Deriving a provisional tolerable intake for intravenous exposure to silver nanoparticles released from medical devices.

Silver nanoparticles (AgNP) are incorporated into medical devices for their anti-microbial characteristics. The potential exposure and toxicity of AgNPs is unknown due to varying physicochemical particle properties and lack of toxicological data. The aim of this safety assessment is to derive a provisional tolerable intake (pTI) value for AgNPs released from blood-contacting medical devices. A literature review of in vivo studies investigating critical health effects induced from intravenous (i. v.) exposure to AgNPs was evaluated by the Annapolis Accords principles and Toxicological Data Reliability Assessment Tool (ToxRTool). The point of departure (POD) was based on an i. v. 28-day repeated AgNP (20 nm) dose toxicity study reporting an increase in relative spleen weight in rats with a 5% lower confidence bound of the benchmark dose (BMDL05) of 0.14 mg/kg bw/day. The POD was extrapolated to humans by a modifying factor of 1,000 to account for intraspecies variability, interspecies differences and lack of long-term toxicity data. The pTI for long-term i. v. exposure to 20 nm AgNPs released from blood-contacting medical devices was 0.14 µg/kg bw/day. This pTI may not be appropriate for nanoparticles of other physicochemical properties or routes of administration. The methodology is appropriate for deriving pTIs for nanoparticles in general.

Global assessment of cadmium concentrations in the skin of free-ranging sperm whales (Physeter macrocephalus).

Cadmium is a non-essential, toxic metal found accumulated in the organs of stranded cetaceans. Currently, there is no baseline cadmium concentration reported in a free-ranging, pelagic cetacean. The aim was to determine cadmium concentrations in the skin of free-ranging sperm whales (n=340) collected from 16 regions around the world during the voyage of the Odyssey (2000-2005) considering region, gender, and age in males. Cadmium was detected in 81% of skin biopsies with a mean of 0.3±0.04µg/g ww (0.02 to 12.4µg/g ww). These concentrations were higher than reported in literature in toothed whale skin (0.002-0.1µg/g ww). Concentrations by region were significantly different (p<0.0001) with the highest mean in Maldives and the Sea of Cortez (0.8 and 0.6µg/g ww, respectively). There was no significant difference in cadmium concentration by gender (p=0.42). Cadmium is known to have a long biological half-life, and cadmium concentrations in males were significantly higher in adults with a mean of 0.3µg/g ww compared to subadults with 0.2µg/g ww (p=0.03). Selenium, an element that binds to cadmium inhibiting its toxicity, had a moderately positive correlation with cadmium (r=0.41). Mercury, a toxic metal that positively correlates with cadmium in cetacean tissue, had a weakly positive relationship (r=0.20). The regional baselines reported in this study may be used to develop residue criteria for prediction of toxicological risk in sperm whale skin. Additionally, this study shows the extent of cadmium exposure in a pelagic cetacean that has global distribution.

Global assessment of arsenic pollution using sperm whales (Physeter macrocephalus) as an emerging aquatic model organism.

Arsenic is an oceanic pollutant of global concern due to its toxicity, ability to bioaccumulate and continued input into the environment by anthropogenic activities. The sperm whale (Physeter macrocephalus) is an emerging aquatic model for both human disease and ocean health having global distribution and high trophic level. The aim of this study was to establish global and regional baselines of total arsenic concentrations using free-ranging sperm whales. Skin biopsies (n=342) were collected during the voyage of the Odyssey (2000-2005) from 17 regions considering gender and age in males. Arsenic was detectable in 99% of samples with a global mean of 1.9µg/g ww ranging from 0.1 to 15.6µg/g ww. Previous work in toothed whale skin found mean concentrations 3 fold lower with 0.6µg/g ww. A significant gender-related effect was found with males having higher mean arsenic concentrations than females. There was no significant age-related effect between adult and subadult males. Arsenic concentrations in sloughed skin samples were similar to levels in skin biopsies indicating that arsenic excretion can occur by skin sloughing. Regional mean concentrations were highest in the Maldives, Seychelles and Sri Lanka with 3.5, 2.5, and 2.4µg/g ww, respectively, raising concern for arsenic pollution in the Indian Ocean. Literature suggests that arsenic exposure is emitted from natural sources and the heavy use of arsenic-containing pesticides and herbicides in this region. These data suggest that research is needed in determining the extent and source of arsenic pollution in the Indian Ocean.

Global assessment of oceanic lead pollution using sperm whales (Physeter macrocephalus) as an indicator species.

Lead (Pb) is an oceanic pollutant of global concern. Anthropogenic activities are increasing oceanic levels, but to an unknown extent. The sperm whale (Physeter macrocephalus) has a global distribution and high trophic level. The aim of this study was to establish a global baseline of oceanic Pb concentrations using free-ranging sperm whales as an indicator species. Skin biopsies (n=337) were collected during the voyage of the Odyssey (2000-2005) from 17 regions considering gender and age. Pb was detectable in 315 samples with a global mean of 1.6 ug/gww ranging from 0.1 to 129.6 ug/gww. Papua New Guinea, Bahamas and Australia had the highest regional mean with 6.1, 3.4, and 3.1 ug/gww, respectively. Pb concentrations were not significantly different between sex and age in males. This is the first global toxicological dataset for Pb in a marine mammal and confirms Pb is widely distributed with hotspots in some regions.

Global mercury and selenium concentrations in skin from free-ranging sperm whales (Physeter macrocephalus).

Pollution of the ocean by mercury (Hg) is a global concern. Hg persists, bioaccumulates and is toxic putting high trophic consumers at risk. The sperm whale (Physeter macrocephalus), is a sentinel of ocean health due to its wide distribution, longevity and high trophic level. Our aim was to survey Hg concentrations worldwide in the skin of free-ranging sperm whales considering region, gender and age. Samples were collected from 343 whales in 17 regions during the voyage of the research vessel, Odyssey, between 1999 and 2005. Skin was analyzed for total Hg and detected in all but three samples with a global mean of 2.5±0.1 µg g(-1) ranging from 0.1 to 16.0 µg g(-1). The Mediterranean Sea had the highest regional mean with 6.1 µg g(-1) followed by Australia with 3.5 µg g(-1). Considering gender, females and males did not have significantly different global Hg concentrations. The variation among regions for females was significantly different with highest levels in the Mediterranean and lowest in Sri Lanka; however, males were not significantly different among regions. Considering age in males, adults and subadults did not have significantly different Hg concentrations, and were not significantly different among regions. The toxic effects of these Hg concentrations are uncertain. Selenium (Se), an essential element, antagonizes Hg at equimolar amounts. We measured total Se concentrations and found detectable levels in all samples with a global mean of 33.1±1.1 µg g(-1) ranging from 2.5 to 179 µg g(-1). Se concentrations were found to be several fold higher than Hg concentrations with the average Se:Hg molar ratio being 59:1 and no correlation between the two elements. It is possible Hg is being detoxified in the skin by another mechanism. These data provide the first global analysis of Hg and Se concentrations in a free-ranging cetacean.

Role of the Fancg gene in protecting cells from particulate chromate-induced chromosome instability.

Particulate hexavalent chromium (Cr(VI)) is a known human lung carcinogen. Cr(VI)-induced tumors exhibit chromosome instability (CIN), but the mechanisms underlying these effects are unknown. We investigated a possible role for the Fanconi anemia (FA) pathway in particulate Cr(VI)-induced chromosomal damage by focusing on the Fancg gene, which plays an important role in cellular resistance to DNA interstrand crosslinks. We used the isogenic Chinese hamster ovary (CHO) KO40 fancg mutant compared with parental and gene-complemented cells. We found that fancg cells treated with lead chromate had lower intracellular Cr ion levels than control cell lines. Accounting for differences of Cr ion levels between cell lines, we discovered that fancg cells treated with lead chromate had increased cytotoxicity and chromosomal aberrations, which was not observed after restoring the Fancg gene. Chromosomal damage was manifest as increased total chromosome damage and percent metaphases with damage, specifically an increase in chromatid and isochromatid breaks. We conclude that Fancg protects cells from particulate Cr(VI)-induced cytotoxicity and chromosome damage, which is consistent with the known sensitivity of fancg cells to crosslinking damage and the ability of Cr(VI) to produce crosslinks.