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      Population Toxicokinetic Modeling of Cadmium for Health Risk Assessment

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          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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          Most cited references30

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          Gender differences in the disposition and toxicity of metals.

          There is increasing evidence that health effects of toxic metals differ in prevalence or are manifested differently in men and women. However, the database is small. The present work aims at evaluating gender differences in the health effects of cadmium, nickel, lead, mercury and arsenic. There is a markedly higher prevalence of nickel-induced allergy and hand eczema in women compared to men, mainly due to differences in exposure. Cadmium retention is generally higher in women than in men, and the severe cadmium-induced Itai-itai disease was mainly a woman's disease. Gender differences in susceptibility at lower exposure are uncertain, but recent data indicate that cadmium has estrogenic effects and affect female offspring. Men generally have higher blood lead levels than women. Lead accumulates in bone and increased endogenous lead exposure has been demonstrated during periods of increased bone turnover, particularly in women in pregnancy and menopause. Lead and mercury, in the form of mercury vapor and methylmercury, are easily transferred from the pregnant women to the fetus. Recent data indicate that boys are more susceptible to neurotoxic effects of lead and methylmercury following exposure early in life, while experimental data suggest that females are more susceptible to immunotoxic effects of lead. Certain gender differences in the biotransformation of arsenic by methylation have been reported, and men seem to be more affected by arsenic-related skin effect than women. Experimental studies indicate major gender differences in arsenic-induced cancer. Obviously, research on gender-related differences in health effects caused by metals needs considerable more focus in the future.
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            Environmental exposure to cadmium and risk of cancer: a prospective population-based study.

            Cadmium is a ubiquitous environmental pollutant, which accumulates in the human body such that 24-h urinary excretion is a biomarker of lifetime exposure. We aimed to assess the association between environmental exposure to cadmium and cancer. We recruited a random population sample (n=994) from an area close to three zinc smelters and a reference population from an area with low exposure to cadmium. At baseline (1985-89), we measured cadmium in urine samples obtained over 24 h and in the soil of participants' gardens, and followed the incidence of cancer until June 30, 2004. We used Cox regression to calculate hazard ratios for cancer in relation to internal (ie, urinary) and external (ie, soil) exposure to cadmium, while adjusting for covariables. Cadmium concentration in soil ranged from 0.8 mg/kg to 17.0 mg/kg. At baseline, geometric mean urinary cadmium excretion was 12.3 nmol/day for people in the high-exposure area, compared with 7.7 nmol/day for those in the reference (ie, low-exposure) area (p<0.0001). During follow-up (median 17.2 years [range 0.6-18.8]), 50 fatal cancers and 20 non-fatal cancers occurred, of which 18 and one, respectively, were lung cancers. Overall cancer risk was significantly associated with a doubling of 24-h cadmium excretion (hazard ratio 1.31 [95% CI 1.03-1.65], p=0.026. Population-attributable risk of lung cancer was 67% (95% CI 33-101) in the high-exposure area, compared with that of 73% (38-108) for smoking. For lung cancer, adjusted hazard ratio was 1.70 (1.13-2.57, p=0.011) for a doubling of 24-h urinary cadmium excretion, 4.17 (1.21-14.4, p=0.024) for residence in the high-exposure area versus the low-exposure area, and 1.57 (1.11-2.24, p=0.012) for a doubling of cadmium concentration in soil. Historical pollution from non-ferrous smelters continues to present a serious health hazard, necessitating targeted preventive measures.
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              Low level exposure to cadmium and early kidney damage: the OSCAR study.

              To study the dose-response relation between cadmium dose and renal tubular damage in a population of workers and people environmentally or occupationally exposed to low concentrations of cadmium. Early kidney damage in 1021 people, occupationally or environmentally exposed to cadmium, was assessed from cadmium in urine to estimate dose, and protein HC (alpha(1)-microglobulin) in urine to assess tubular proteinuria. There was an age and sex adjusted correlation between cadmium in urine and urinary protein HC. The prevalence of tubular proteinuria ranged from 5% among unexposed people to 50% in the most exposed group. The corresponding prevalence odds ratio was 6.0 (95% confidence interval (95% CI) 1.6 to 22) for the highest exposure group, adjusted for age and sex. Multiple logistic regression analysis showed an increasing prevalence of tubular proteinuria with urinary cadmium as well as with age. After adjustment to the mean age of the study population (53 years), the results show an increased prevalence of 10% tubular proteinuria (taking into account a background prevalence of 5%) at a urinary cadmium concentration of 1.0 nmol/mmol creatinine. Renal tubular damage due to exposure to cadmium develops at lower levels of cadmium body burden than previously anticipated.
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                Author and article information

                Journal
                Environ Health Perspect
                Environmental Health Perspectives
                National Institute of Environmental Health Sciences
                0091-6765
                1552-9924
                August 2009
                6 May 2009
                : 117
                : 8
                : 1293-1301
                Affiliations
                [1 ] Assessment Methodology Unit, European Food Safety Authority, Parma, Italy
                [2 ] Unit of Nutritional Epidemiology
                [3 ] Unit of Metals and Health and
                [4 ] Unit of Work Environment Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
                Author notes
                Address correspondence to B. Amzal, Assessment Methodology Unit, European Food Safety Authority, Largo N. Palli 5/A, I-43100 Parma, Italy. Telephone: 39-0521-036-432. Fax: 39-0521-036-110. E-mail: Billy.AMZAL@ 123456efsa.europa.eu
                [*]

                These authors contributed equally to this work.

                The authors declare they have no competing financial interests.

                Article
                ehp-117-1293
                10.1289/ehp.0800317
                2721875
                19672411
                a8cd266d-129b-4060-862c-f72b956a4f57
                This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original DOI.
                History
                : 23 October 2008
                : 6 May 2009
                Categories
                Research

                Public health
                risk assessment,urinary cadmium,toxicokinetic models,bayesian inference,cadmium toxicokinetics,population variability,alternative model development

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