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Population toxicokinetic modeling of cadmium for health risk assessment.

Amzal B, Julin B, Vahter M, Wolk A, Johanson G, Akesson A - Environ. Health Perspect. (2009)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Assessment Methodology Unit, European Food Safety Authority, Parma, Italy. Billy.AMZAL@efsa.europa.eu

ABSTRACT

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-Kjellström 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.

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Related in: MedlinePlus

Measured individual urinary cadmium (U-Cd) concentrations versus individual predictions from the one-compartment population model, using additional 25% intraindividual variability on U-Cd.
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f8-ehp-117-1293: Measured individual urinary cadmium (U-Cd) concentrations versus individual predictions from the one-compartment population model, using additional 25% intraindividual variability on U-Cd.

Mentions: Finally, a sensitivity analysis was also performed with respect to additional intra-individual variability of urinary cadmium concentrations, which could not directly be estimated from the data. In the final model, we estimated the residual variance to be about CV = 13% on average of the urinary cadmium measured. This variance encompasses mainly the intraindividual variability (e.g., intraoccasion variation), but also some measurement error. This may be too small, so some of this intraindividual variability may have been transferred into the population variability, hence inflating the variability shown in Figure 6. In order to assess what would be the outcome of a similar analysis but fixing some predetermined interoccasion variability, we added an additional variance term in the error model, which we set as a multiplicative (lognormal) error with CV = 25%, hence describing an additional 25% variability of urinary cadmium concentrations within subjects. A similar statistical inference was subsequently performed. The resulting fit was not as good as the fit without this new assumption, especially for urinary cadmium concentrations > 0.4 μg/g creatinine, leading to a consistent underestimation of the model (Figure 8). Although the data do not fully support this new assumption, the parameter estimates could be derived. We estimated the new mean half-life to be 11.6 years (95% CI = 9.3–16) and the new intersubject variability to 2.7 years (95% CI = 2–4). As expected, the intersubject variability had been transferred to intrasubject variability, although in a moderate way. The 5th percentiles of daily cadmium intake needed to achieve a given urinary cadmium value were seen to be relatively robust with respect to this extravariability assumption (~ 10% higher when such a variability is taken into account).


Population toxicokinetic modeling of cadmium for health risk assessment.

Amzal B, Julin B, Vahter M, Wolk A, Johanson G, Akesson A - Environ. Health Perspect. (2009)

Measured individual urinary cadmium (U-Cd) concentrations versus individual predictions from the one-compartment population model, using additional 25% intraindividual variability on U-Cd.
© Copyright Policy - public-domain
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2721875&req=5

f8-ehp-117-1293: Measured individual urinary cadmium (U-Cd) concentrations versus individual predictions from the one-compartment population model, using additional 25% intraindividual variability on U-Cd.
Mentions: Finally, a sensitivity analysis was also performed with respect to additional intra-individual variability of urinary cadmium concentrations, which could not directly be estimated from the data. In the final model, we estimated the residual variance to be about CV = 13% on average of the urinary cadmium measured. This variance encompasses mainly the intraindividual variability (e.g., intraoccasion variation), but also some measurement error. This may be too small, so some of this intraindividual variability may have been transferred into the population variability, hence inflating the variability shown in Figure 6. In order to assess what would be the outcome of a similar analysis but fixing some predetermined interoccasion variability, we added an additional variance term in the error model, which we set as a multiplicative (lognormal) error with CV = 25%, hence describing an additional 25% variability of urinary cadmium concentrations within subjects. A similar statistical inference was subsequently performed. The resulting fit was not as good as the fit without this new assumption, especially for urinary cadmium concentrations > 0.4 μg/g creatinine, leading to a consistent underestimation of the model (Figure 8). Although the data do not fully support this new assumption, the parameter estimates could be derived. We estimated the new mean half-life to be 11.6 years (95% CI = 9.3–16) and the new intersubject variability to 2.7 years (95% CI = 2–4). As expected, the intersubject variability had been transferred to intrasubject variability, although in a moderate way. The 5th percentiles of daily cadmium intake needed to achieve a given urinary cadmium value were seen to be relatively robust with respect to this extravariability assumption (~ 10% higher when such a variability is taken into account).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Assessment Methodology Unit, European Food Safety Authority, Parma, Italy. Billy.AMZAL@efsa.europa.eu

ABSTRACT

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-Kjellström 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.

Show MeSH
Related in: MedlinePlus