Multiple Targets of Toxicity in Environmental Exposure to Low-Dose Cadmium

Abstract

Dietary assessment reports and population surveillance programs show that chronic exposure to low levels of environmental cadmium (Cd) is inevitable for most people, and adversely impacts the health of children and adults. Based on a risk assessment model that considers an increase in the excretion of β₂-microglobulin (β₂M) above 300 μg/g creatinine to be the "critical" toxicity endpoint, the tolerable intake level of Cd was set at 0.83 µg/kg body weight/day, and a urinary Cd excretion rate of 5.24 µg/g creatinine was considered to be the toxicity threshold level. The aim of this review is to draw attention to the many other toxicity endpoints that are both clinically relevant and more appropriate to derive Cd exposure limits than a β₂M endpoint. In the present review, we focus on a reduction in the glomerular filtration rate and diminished fecundity because chronic exposure to low-dose Cd, reflected by its excretion levels as low as 0.5 µg/g creatinine, have been associated with dose-dependent increases in risk of these pathological symptoms. Some protective effects of the nutritionally essential elements selenium and zinc are highlighted. Cd-induced mitochondrial dysfunction is discussed as a potential mechanism underlying gonadal toxicities and infertility.

Keywords: GFR loss; cadmium; dietary exposure; fecundity; nephrotoxicity; selenium; toxicity threshold level; zinc.

Figure 1

Multiple toxicity targets of cadmium. Ingested Cd is absorbed and transported to liver, where synthesis of MT is induced, and CdMT is formed. The fraction of absorbed Cd not taken up by hepatocytes in the first pass reaches systemic circulation and is taken up and accumulated by cells throughout the body. After glomerular filtration, CdMT is reabsorbed by kidney tubular cells. Other forms of filtered Cd can be reabsorbed by the kidney nephron transporters for iron, zinc, manganese, and calcium. Abbreviations: Cd—cadmium; MT—metallothionein; CdMT—cadmium-metallothionein complex; α₁MG—α₁-microgloulin; β₂MG—β₂-microglobulin; GSH—glutathione; ALT—alanine aminotransferase; AST—aspartate aminotransferase; GFR—glomerular filtration rate; CKD—chronic kidney disease.

Figure 2

Metal transporters and receptors involved in cadmium reabsorption. (a) Metal transporters and receptors in the kidney tubule; (b) receptor-mediated endocytosis of filtered proteins. Reabsorption of Cd and CdMT by kidney tubular epithelial cells are mediated by multiple transporter systems such as the megalin/cubilin and NGAL/lipocalin 2 systems and transporters for zinc (Zn), iron (Fe), calcium (Ca) and manganese (Mn).