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These findings demonstrate the in vivo release (through transmetallation) of the toxic free Gd3+ from gadodiamide, and its retention in apatite-like deposits. We suggest that Gd may be mobilized over time from bone stores, explaining variably delayed onset of NSF and increasing skin concentration over time in patients with NSF.

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Nephrogenic systemic fibrosis (NSF) is a painful and debilitating fibrosing disorder of the skin and systemic tissues. It is associated with exposure to Gd, used in MRIs and MRAs, in patients with renal insufficiency. We here present an illustrative example of a young patient who underwent multiple Gd-enhanced scans, both before and after developing severe NSF. We examined biopsy tissues for quantification of detectable insoluble Gd deposits using automated scanning electron microscopy/energy dispersive X-ray spectroscopy. High concentrations of Gd associated with calcium and phosphorus in skin persisted even 3 years after the last exposure to Gd. Such long-term retention of Gd raises further concerns about the utility and safety of Gd-based contrast agents. Residual Gd chelates, after initial and rapid renal clearance, can dissociate into insoluble, toxic Gd(3+) that precipitates with tissue anions. Bone serves as a site for Gd storage. Subsequent clearance and mobilization from such stores may explain the variable latency of onset of NSF. We hypothesize that long-term persistence and slow release of Gd(3+) from bone stores can be a cause for concern of Gd-associated toxicity with long latency.

Although asbestos research has been ongoing for decades, this increased knowledge has not led to consensus in many areas of the field. Two such areas of controversy include the specific definitions of asbestos, and limitations in understanding exposure-response relationships for various asbestos types and exposure levels and disease. This document reviews the current regulatory and mineralogical definitions and how variability in these definitions has led to difficulties in the discussion and comparison of both experimental laboratory and human epidemiological studies for asbestos. This review also examines the issues of exposure measurement in both animal and human studies, and discusses the impact of these issues on determination of cause for asbestos-related diseases. Limitations include the lack of detailed characterization and limited quantification of the fibers in most studies. Associated data gaps and research needs are also enumerated in this review.

Rationale: Recent reports of progressive massive fibrosis and rapidly progressive pneumoconiosis in U.S. coal miners have raised concerns about excessive exposures to coal mine dust, despite reports of declining dust levels.Objectives: To evaluate the histologic abnormalities and retained dust particles in available coal miner lung pathology specimens, and to compare these findings with those derived from corresponding chest radiographs.Methods: Miners with severe disease and available lung tissue were identified through investigator outreach. Demographic as well as smoking and work history information was obtained. Chest radiographs were interpreted according to the International Labor Organization classification scheme to determine if criteria for rapidly progressive pneumoconiosis were confirmed. Pathology slides were scored by three expert pulmonary pathologists using a standardized nomenclature and scoring system. Measurements and Main Results:Thirteen cases were reviewed, many of which had features of accelerated silicosis and mixed dust lesions. Twelve had progressive massive fibrosis, and 11 had silicosis. Only four had classic lesions of simple coal workers' pneumoconiosis. Four had diffuse interstitial fibrosis with chronic inflammation, and two had focal alveolar proteinosis. Polarized light microscopy revealed large amounts of birefringent mineral dust particles consistent with silica and silicates; carbonaceous coal dust was less prominent. On the basis of chest imaging studies, specimens with features of silicosis were significantly associated (P = 0.047) with rounded (type p, q, or r) opacities, whereas grade 3 interstitial fibrosis was associated (P = 0.02) with the presence of irregular (type s, t, or u) opacities.Conclusions: Our findings suggest that rapidly progressive pneumoconiosis in these miners was associated with exposure to coal mine dust containing high concentrations of respirable silica and silicates.

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Vascular and extracellular Gd deposits are found in multiple organs of NSF patients, associated with calcification, and often in fibrotic areas. Gd deposits are not seen in patients with CRF unexposed to GBCAs but rarely may be seen in GBCA-exposed patients without clinical signs of NSF. Apart from diagnostic findings in skin, fibrosis of muscle and dura may be more prominent in NSF patients. Our findings should stimulate further investigation of mechanisms of fibrosis and pathologic calcification.