ Health Perspect2002;110:1185-90 PMCID:PMC1241104

[11] Vasco E,Oliveira L.The first harmonised total diet study in Portugal: Arsenic, cadmium and lead exposure assessment.Chemosphere2025;372:144003.

[12] Cantoral A,Betanzos-Robledo L.Dietary risk assessment of cadmium exposure through commonly consumed foodstuffs in Mexico.Foods2024;13:3649 PMCID:PMC11593398

[13] Zhu H,Gu C,Liu Y,Zhang Z.Assessment of human exposure to cadmium and its nephrotoxicity in the Chinese population.Sci Total Environ2024;918:170488

[14] Kolbaum AE,Jaeger A,Lindtner O.Assessment of long-term dietary cadmium exposure in children in Germany: does consideration of data from total diet studies reduce uncertainties from food monitoring programmes?.Food Chem Toxicol2024;184:114404

[15] Hill DT,Petroni M.Airborne levels of cadmium are correlated with urinary cadmium concentrations among young children living in the New York state city of Syracuse, USA.Environ Res2023;223:115450 PMCID:PMC9992329

[16] Almerud P,Lindroos AK.Cadmium, total mercury, and lead in blood and associations with diet, sociodemographic factors, and smoking in Swedish adolescents.Environ Res2021;197:110991

[17] Fagerberg B.Review of cadmium exposure and smoking-independent effects on atherosclerotic cardiovascular disease in the general population.J Intern Med2021;290:1153-79

[18] Kim J,Lee J.Smoking and passive smoking increases mortality through mediation effect of cadmium exposure in the United States.Sci Rep2023;13:3878 PMCID:PMC9995499

[19] Wong C,Saab IN.Review of regulatory reference values and background levels for heavy metals in the human diet.Regul Toxicol Pharmacol2022;130:105122

[20] Crump KS.A new method for determining allowable daily intakes.Fundam Appl Toxicol1984;4:854-71

[21] Gaylor D,Krewski D.Procedures for calculating benchmark doses for health risk assessment.Regul Toxicol Pharmacol1998;28:150-64

[22] Ginsberg GL.Cadmium risk assessment in relation to background risk of chronic kidney disease.J Toxicol Environ Health A2012;75:374-90

[23] Moffett D.B., Mumtaz M.M., Sullivan D.W., Jr., Whittaker M.H. Chapter 13, General Considerations of Dose-Effect and Dose-Response Relationships. In: Nordberg G., Costa M., editors. Handbook on the Toxicology of Metals. 5th ed. Cambridge, MA, USA: Academic Press; 2022. pp. 299-317.

[24] Codex Alimentarius. Codex general standard for contaminants and toxins in food and feed. 2010. Available from: chrome-extension://efaidnbmnnnibpcajpcglclefindmkaj/https://www.fao.org/fileadmin/user_upload/agns/pdf/CXS_193e.pdf (accessed on 2025-8-15)

[25] Nogawa K,Ishizaki M,Nakagawa H.Threshold limit values of the cadmium concentration in rice in the development of itai-itai disease using benchmark dose analysis.J Appl Toxicol2017;37:962-6

[26] Nishijo M,Suwazono Y,Sakurai M.Lifetime cadmium exposure and mortality for renal diseases in residents of the cadmium-polluted Kakehashi river basin in Japan.Toxics2020;8:81 PMCID:PMC7711806

[27] Joint FAO/WHO Expert Committee on Food Additives. Safety evaluation of certain food additives and contaminants. In: Joint FAO/WHO Expert Committee on Food Additives and Contaminants, Seventy-Third Meeting: Proceedings of the Joint FAO/WHO Expert Committee on Food Additives and Contaminants, Seventy-Third Meeting; 2010 Jun 8-17; Geneva, Switzerland; Geneva: 2011. Available from: https://apps.who.int/iris/handle/10665/44521 (accessed on 2025-8-15).

[28] Murton M,Bobrowska A.Burden of chronic kidney disease by KDIGO categories of glomerular filtration rate and albuminuria: a systematic review.Adv Ther2021;38:180-200 PMCID:PMC7854398

[29] Kalantar-Zadeh K,Nitsch D,Perkovic V.Chronic kidney disease.Lancet2021;398:786-802

[30] Farrell DR.Screening, identifying, and treating chronic kidney disease: why, who, when, how, and what?.BMC Nephrol2024;25:34 PMCID:PMC10809507

[31] Foreman KJ,Dolgert A.Forecasting life expectancy, years of life lost, and all-cause and cause-specific mortality for 250 causes of death: reference and alternative scenarios for 2016-40 for 195 countries and territories.Lancet2018;392:2052-90 PMCID:PMC6227505

[32] 2021 Forecasting Collaborators. Burden of disease scenarios for 204 countries and territories, 2022-2050: a forecasting analysis for the Global Burden of Disease Study 2021.Lancet2024;403:2204-56 PMCID:PMC11121021

[33] Satarug S,Yimthiang S,Gobe GC.The NOAEL equivalent of environmental cadmium exposure associated with GFR reduction and chronic kidney disease.Toxics2022;10:614 PMCID:PMC9607051

[34] Feng X,Jiang Q,Yu C.Analysis of cadmium accumulation in community adults and its correlation with low-grade albuminuria.Sci Total Environ2022;834:155210

[35] Grau-Perez M,Galan-Chilet I.Urine cadmium levels and albuminuria in a general population from Spain: a gene-environment interaction analysis.Environ Int2017;106:27-36

[36] Satarug S,Ruangyuttikarn W,Ruiz P.Modeling cadmium exposures in low- and high-exposure areas in Thailand.Environ Health Perspect2013;121:531-6 PMCID:PMC3673184

[37] Xie S,Golshayan D.Association between urinary heavy metal/trace element concentrations and kidney function: a prospective study.Clin Kidney J2025;18:sfae378 PMCID:PMC11822291

[38] Shi Z,Riley M,Liu J.Association between dietary patterns, cadmium intake and chronic kidney disease among adults.Clin Nutr2018;37:276-84

[39] Cadmium and cadmium compounds.IARC Monogr Eval Carcinog Risks Hum1993; 58:119-237 PMCID:PMC7681575

[40] Huff J,Waalkes MP,Infante PF.Cadmium-induced cancers in animals and in humans.Int J Occup Environ Health2007;13:202-12 PMCID:PMC3399253

[41] Tokar EJ,Waalkes MP.Metal ions in human cancer development.Met Ions Life Sci2011;8:375-401

[42] Waalkes MP.Chronic toxic and carcinogenic effects of cadmium chloride in male DBA/2NCr and NFS/NCr mice: strain-dependent association with tumors of the hematopoietic system, injection site, liver, and lung.Fundam Appl Toxicol1994;23:21-31

[43] Cirovic A.Toxicity tolerance in the carcinogenesis of environmental cadmium.Int J Mol Sci2024;25:1851 PMCID:PMC10855822

[44] Kim YJ,Seomun G.Whole-blood lead, mercury, and cadmium concentrations and their associations with cancer in Korean elders (2007-2018).Arch Environ Occup Health2025;80:39-48

[45] Food Safety Authority (EFSA). Cadmium in food - scientific opinion of the panel on contaminants in the food chain.EFSA J2009;980:1-139

[46] Food Safety Authority (EFSA). Statement on tolerable weekly intake for cadmium.EFSA J2011;9:1975

[47] Qing Y,Zhu Y.Dose-response evaluation of urinary cadmium and kidney injury biomarkers in Chinese residents and dietary limit standards.Environ Health2021;20:75 PMCID:PMC8247151

[48] Qing Y,Chen Y.Urinary cadmium in relation to bone damage: cadmium exposure threshold dose and health-based guidance value estimation.Ecotoxicol Environ Saf2021;226:112824

[49] Leconte S,Bodin L,Carne G.Refinement of health-based guidance values for cadmium in the French population based on modelling.Toxicol Lett2021;340:43-51

[50] Schaefer HR,Crosby LM.Reassessment of the cadmium toxicological reference value for use in human health assessments of foods.Regul Toxicol Pharmacol2023;144:105487

[51] Pouillot R,Spungen J,Flannery BM.Cadmium physiologically based pharmacokinetic (PBPK) models for forward and reverse dosimetry: Review, evaluation, and adaptation to the U.S. population.Toxicol Lett2022;367:67-75

[52] Wu X,Wei Y.The reference dose for subchronic exposure of pigs to cadmium leading to early renal damage by benchmark dose method.Toxicol Sci2012;128:524-31

[53] Chaumont A,Dumont X,Bernard A.The threshold level of urinary cadmium associated with increased urinary excretion of retinol-binding protein and beta 2-microglobulin: a re-assessment in a large cohort of nickel-cadmium battery workers.Occup Environ Med2011;68:257-64 PMCID:PMC3060309

[54] Committee for Recommendation of Occupational Exposure Limits, Japan Society for Occupational HealthOccupational exposure limits for acetaldehyde, 2-bromopropane, glyphosate, manganese and inorganic manganese compounds, and zinc oxide nanoparticle, and the biological exposure indices for cadmium and cadmium compounds and ethylbenzene, and carcinogenicity, occupational sensitizer, and reproductive toxicant classifications.J Occup Health2021;63:e12294 PMCID:PMC8605477

[55] Nogawa K,Watanabe Y.Estimation of benchmark dose of cumulative cadmium exposure for renal tubular effect.Int J Environ Res Public Health2021;18:5177 PMCID:PMC8152986

[56] Hoshino K,Yoshioka N.Increased risk of proximal tubular dysfunction due to occupational cadmium exposure: a survival analysis study.J Occup Health2025;67 PMCID:PMC11977533

[57] Choi WJ,Ham S,Kim AJ.Chronic cadmium intoxication and renal injury among workers of a small-scale silver soldering company.Saf Health Work2020;11:235-40 PMCID:PMC7303519

[58] Brzóska MM.Disorders in bone metabolism of female rats chronically exposed to cadmium.Toxicol Appl Pharmacol2005;202:68-83

[59] Brzóska MM.Bone metabolism of male rats chronically exposed to cadmium.Toxicol Appl Pharmacol2005;207:195-211

[60] Brzóska MM.Effect of low-level lifetime exposure to cadmium on calciotropic hormones in aged female rats.Arch Toxicol2005;79:636-46

[61] Faroon O,Mumtaz M.Minimal risk level derivation for cadmium: acute and intermediate duration exposures.J Exp Clin Toxicol2017;1:1-12 PMCID:PMC8372830

[62] National Toxicology Program. NTP technical report on toxicity studies of cadmium oxide (CAS No. 1306–19-0) Administered by Inhalation to F344/N Rats and B6C3F1 Mice. 1995 Feb. Report No. NIH/PUB--95-3388. U.S. Department of Health and Human Services. National Institutes of Health. National Toxicology Program, Research Triangle Park, NC, USA. Available from: https://www.osti.gov/biblio/121897#:~:text=This%20report%20describes%20toxicity%20studies%20of%20cadmium%20oxide,aerosol%20in%20Sprague-Dawley%20rats%20and%20Swiss%20%28CD-1%29%20mice. (accessed on 2025-8-15).

[63] Hardy A,Halldorsson T.EFSA Scientific CommitteeUpdate: use of the benchmark dose approach in risk assessment.EFSA J2017;15:e04658.

[64] Filipsson AF,Nilsson J.The benchmark dose method - review of available models, and recommendations for application in health risk assessment.Crit Rev Toxicol2003;33:505-42

[65] Slob W.A general theory of effect size, and its consequences for defining the benchmark response (BMR) for continuous endpoints.Crit Rev Toxicol2017;47:342-51

[66] Sand SJ,Filipsson AF.Benchmark calculations in risk assessment using continuous dose-response information: the influence of variance and the determination of a cut-off value.Risk Anal2003;23:1059-68

[67] Slob W,Rauniomaa E.A statistical evaluation of toxicity study designs for the estimation of the benchmark dose in continuous endpoints.Toxicol Sci2005;84:167-85

[68] Sand S,Victorin K.Evaluation of the benchmark dose method for dichotomous data: model dependence and model selection.Regul Toxicol Pharmacol2002;36:184-97

[69] Slob W.Shape and steepness of toxicological dose-response relationships of continuous endpoints.Crit Rev Toxicol2014;44:270-97

[70] Zhu Y,Jelsovsky JZ.Bootstrap estimation of benchmark doses and confidence limits with clustered quantal data.Risk Anal2007;27:447-65

[71] Woo HD,Jo S.Benchmark dose for urinary cadmium based on a marker of renal dysfunction: a meta-analysis.PLoS One2015;10:e0126680 PMCID:PMC4430293

[72] Wang X,Feng L.Application of the benchmark dose (BMD) method to identify thresholds of cadmium-induced renal effects in non-polluted areas in China.PLoS One2016;11:e0161240 PMCID:PMC4990304

[73] Suwazono Y,Vahter M.Benchmark dose for cadmium-induced renal effects in humans.Environ Health Perspect2006;114:1072-6 PMCID:PMC1513341

[74] Hayashi T,Watanabe Y.Benchmark dose of urinary cadmium for assessing renal tubular and glomerular function in a cadmium-polluted area of Japan.Toxics2024;12:836 PMCID:PMC11679213

[75] Satarug S,Gobe GC.The Validity of Benchmark dose limit analysis for estimating permissible accumulation of cadmium.Int J Environ Res Public Health2022;19:15697 PMCID:PMC9736539

[76] Satarug S,Đorđević AB.The NOAEL equivalent for the cumulative body burden of cadmium: focus on proteinuria as an endpoint.J Environ Expo Assess2024;3:26.

[77] Liu C,Zhu C.Benchmark dose for cadmium exposure and elevated N-acetyl-β-D-glucosaminidase: a meta-analysis.Environ Sci Pollut Res Int2016;23:20528-38

[78] Thomas LD,Nieuwenhuijsen M.Early kidney damage in a population exposed to cadmium and other heavy metals.Environ Health Perspect2009;117:181-4 PMCID:PMC2649217

[79] Kunioka CT,Carvalho M.Association between environmental cadmium exposure and osteoporosis risk in postmenopausal women: a systematic review and meta-analysis.Int J Environ Res Public Health2022;20:485 PMCID:PMC9820024

[80] Wallin M,Lundh T.Low-level cadmium exposure and effects on kidney function.Occup Environ Med2014;71:848-54 PMCID:PMC4251161

[81] Phelps KR,Pouyfung P,Vesey DA.Homeostasis of β2-Microglobulin in diabetics and non-diabetics with modest cadmium intoxication. Version: 1 ScieRxiv [Preprints] 2025 [Received: 20 Feb 2025; Approved: 20 Feb 2025; Cited 15 Aug 2025] [35 p.].

[82] Đorđević AB,Satarug S.Cadmium-induced nephrotoxicity assessed by benchmark dose calculations in two exposure-effect datasets. 10.21203/rs.3.rs-6799604/v1.

[83] Makhammajanov Z,Myngbay A,Aljofan M.Tubular toxicity of proteinuria and the progression of chronic kidney disease.Nephrol Dial Transplant2024;39:589-99

[84] Faivre A,de Seigneux S.Proteinuria and tubular cells: plasticity and toxicity.Acta Physiol (Oxf)2025;241:e14263

[85] Liu D.New Understanding on the role of proteinuria in progression of chronic kidney disease. In: Liu B, Lan H, Lv L, editors. Renal Fibrosis: Mechanisms and Therapies. Singapore: Springer; 2019. pp. 487-500.

[86] Schneider SN,Wang B.Oral cadmium in mice carrying 5 versus 2 copies of the Slc39a8 gene: comparison of uptake, distribution, metal content, and toxicity.Int J Toxicol2014;33:14-20

[87] Fujishiro H.New insights into the roles of ZIP8, a cadmium and manganese transporter, and its relation to human diseases.Biol Pharm Bull2019;42:1076-82

[88] Thévenod F,Lee WK.Channels, transporters and receptors for cadmium and cadmium complexes in eukaryotic cells: myths and facts.Biometals2019;32:469-89

[89] Ohta H.Involvement of metal transporters in the intestinal uptake of cadmium.J Toxicol Sci2020;45:539-48

[90] Fujita Y,Min KS,Okada Y,Mutoh N.Fate of cadmium bound to phytochelatin in rats.Res Commun Chem Pathol Pharmacol1993;82:357-65

[91] Langelueddecke C,Fenton RA.Expression and function of the lipocalin-2 (24p3/NGAL) receptor in rodent and human intestinal epithelia.PLoS One2013;8:e71586 PMCID:PMC3734285

[92] Langelueddecke C,Thévenod F.Differential transcytosis and toxicity of the hNGAL receptor ligands cadmium-metallothionein and cadmium-phytochelatin in colon-like Caco-2 cells: implications for in vivo cadmium toxicity.Toxicol Lett2014;226:228-35

[93] Kikuchi Y,Kumagai N.Uptake of cadmium in meals from the digestive tract of young non-smoking Japanese female volunteers.J Occup Health2003;45:43-52

[94] Horiguchi H,Sasaki S.Comprehensive study of the effects of age, iron deficiency, diabetes mellitus, and cadmium burden on dietary cadmium absorption in cadmium-exposed female Japanese farmers.Toxicol Appl Pharmacol2004;196:114-23

[95] Julin B,Amzal B,Berglund M.Relation between dietary cadmium intake and biomarkers of cadmium exposure in premenopausal women accounting for body iron stores.Environ Health2011;10:105 PMCID:PMC3265442

[96] Elinder CG,Kjellström T,Friberg L.Cadmium in kidney cortex, liver, and pancreas from Swedish autopsies. Estimation of biological half time in kidney cortex, considering calorie intake and smoking habits.Arch Environ Health1976;31:292-302

[97] Elinder CG,Lind B,Silander T.Cadmium concentrations in human liver, blood, and bile: comparison with a metabolic model.Environ Res1978;17:236-41

[98] Qing Y,Cai X,Liu S,Jiang M,Wang J,Chen Y,Li Y.Assessment of cadmium concentrations in foodstuffs and dietary exposure risk across China: a metadata analysis.Expo Health2023;15:951-61.

[99] Callan A,Devine A.Metals in commonly eaten groceries in Western Australia: a market basket survey and dietary assessment.Food Addit Contam Part A Chem Anal Control Expo Risk Assess2014;31:1968-81

[100] Satarug S,Reilly PE,Williams DJ.Cadmium levels in the lung, liver, kidney cortex, and urine samples from Australians without occupational exposure to metals.Arch Environ Health2002;57:69-77

[101] Akerstrom M,Lundh T.The relationship between cadmium in kidney and cadmium in urine and blood in an environmentally exposed population.Toxicol Appl Pharmacol2013;268:286-93

[102] Barregard L,Lundh T.Cadmium, mercury, and lead in kidney cortex of living kidney donors: Impact of different exposure sources.Environ Res2010;110:47-54

[103] Sand S.Assessment of dietary cadmium exposure in Sweden and population health concern including scenario analysis.Food Chem Toxicol2012;50:536-44

[104] Barregard L,Lundh T.Low-level exposure to lead, cadmium and mercury, and histopathological findings in kidney biopsies.Environ Res2022;211:113119

[105] Lenoir O,Huber TB.Autophagy in kidney disease and aging: lessons from rodent models.Kidney Int2016;90:950-64

[106] Fujiwara Y,Tokumoto M.Cadmium renal toxicity via apoptotic pathways.Biol Pharm Bull2012;35:1892-7

[107] Thévenod F,Garrick MD.Iron and cadmium entry into renal mitochondria: physiological and toxicological implications.Front Cell Dev Biol2020;8:848 PMCID:PMC7492674

[108] Dong PF,Chen K.Cadmium targeting transcription factor EB to inhibit autophagy-lysosome function contributes to acute kidney injury.J Adv Res2025;72:653-69 PMCID:PMC12147601

[109] Lv YT,Li Y,Lian CY.HO-1 activation contributes to cadmium-induced ferroptosis in renal tubular epithelial cells via increasing the labile iron pool and promoting mitochondrial ROS generation.Chem Biol Interact2024;399:111152

[110] Ning B,Kong A.Calcium signaling mediates cell death and crosstalk with autophagy in kidney disease.Cells2021;10:3204 PMCID:PMC8622220

[111] Li K,Ruan J.Cadmium disrupted ER Ca²⁺ homeostasis by inhibiting SERCA2 expression and activity to induce apoptosis in renal proximal tubular cells.Int J Mol Sci2023;24:5979 PMCID:PMC10053525

[112] Liu F,Wang ZY.Role of subcellular calcium redistribution in regulating apoptosis and autophagy in cadmium-exposed primary rat proximal tubular cells.J Inorg Biochem2016;164:99-109

[113] Lang SM.Smoking status, cadmium, and chronic kidney disease.Ren Replace Ther2024;10:17

[114] Grandjean P.Total imprecision of exposure biomarkers: implications for calculating exposure limits.Am J Ind Med2007;50:712-9 PMCID:PMC2855962

[115] Byber K,Verougstraete V,Hotz P.Cadmium or cadmium compounds and chronic kidney disease in workers and the general population: a systematic review.Crit Rev Toxicol2016;46:191-240

[116] Jalili C,Cheng H.Associations between exposure to heavy metals and the risk of chronic kidney disease: a systematic review and meta-analysis.Crit Rev Toxicol2021;51:165-82

[117] Doccioli C,Francavilla A,Biggeri A.Association of cadmium environmental exposure with chronic kidney disease: a systematic review and meta-analysis.Sci Total Environ2024;906:167165

[118] Johri N,Unwin R.Heavy metal poisoning: the effects of cadmium on the kidney.Biometals2010;23:783-92

[119] Phelps KR.A generic method for analysis of plasma concentrations
.Clin Nephrol2020;94:43-49

[120] Argyropoulos CP,Ng YH.Rediscovering beta-2 microglobulin as a biomarker across the spectrum of kidney diseases.Front Med (Lausanne)2017;4:73 PMCID:PMC5471312

[121] Sivanathan PC,Mohammad Haniff MAS.Lifting the veil: characteristics, clinical significance, and application of β-2-microglobulin as biomarkers and its detection with biosensors.ACS Biomater Sci Eng2022;8:3142-61

[122] Molitoris BA,Yadav SPS.Albumin uptake and processing by the proximal tubule: physiological, pathological, and therapeutic implications.Physiol Rev2022;102:1625-67 PMCID:PMC9255719

[123] Comper WD,McCarthy KJ.New insights into proteinuria/albuminuria.Front Physiol2022;13:991756 PMCID:PMC9548894

[124] Benzing T.Insights into glomerular filtration and albuminuria.N Engl J Med2021;384:1437-46

[125] Satarug S,Gobe GC.The pathogenesis of albuminuria in cadmium nephropathy.Curr Res Toxicol2024;6:100140 PMCID:PMC10726218

[126] Satarug S,Gobe GC,Buha Đorđević A.Health risk in a geographic area of Thailand with endemic cadmium contamination: focus on albuminuria.Toxics2023;11:68 PMCID:PMC9866753

[127] Shi P,Fan X.A benchmark dose analysis for urinary cadmium and type 2 diabetes mellitus.Environ Pollut2021;273:116519

[128] Schwartz GG,Ivanova A.Urinary cadmium, impaired fasting glucose, and diabetes in the NHANES III.Diabetes Care2003;26:468-70

[129] Jiang F,Xu M,Zhang Z.Gender-specific differences of interaction between cadmium exposure and obesity on prediabetes in the NHANES 2007-2012 population.Endocrine2018;61:258-66

[130] Wallia A,Badon S.Association between urinary cadmium levels and prediabetes in the NHANES 2005-2010 population.Int J Hyg Environ Health2014;217:854-60 PMCID:PMC4194078

[131] Hagedoorn IJM,Huizen SV.Lifestyle-related exposure to cadmium and lead is associated with diabetic kidney disease.J Clin Med2020;9:2432 PMCID:PMC7463543

[132] Oosterwijk MM,Maatman RGHJ,Navis G.Cadmium, active smoking and renal function deterioration in patients with type 2 diabetes.Nephrol Dial Transplant2023;38:876-83

[133] Okubo A,Doi S.High-normal albuminuria is strongly associated with incident chronic kidney disease in a nondiabetic population with normal range of albuminuria and normal kidney function.Clin Exp Nephrol2020;24:435-43

[134] Lin X,Zhou Y.Elevated urine albumin creatinine ratio increases cardiovascular mortality in coronary artery disease patients with or without type 2 diabetes mellitus: a multicenter retrospective study.Cardiovasc Diabetol2023;22:203 PMCID:PMC10416404