Population Toxicokinetic Modeling of Cadmium for Health Risk Assessment
Amzal, Billy, Julin, Bettina, Vahter, Marie, Wolk, Alicja, Johanson, Gunnar, Akesson, Agneta, Environmental Health Perspectives
BACKGROUND: Cadmium is a widespread environmental pollutant that has been shown to exert toxic effects on kidney and bones in humans after long-term exposure. Urinary cadmium concentration is considered a good biomarker of accumulated cadmium in kidney, and diet is the main source of cadmium among nonsmokers.
OBJECTIVE: Modeling the link between urinary cadmium and dietary cadmium intake is a key step in the risk assessment of long-term cadmium exposure. There is, however, little knowledge on how this link may vary, especially for susceptible population strata.
METHODS: We used a large population-based study (the Swedish Mammography Cohort), with repeated dietary intake data covering a period of 20 years, to compare estimated dietary cadmium intake with urinary cadmium concentrations on an individual basis. A modified version of the Nordberg-Kjellstrom model and a one-compartment model were evaluated in terms of their predictions of urinary cadmium. We integrated the models and quantified the between-person variability of cadmium half-life in the population. Finally, sensitivity analyses and Monte Carlo simulations were performed to illustrate how the latter model could serve as a robust tool supporting the risk assessment of cadmium in humans.
RESULTS: The one-compartment population model appeared to be an adequate modeling option to link cadmium intake to urinary cadmium and to describe the population variability. We estimated the cadmium half-life to be about 11.6 years, with about 25% population variability.
CONCLUSIONS: Population toxicokinetic models can be robust and useful tools for risk assessment of chemicals, because they allow quantification and integration of population variability in toxicokinetics.
KEY WORDS: alternative model development, Bayesian inference, cadmium toxicokinetics, population variability, risk assessment, toxicokinetic models, urinary cadmium. Environ Health Perspect 117:1293-1301 (2009). doi:10.1289/ehp.0800317 available via http://dx.doi.org/ [Online 6 May 2009]
Cadmium is a widespread environmental pollutant (Nordberg et al. 2007). There is accumulating data of toxic effects on kidney (Buchet et al. 1990; de Burbure et al. 2003; Jarup et al. 2000; Nishijo et al. 2006; Suwazono et al. 2006) and bone (Akesson et al. 2006; Alfven et al. 2004; Gallagher et al. 2008; Schutte et al. 2008; Staessen et al. 1999) at urinary cadmium concentrations < 2.5 [[micro]g/g] creatinine, previously considered to represent a safe exposure [Joint Food and Agriculture Organization of the United Nations (FAO)/World Health Organization (WHO) Expert Committee on Food Additives 2003]. A precautionary approach in the risk assessment of cadmium is further supported by recent findings suggesting increased risk of cancer and overall mortality in relation to low-level cadmium exposure (Akesson et al. 2008; Nawrot et al. 2006, 2008), as well as variation in susceptibility (Vahter et al. 2007).
Diet is the major source of cadmium exposure in nonsmokers (Nordberg et al. 2007). The concentrations of cadmium in food vary considerably, but often foods of plant origin, such as cereals, potatoes, roots, and vegetables, are the major contributors to the exposure (Olsson et al. 2002). Cadmium accumulates mainly in the kidneys, and the kidney concentration of the metal is reflected in the concentration in urine, which thereby can be used as a marker of long-term cadmium exposure (Nordberg et al. 2007). Urinary cadmium concentrations are therefore commonly used as a surrogate for the body burden in health risk assessment. In order to perform a reliable and comprehensive assessment of the health risks associated with long-term exposure to cadmium in food, data on dietary intake of cadmium need to be related to the internal dose over many years.
To assess the variation in the association between dietary cadmium intake and urinary cadmium in the general population, various individual physiologic parameters affecting the internal dose of cadmium need to be taken into account. …