Modeling of local and systemic exposure to metals and metalloids after inhalation exposure: Recommended update to the USEPA metals framework.

The USEPA issued the "Framework for Metal Risk Assessment" in 2007, recognizing that human and environmental exposure to metals and metalloids (MMEs) poses challenges risk assessment. Inhalation of aerosols containing MMEs is a primary pathway for exposure in the occupational setting, for consumer exposure, and to general population exposure associated with point-source emissions or ambient sources. The impacts of inhalation can be at the point of deposition (local exposure) or may manifest after uptake into the body (systemic exposure). Both local and systemic exposure can vary with factors that determine the regional deposition of MME-containing aerosols. Aerosol characteristics such as particle size combine with species-specific characteristics of airway morphology and lung function to modulate the deposition and clearance of MME particulates. In contrast to oral exposure, often monitored by measuring MME levels in blood or urine, inhalation exposure can produce local pulmonary impacts in the absence of significant systemic distribution. Exposure assessment for nutritionally essential MMEs can be further complicated by homeostatic controls that regulate systemic MME levels. Predictions of local exposure can be facilitated by computer models that estimate regional patterns of aerosol deposition, permitting calculation of exposure intensity in different regions of the respiratory tract. The utility of deposition modeling has been demonstrated in assessments of nutritionally essential MMEs regulated by homeostatic controls and in the comparison of results from inhalation studies in experimental animals. This facilitates extrapolation from animal data to humans and comparisons of exposures possessing mechanistic linkages to pulmonary toxicity and carcinogenesis. Pulmonary deposition models have significantly advanced and have been applied by USEPA in evaluations of particulate matter. However, regional deposition modeling has yet to be incorporated into the general guidance offered by the agency for evaluating inhalation exposure. Integr Environ Assess Manag 2023;00:1-13. © 2023 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

Mode of action assessment of the genotoxic properties of antimony and its compounds evaluated in the ToxTracker assay.

Antimony (Sb) and its compounds are negative in gene mutation assays in bacteria and cultured mammalian cells but positive in some assays for clastogenicity and/or DNA damage. In order to better understand the modes of action for antimony genotoxicity, we assessed reporter gene activation by antimony and antimony compounds in the new expanded ToxTracker assay. ToxTracker evaluates the activation of biomarkers for different cellular defense mechanisms using a series of green fluorescent protein reporters inserted into mouse embryonic stem cell lines. The assay responds to: 1) DNA damage and inhibition of DNA replication; 2) oxidative stress; 3) unfolded protein response (protein damage); and 4) p53-dependent cellular stress. Sb metal powder, six trivalent (Sb(III)) compounds, and five pentavalent antimony (Sb(V)) compounds were assessed. Sb powder and all six Sb(III) compounds activated oxidative stress ToxTracker reporters at non-toxic doses. Of the five Sb(V) compounds, antimony pentachloride and potassium hexahydroantimonate induced a robust oxidative stress response while sodium antimonate induced only a weak oxidative stress response. At higher concentrations (up to either 75 % toxicity or the highest dissolved concentration tested), Sb powder and all Sb(III) compounds except for antimony trichloride induced the unfolded protein response. Of the five Sb(V) compounds tested, only potassium hexahydroantimonate induced weak activation of the unfolded protein response and was also the only pentavalent compound to yield modest (30 %) cytotoxicity. None of the compounds tested activated the DNA damage/inhibition of DNA replication reporters, nor did they activate the p53-dependent response. All Sb(III) compounds, Sb powder, and three of the five Sb(V) compounds activated the oxidative stress reporters, but there was no activation of reporters associated with DNA damage and repair or p53-dependent cellular stress. The consistent activation of reporters for oxidative stress suggests this mode of action may underlie genotoxicity responses for antimony and its compounds.

Antimony and its compounds: Health impacts related to pulmonary toxicity, cancer, and genotoxicity.

Although occupational exposure to antimony and its compounds can produce pulmonary toxicity, human carcinogenic impacts have not been observed. Inhalation studies with respirable antimony trioxide particles administered to rats and mice have, however, induced carcinogenic responses in the lungs and related tissue sites. Genotoxicity studies conducted to elucidate mechanism(s) for tumor induction have produced mixed results. Antimony compounds do not induce gene mutations in bacteria or cultured mammalian cells, but chromosome aberrations and micronuclei have been observed, usually at highly cytotoxic concentrations. Indirect mechanisms of genotoxicity have been proposed to mediate these responses. In vivo genotoxicity tests have generally yielded negative results although several positive studies of marginal quality have been reported. Genotoxic effects may be related to indirect modes of action such as the generation of excessive reactive oxygen species (ROS), altered gene expression or interference with DNA repair processes. Such indirect mechanisms may exhibit dose-response thresholds. For example, interaction of ROS with in vivo antioxidant systems could yield a threshold for genotoxicity (and cancer) only at concentrations above the capacity of antioxidant defense mechanisms to control and/or eliminate damage from ROS.

Migration protocol to estimate metal exposure from mouthing copper and tin alloy objects.

BACKGROUND: Low blood lead levels previously thought to pose no health risks may have an adverse impact on the cognitive development of children. This concern has given rise to new regulatory restrictions upon lead metal containing products intended for child use. However few reliable experimental testing methods to estimate exposure levels from these materials are available. METHODS: The present work describes a migration test using a mimetic saliva fluid to estimate the chronic exposure of children to metals such as lead while mouthing metallic objects. The surrogate saliva medium was composed of: 150 mM NaCl, 0.16% porcine Mucin and 5 mM buffer MOPS, adjusted to pH 7.2. Alloys samples, in the form of polished metallic disc of known surface area, were subjected to an eight hours test. RESULTS: Two whitemetal alloys Sn/Pb/Sb/Cu and three brass alloys Cu/Zn/Pb were tested using the saliva migration protocol. In the case of the whitemetal alloys, first order release kinetics resulting in the release of 0.03 and 0.51 µg lead/cm2 after 8 hours of tests were observed, for lead contents of 0.05-0.07% and 5.5%, respectively. Brasses exhibited linear incremental release rates of 0.043, 0.175 and 0.243 µg lead/cm2h for lead contents of 0.1-0.2%, 1.7-2.2% and 3.1-3.5%, respectively. The linear regression analysis of lead release rates relative to Pb content in brasses yielded a slope of 0.08 µg lead/cm2h%Pb (r2 = 0.92). Lead release rates were used to estimate the mean daily mouthing exposure of a child to lead, according to age-specific estimates of mouthing time behavior. Calculated daily intakes were used as oral inputs for the IEUBK toxicokinetic model, predicting only marginal changes in blood lead levels (0.2 µg lead/dL or less) for children aged 0.5 to 1 years old exposed to either class of alloy. CONCLUSIONS: The results of this study as a whole support the use of migration data of metal ions, rather than total metal content, to estimate health risk from exposure to metals and metal alloys substances in children.

Overview of health risk assessments for zinc.

Zinc is an essential trace mineral nutrient required for growth and reproduction in man and other living organisms. Zinc deficiency has been identified as global public health issue that significantly impacts developing countries; as a result, zinc essentiality and the impacts of deficiency have been extensively studied. Zinc is also widely used in commercial products and is a high-production-volume industrial metal. This has provided opportunities for human exposure and prompted multiple assessments of adverse health impacts that might result from exposure excess. Zinc thus provides an illustrative case study of the methodological contrasts between nutritional and toxicological evaluations and highlights the need for risk assessment guidelines that may be tailored to accommodate the properties of essential trace elements.