Metabolic profiling detects early effects of environmental and lifestyle exposure to cadmium in a human population.

BACKGROUND: The 'exposome' represents the accumulation of all environmental exposures across a lifetime. Top-down strategies are required to assess something this comprehensive, and could transform our understanding of how environmental factors affect human health. Metabolic profiling (metabonomics/metabolomics) defines an individual's metabolic phenotype, which is influenced by genotype, diet, lifestyle, health and xenobiotic exposure, and could also reveal intermediate biomarkers for disease risk that reflect adaptive response to exposure. We investigated changes in metabolism in volunteers living near a point source of environmental pollution: a closed zinc smelter with associated elevated levels of environmental cadmium. METHODS: High-resolution ¹H NMR spectroscopy (metabonomics) was used to acquire urinary metabolic profiles from 178 human volunteers. The spectral data were subjected to multivariate and univariate analysis to identify metabolites that were correlated with lifestyle or biological factors. Urinary levels of 8-oxo-deoxyguanosine were also measured, using mass spectrometry, as a marker of systemic oxidative stress. RESULTS: Six urinary metabolites, either associated with mitochondrial metabolism (citrate, 3-hydroxyisovalerate, 4-deoxy-erythronic acid) or one-carbon metabolism (dimethylglycine, creatinine, creatine), were associated with cadmium exposure. In particular, citrate levels retained a significant correlation to urinary cadmium and smoking status after controlling for age and sex. Oxidative stress (as determined by urinary 8-oxo-deoxyguanosine levels) was elevated in individuals with high cadmium exposure, supporting the hypothesis that heavy metal accumulation was causing mitochondrial dysfunction. CONCLUSIONS: This study shows evidence that an NMR-based metabolic profiling study in an uncontrolled human population is capable of identifying intermediate biomarkers of response to toxicants at true environmental concentrations, paving the way for exposome research.

Early kidney damage in a population exposed to cadmium and other heavy metals.

BACKGROUND: Exposure to heavy metals may cause kidney damage. The population living near the Avonmouth zinc smelter has been exposed to cadmium and other heavy metals for many decades. OBJECTIVES: We aimed to assess Cd body burden and early signs of kidney damage in the Avonmouth population. METHODS: We used dispersion modeling to assess exposure to Cd. We analyzed urine samples from the local population (n = 180) for Cd (U-Cd) to assess dose (body burden) and for three biomarkers of early kidney damage [N-acetyl-beta-d-glucosaminidase (U-NAG), retinol-binding protein, and alpha-1-microglobulin]. We collected information on occupation, intake of homegrown vegetables, smoking, and medical history by questionnaire. RESULTS: Median U-Cd concentrations were 0.22 nmol/mmol creatinine (nonsmoking 0.18/smoking 0.40) and 0.34 nmol/mmol creatinine (nonsmoking 0.31/smoking 0.46) in non-occupationally exposed men and women, respectively. There was a significant dose-response relationship between U-Cd and the prevalence of early renal damage-defined as U-NAG > 0.22 IU/mmol-with odds ratios of 2.64 [95% confidence interval (95% CI), 0.70-9.97] and 3.64 (95% CI, 0.98-13.5) for U-Cd levels of 0.3 to < 0.5 and levels >or= 0.5 nmol/mmol creatinine, respectively (p for trend = 0.045). CONCLUSION: U-Cd concentrations were close to levels where kidney and bone effects have been found in other populations. The dose-response relationship between U-Cd levels and prevalence of U-NAG above the reference value support the need for measures to reduce environmental Cd exposure.

Dietary cadmium exposure and chronic kidney disease: a population-based prospective cohort study of men and women.

The kidney is widely regarded as the critical organ for cadmium toxicity, however, considerable uncertainty remains regarding the clinical significance of the renal effects of cadmium at low levels of exposure. Food is the primary source of cadmium exposure in the general population with tobacco representing an important additional source. We aimed to assess the association between dietary cadmium exposure and chronic kidney disease (CKD) incidence in two large population-based, prospective cohorts of men (Cohort of Swedish Men (COSM)) and women (The Swedish Mammography Cohort (SMC)) with no history of kidney disease. At baseline 1997, men (45-79 years) and women (48-83 years), completed a self-administered questionnaire on diet and lifestyle. Dietary cadmium exposure for each individual was estimated using dietary data and concentrations of cadmium in food. During 13 years of follow-up, we ascertained 599 incident cases of CKD among men (in 481,591 person-years) and 253 cases among women (in 415,432 person-years) through linkage of the cohorts to national inpatient and outpatient registers. Hazard ratios (HR) were calculated using the Cox proportional-hazard regression model. Estimated dietary cadmium exposure was not associated with increased CKD incidence among men HR 0.97 (95% confidence interval (CI): 0.77-1.21) or women HR 0.74 (95% CI: 0.53-1.04), comparing highest tertile with lowest. Our results do not support a strong association between dietary cadmium exposure and CKD at the exposure levels seen in the general population.

Dietary cadmium exposure and kidney stone incidence: a population-based prospective cohort study of men & women.

Cadmium exposure is associated with increased urinary calcium excretion. Hypercalciuria is recognised as a major risk factor for kidney stone formation. Increased prevalence of kidney stones among those occupationally exposed to cadmium has previously been suggested. Food is the main source of cadmium exposure in the general population with tobacco representing an important additional source among smokers. We aimed to assess the association between dietary cadmium exposure and kidney stone incidence in two large population-based, prospective cohorts of men (Cohort of Swedish Men; COSM) and women (The Swedish Mammography Cohort; SMC). Those with a history of kidney stones were excluded. At baseline 1997, men (45-79yrs) and women (48 to 83yrs), completed a self-administered questionnaire on diet and lifestyle. During 12years of follow-up, we ascertained 707 cases of kidney stones in men and 290 in women through linkage of the cohorts to the national inpatient and outpatient registers. Individual dietary cadmium exposure was estimated using dietary data and concentrations of cadmium in food. Hazard ratios (HR) were calculated using the Cox proportional hazards regression models with adjustment for other risk factors. Estimated dietary cadmium exposure was not associated with increased kidney stone incidence among men HR 0.97 (95% confidence interval (CI): 0.77-1.23) or women HR 0.99 (95% CI: 0.89-1.43), comparing the highest tertile with the lowest. In conclusion, our results do not support a strong association between dietary cadmium and kidney stone risk at the exposure levels seen in the general population.

Dietary cadmium exposure and fracture incidence among men: a population-based prospective cohort study.

Cadmium is an osteotoxic metal present in food. It causes multiple fractures in those highly exposed and is associated with reduced bone mineral density at considerably lower exposures. Little is known about fracture rates following low-level cadmium exposure. We assessed the associations between dietary cadmium exposure and fracture incidence. Within a population-based prospective cohort of 22,173 Swedish men, we estimated individual dietary cadmium exposure using food frequency questionnaire data and levels of cadmium in food. The average intake was 19 µg/day. Hazard ratios (HRs) for any fracture and hip fracture were estimated using Cox's regression. During 10 years of follow-up, we ascertained 2183 cases of any fracture and 374 hip fractures by computerized linkage of the cohort to registry data. Multivariable-adjusted dietary cadmium intake was associated with a statistically significant 19% [HR = 1.19, 95% confidence interval (CI) 1.06-1.34] higher rate of any fracture comparing highest tertile with lowest (p ≤ .01 for trend). Moreover, men in the highest tertile of dietary cadmium and lowest tertile of fruit and vegetable consumption had a 41% higher rate of any fracture compared with contrasting tertiles. Hip fracture rates also were higher in the highest tertile of cadmium intake but only statistically significant among never smokers (HR = 1.70, 95% CI 1.04-2.77). Our results indicate that dietary cadmium exposure at general population levels is associated with an increased rate of fractures among men. This association was independent of smoking and was most pronounced among men with low fruit and vegetable consumption.

Outdoor and indoor cadmium distributions near an abandoned smelting works and their relations to human exposure.

The relationship of measured or modelled Cd concentrations in soil, house dust and available to plants with human urinary Cd concentrations were assessed in a population living around a Cd/Pb/Zn smelter in the UK. Modelled air concentrations explained 35% of soil Cd variation indicating the smelter contributed to soil Cd loads. Multi-variate analysis confirmed a significant role of biological and life-style factors in determining urinary Cd levels. Significant correlations of urinary Cd with soil, house dust and modelled plant available Cd concentrations were not, however, found. Potential reasons for the absence of clear relationships include limited environmental contact in urban populations; the role of undefined factors in determining exposure; and the limited spatial scope of the survey which did not sample from the full pollution gradient. Further, the absence of any significant relationship indicates that environmental measures provide limited advantage over atmospheric model outputs for first stage human exposure assessment.