Clinical Pharmacist and Master’s student in Clinical Pharmacy with research interests in pharmacovigilance, behavioral interventions in mental health, and AI applications in clinical decision support. Experience includes digital health research with Bloomsbury Health (London) and pharmacovigilance practice in patient support programs. Published work covers drug awareness among healthcare providers, postpartum depression management, and patient safety reporting. 
Clinical Pharmacist and Master’s student in Clinical Pharmacy with research interests in pharmacovigilance, behavioral interventions in mental health, and AI applications in clinical decision support. Experience includes digital health research with Bloomsbury Health (London) and pharmacovigilance practice in patient support programs. Published work covers drug awareness among healthcare providers, postpartum depression management, and patient safety reporting. What was studied?
This original study assessed combined dietary exposure to nephrotoxic metals, specifically cadmium, lead, inorganic arsenic, and inorganic mercury, using mixture risk assessment methods to determine whether chronic intakes in European adults exceed tolerable levels. Two approaches were applied: a classical modified Reference Point Index (mRPI) and a personalized mRPI that aggregates individual-level exposures as cadmium equivalents. Endpoint-specific reference values were derived from human data where possible, anchoring cadmium to a BMDL05-based urinary effect, lead to a CKD-related blood BMDL with an additional uncertainty factor, inorganic arsenic to an eGFR-based BMDL05, and inorganic mercury to a human NOAEL converted to an external dose. The analysis focused on long-term intake and target-organ (kidney) effects relevant to HTMC.
Who was studied?
Adults aged 18–64 years from national dietary surveys in ten European countries, Austria, Croatia, Cyprus, the Czech Republic, Denmark, France, Italy, the Netherlands, Portugal, and Slovenia, were included. Food concentration data for the four metals came from EFSA submissions (2014–2018; plus Portuguese cadmium 2014–2016), harmonized with FoodEx1 codes and, where necessary, translated via recipes to raw commodities. Lower- and upper-bound scenarios handled left-censored data. This population-level framework allowed both country-specific exposure distributions and an aggregation of mixture risk that aligns with HTMC’s certification scope.
Most important findings
| Critical point | Details |
|---|---|
| Lead and cadmium dominate the mixture risk | Across countries, lead contributed ~51–61% (LB) and 55–62% (UB), and cadmium ~21–31% (LB) and 19–25% (UB) to the combined exposure; inorganic arsenic contributed ~11–20% and inorganic mercury ≤7%. Prioritization for HTMC should therefore emphasize lead and cadmium controls. |
| Single-metal exceedances are already common | Combined exposure exceeds the tolerable levels broadly |
| Key food–metal drivers are ubiquitous staples | Lead in vegetables and in grains consistently ranked as top contributors; cadmium in grains was prominent in LB analyses. Additional contributors (country- and scenario-dependent) included lead in drinking water, fruits, meat, herbs/spices/condiments, potatoes and starchy roots, and legumes/nuts/oilseeds. For inorganic arsenic, non-rice grains and seafood contributed 5–10%. No food for inorganic mercury individually exceeded a 5% contribution. |
| Single-metal exceedances already common | In every country, the mean combined exposure (personalized mRPI) surpassed the cadmium ESRV by ~2.5–3.7× in lower-bound and ~5.8–8.3× in upper-bound scenarios; P95 exceedances reached ~4.5–7.4× (LB) and ~10–14× (UB). Table 4 summarizes these exceedances; Figure 1 visualizes population distributions crossing the threshold mRPI=1. These magnitudes indicate that routine diets can exceed the tolerable combined nephrotoxic burden even absent extreme consumers. |
| Methodological strengths and uncertainties | The personalized mRPI reduces over-conservatism of summing high percentiles and still shows substantial exceedance. Uncertainties include conversion of total to inorganic arsenic/mercury, recipe mapping, and heterogeneity in reference point derivation. Despite these, both LB and UB scenarios exceed tolerable intakes, supporting robust concern signals for HTMC. |
Key implications
For HTMC, the primary regulatory impacts include recognizing that combined dietary exposure to nephrotoxic metals frequently exceeds tolerable levels, necessitating mixture-aware limits. Certification requirements should target controls for lead and cadmium in grains, vegetables, and drinking water while monitoring inorganic arsenic in non-rice grains and seafood. Industry applications include supply-chain testing of cereal, vegetable, and water inputs and recipe reformulation to lower aggregate metal equivalents. Research gaps involve direct inorganic species measurements and harmonized relative potency factors. Practical recommendations are to implement cadmium and lead reduction plans, verify water sources, and require species-specific arsenic testing.
Citation
Sprong RC, van den Brand AD, van Donkersgoed G, Blaznik U, Christodoulou D, Crépet A, da Graça Dias M, Jensen BH, Morretto A, Rauscher-Gabernig E, Ruprich J, Sokolić D, van Klaveren JD, Luijten M, Mengelers MJB. Combined chronic dietary exposure to four nephrotoxic metals exceeds tolerable intake levels in the adult population of 10 European countries. Food Additives & Contaminants: Part A. 2023;40(12):1568-1588. doi:10.1080/19440049.2023.2272716.
Cadmium is a persistent heavy metal that accumulates in kidneys and bones. Dietary sources include cereals, cocoa, shellfish and vegetables, while smokers and industrial workers receive higher exposures. Studies link cadmium to kidney dysfunction, bone fractures and cancer.
Lead is a neurotoxic heavy metal with no safe exposure level. It contaminates food, consumer goods and drinking water, causing cognitive deficits, birth defects and cardiovascular disease. HMTC’s rigorous lead testing applies ALARA principles to protect infants and consumers and to prepare brands for tightening regulations.
Arsenic is a naturally occurring metalloid that ranks first on the ATSDR toxic substances list. Inorganic arsenic contaminates water, rice and consumer products, and exposure is linked to cardiovascular disease, cognitive deficits, low birth weight and cancer. HMTC’s stringent certification applies ALARA principles to protect vulnerable populations.
Mercury (Hg) is a neurotoxic heavy metal found in various consumer products and environmental sources, making it a major public health concern. Its regulation is critical to protect vulnerable populations from long-term health effects, such as neurological impairment and cardiovascular disease. The HMTC program ensures that products meet the highest standards for mercury safety.
