Asthma-inducing potential of 28 substances in spray cleaning products-Assessed by quantitative structure activity relationship (QSAR) testing and literature review.

Exposure to spray cleaning products constitutes a potential risk for asthma induction. We set out to review whether substances in such products are potential inducers of asthma. We identified 101 spray cleaning products for professional use. Twenty-eight of their chemical substances were selected. We based the selection on (a) positive prediction for respiratory sensitisation in humans based on quantitative structure activity relationship (QSAR) in the Danish (Q)SAR Database, (b) positive QSAR prediction for severe skin irritation in rabbits and (c) knowledge on the substances' physico-chemical characteristics and toxicity. Combining the findings in the literature and QSAR predictions, we could group substances into four classes: (1) some indication in humans for asthma induction: chloramine, benzalkonium chloride; (2) some indication in animals for asthma induction: ethylenediaminetetraacetic acid (EDTA), citric acid; (3) equivocal data: hypochlorite; (4) few or lacking data: nitriloacetic acid, monoethanolamine, 2-(2-aminoethoxy)ethanol, 2-diethylaminoethanol, alkyldimethylamin oxide, 1-aminopropan-2-ol, methylisothiazolinone, benzisothiazolinone and chlormethylisothiazolinone; three specific sulphonates and sulfamic acid, salicylic acid and its analogue sodium benzoate, propane-1,2-diol, glycerol, propylidynetrimethanol, lactic acid, disodium malate, morpholine, bronopol and benzyl alcohol. In conclusion, we identified an asthma induction potential for some of the substances. In addition, we identified major knowledge gaps for most substances. Thus, more data are needed to feed into a strategy of safe-by-design, where substances with potential for induction of asthma are avoided in future (spray) cleaning products. Moreover, we suggest that QSAR predictions can serve to prioritise substances that need further testing in various areas of toxicology.

Distribution, metabolism, excretion, and toxicity of implanted silver: a review.

Some implantable medical devices contain silver. We aimed to assess at what amount implanted silver becomes toxic. Silver was elevated in bodily fluids and tissues surrounding silver-containing implants. Silver released from implants also distributes to blood and other tissues; there is evidence to suggest silver can pass the blood-brain-barrier. Silver can be deposited as nano-sized particles in various tissues. Such particles, in addition to silver, often contain other elements too, e.g., selenium and sulfur. Silver released from implants seems to stay in the body for long periods (years). Reported excretion pathways following implantation are urinary and fecal ones. Reported toxicological effects were virtually all local reactions surrounding the implants. Argyria is a blue-gray discoloration of the skin due to deposited silver granules. Localized argyria has been described after the implantation of acupuncture needles and silver-coated prostheses, although the presence of silver was tested only for and shown in the former. Other toxicological effects include local tissue reactivity and examples of neurotoxic and vascular effects. We did not include genotoxicity studies in the present publication as we recently evaluated silver to be genotoxic. Carcinogenicity studies were absent. We conclude that local toxicity of implanted silver can be foreseen in some situations.

Toxicity of boric acid, borax and other boron containing compounds: A review.

Boron, often in the form of boric acid, is widely used as a flame retardant in insulation products, and although humans ingest boron through food, high exposure may lead to unwanted health effects. We assessed the toxicity of boric acid, borax and other forms of boron, after inhalation, dermal and oral exposure. After oral exposure, boron is absorbed over the gastrointestinal tract. Intact skin seems to pose a more effective barrier to boron than compromised skin. Boron excretion seems to mainly occur via the urine, although after skin exposure boron has been demonstrated in bile and gastrointestinal contents. Inhalation toxicity data are sparse, but one animal study showed reduced foetal weight after inhalation of cellulose that had a boric acid content of 20%. Skin exposure to boric acid has proven fatal in some cases, and the range of toxicity effects include abdominal as well as local effects on the skin. Fatalities from boric acid also have occurred after oral ingestion, and the endpoints in animals are weight loss and reproductive toxicity. Concerning genotoxicity studies, the overall picture indicates that boron-containing compounds are not genotoxic. There was no evidence of the carcinogenicity of boric acid in a 2-year study in mice.

Acute Phase Response as a Biological Mechanism-of-Action of (Nano)particle-Induced Cardiovascular Disease.

Inhaled nanoparticles constitute a potential health hazard due to their size-dependent lung deposition and large surface to mass ratio. Exposure to high levels contributes to the risk of developing respiratory and cardiovascular diseases, as well as of lung cancer. Particle-induced acute phase response may be an important mechanism of action of particle-induced cardiovascular disease. Here, the authors review new important scientific evidence showing causal relationships between inhalation of particle and nanomaterials, induction of acute phase response, and risk of cardiovascular disease. Particle-induced acute phase response provides a means for risk assessment of particle-induced cardiovascular disease and underscores cardiovascular disease as an occupational disease.

Toward Rigorous Materials Production: New Approach Methodologies Have Extensive Potential to Improve Current Safety Assessment Practices.

Advanced material development, including at the nanoscale, comprises costly and complex challenges coupled to ensuring human and environmental safety. Governmental agencies regulating safety have announced interest toward acceptance of safety data generated under the collective term New Approach Methodologies (NAMs), as such technologies/approaches offer marked potential to progress the integration of safety testing measures during innovation from idea to product launch of nanomaterials. Divided in overall eight main categories, searchable databases for grouping and read across purposes, exposure assessment and modeling, in silico modeling of physicochemical structure and hazard data, in vitro high-throughput and high-content screening assays, dose-response assessments and modeling, analyses of biological processes and toxicity pathways, kinetics and dose extrapolation, consideration of relevant exposure levels and biomarker endpoints typify such useful NAMs. Their application generally agrees with articulated stakeholder needs for improvement of safety testing procedures. They further fit for inclusion and add value in nanomaterials risk assessment tools. Overall 37 of 50 evaluated NAMs and tiered workflows applying NAMs are recommended for considering safer-by-design innovation, including guidance to the selection of specific NAMs in the eight categories. An innovation funnel enriched with safety methods is ultimately proposed under the central aim of promoting rigorous nanomaterials innovation.

A response to the letter to the editor by Driscoll et al.

In response to the Letter to the Editor by Kevin Driscoll et al., we certainly agree that particle clearance halftimes are increased with increasing lung burden in rats, hamsters and mice, whereas complete inhibition of particle clearance has only been observed in rats, and only at high particle concentrations (50 mg/m3). Where we disagree with Kevin Driscoll and colleagues, is on the implications of the increased clearance halftimes observed at higher lung burden. We argue that it does not hamper the extrapolations from relatively high dose levels to lower dose levels.Furthermore, we highlight, again, the challenges of detecting particle-induced lung cancer in epidemiological studies where occupational, particle-induced lung cancer has to be detected on top of the background lung cancer incidence. Almost all available epidemiological studies on carbon black and titanium dioxide suffer from a number of limitations, including lack of control for smoking, the use of background population cancer rates as reference in the US studies, lack of information regarding particle size of the exposure, and incomplete follow-up for cause of death of the study population.

Pulmonary toxicity of silver vapours, nanoparticles and fine dusts: A review.

Silver is used in a wide range of products, and during their production and use, humans may be exposed through inhalation. Therefore, it is critical to know the concentration levels at which adverse effects may occur. In rodents, inhalation of silver nanoparticles has resulted in increased silver in the lungs, lymph nodes, liver, kidney, spleen, ovaries, and testes. Reported excretion pathways of pulmonary silver are urinary and faecal excretion. Acute effects in humans of the inhalation of silver include lung failure that involved increased heart rate and decreased arterial blood oxygen pressure. Argyria-a blue-grey discoloration of skin due to deposited silver-was observed after pulmonary exposure in 3 individuals; however, the presence of silver in the discolorations was not tested. Argyria after inhalation seems to be less likely than after oral or dermal exposure. Repeated inhalation findings in rodents have shown effects on lung function, pulmonary inflammation, bile duct hyperplasia, and genotoxicity. In our evaluation, the range of NOAEC values was 0.11-0.75 mg/m3. Silver in the ionic form is likely more toxic than in the nanoparticle form but that difference could reflect their different biokinetics. However, silver nanoparticles and ions have a similar pattern of toxicity, probably reflecting that the effect of silver nanoparticles is primarily mediated by released ions. Concerning genotoxicity studies, we evaluated silver to be positive based on studies in mammalian cells in vitro and in vivo when considering various exposure routes. Carcinogenicity data are absent; therefore, no conclusion can be provided on this endpoint.

Association between a urinary biomarker for exposure to PAH and blood level of the acute phase protein serum amyloid A in coke oven workers.

BACKGROUND: Coke oven workers are exposed to both free and particle bound PAH. Through this exposure, the workers may be at increased risk of cardiovascular diseases. Systemic levels of acute phase response proteins have been linked to cardiovascular disease in epidemiological studies, suggesting it as a marker of these conditions. The aim of this study was to assess whether there was association between PAH exposure and the blood level of the acute phase inflammatory response marker serum amyloid A (SAA) in coke oven workers. METHODS: A total of 87 male Polish coke oven workers from two different plants comprised the study population. Exposure was assessed by means of the individual post-shift urinary excretion of 1-hydroxypyrene, as internal dose of short-term PAH exposure, and by anti-benzo[a]pyrene diolepoxide (anti-B[a]PDE)-DNA), as a biomarker of long-term PAH exposure. Blood levels of acute phase proteins SAA and CRP were measured by immunoassay. C-reactive protein (CRP) levels were included to adjust for baseline levels of SAA. RESULTS: Multiple linear regression showed that the major determinants of increased SAA levels were urinary 1-hydroxypyrene (beta = 0.56, p = 0.030) and serum CRP levels (beta = 7.08; p < 0.0001) whereas anti-B[a]PDE-DNA, the GSTM1 detoxifying genotype, diet, and smoking were not associated with SAA levels. CONCLUSIONS: Urinary 1-hydroxypyrene as biomarker of short-term PAH exposure and serum levels of CRP were predictive of serum levels of SAA in coke oven workers. Our data suggest that exposure of coke oven workers to PAH can lead to increased systemic acute response and therefore potentially increased risk of cardiovascular disease.

Commentary: the chronic inhalation study in rats for assessing lung cancer risk may be better than its reputation.

Recently, Borm and Driscoll published a commentary discussing grouping of Poorly Soluble particles of Low Toxicity (PSLTs) and the use of rats as an animal model for human hazard assessment of PSLTs (Particle and Fibre Toxicology (2019) 16(1):11). The commentary was based on the scientific opinion of several international experts on these topics. The general conclusion from the authors was a cautious approach towards using chronic inhalation studies in rats for human hazard assessment of PSLTs. This was based on evidence of inhibition of particle clearance leading to overload in the rats after high dose exposure, and a suggested over reactivity of rat lung cancer responses compared to human risk.As a response to the commentary, we here discuss evidence from the scientific literature showing that a) diesel exhaust particles, carbon black nanoparticles and TiO2 nanoparticles have similar carcinogenic potential in rats, and induce lung cancer at air concentrations below the air concentrations that inhibit particle clearance in rats, and b) chronic inhalation studies of diesel exhaust particles are less sensitive than epidemiological studies, leading to higher risk estimates for lung cancer. Thus, evidence suggests that the chronic inhalation study in rats can be used for assessing lung cancer risk insoluble nanomaterials.

Subacute oral toxicity investigation of selenium nanoparticles and selenite in rats.

Selenium (Se) nanoparticles have been proposed as food supplements. However, the particle formulation may exert unexpected toxicity. The aim was therefore to compare toxicity of low doses of Se nanoparticles and the dissolved, ionized Se species selenite. Female rats were dosed orally for 28 d with either: 0.05, 0.5, or 4 mg Se/kg body weight (bw)/day as 20 nm Se nanoparticles or 0.05 or 0.5 mg Se/kg bw/day as sodium selenite. Male rats were dosed 4 mg Se/kg bw/day as Se nanoparticles. Body weight and clinical appearance were recorded throughout the experiment. At necropsy, blood samples were taken for hematological and clinical chemistry analyses; organ weights were recorded. At the high-dose of Se nanoparticles, overt toxicity occurred and the female animals had to be euthanized prematurely, whereas the male animals were reduced in dose. At all doses of Se nanoparticles and at 0.5 mg Se/kg bw/day as selenite, a lower body weight gain as compared to vehicle occurred. Relative liver weight was increased for both Se formulations at 0.5 mg Se/kg bw/day. Creatinine clearance and urinary pH were affected in some Se dosed groups. There were no effects among dosed groups on brain neurotransmitters or on hematological parameters compared with controls. There were no histological changes in the livers of animals exposed to Se nanoparticles or to selenite. Based on effects on body weight and liver weight, selenium nanoparticles and ionic Se exerted similar toxicity. This suggests that a nanoparticle-specific toxicity of Se did not occur.

Toxicity of silver ions, metallic silver, and silver nanoparticle materials after in vivo dermal and mucosal surface exposure: A review.

Silver is used in different applications that result in contact with skin and mucosal surfaces (e.g., jewelry, wound dressings, or eye drops). Intact skin poses an effective barrier against the absorption of silver. Mucosal surfaces are observed to be less effective barriers and compromised skin is often a poor barrier. Silver can deposit as particles in the human body causing a blue-gray discoloration known as argyria. Urine and feces are reported pathways of excretion. Acute human mortality has been observed following an abortion procedure involving the intrauterine administration of 7 g silver nitrate (64 mg silver/kg body weight). Localized argyria has been reported with exposure to silver ions, metallic surfaces, and nanocrystalline silver. Generalized argyria was observed with ionic and nanocrystalline silver in humans at cumulative doses in the range of 70-1500 mg silver/kg body weight. Silver is observed to have a low potential for skin irritation. Eye irritation and some cases of allergic contact dermatitis have been reported. Silver may cause genotoxicity, but additional data are required to assess its carcinogenic potential. Other reported toxicities include hepatic, renal, neurological, and hematological effects.

Influence of dispersion medium on nanomaterial-induced pulmonary inflammation and DNA strand breaks: investigation of carbon black, carbon nanotubes and three titanium dioxide nanoparticles.

Intratracheal instillation serves as a model for inhalation exposure. However, for this, materials are dispersed in appropriate media that may influence toxicity. We tested whether different intratracheal instillation dispersion media influence the pulmonary toxicity of different nanomaterials. Rodents were intratracheally instilled with 162 µg/mouse/1620 µg/rat carbon black (CB), 67 µg/mouse titanium dioxide nanoparticles (TiO2) or 54 µg/mouse carbon nanotubes (CNT). The dispersion media were as follows: water (CB, TiO2); 2% serum in water (CB, CNT, TiO2); 0.05% serum albumin in water (CB, CNT, TiO2); 10% bronchoalveolar lavage fluid in 0.9% NaCl (CB), 10% bronchoalveolar lavage (BAL) fluid in water (CB) or 0.1% Tween-80 in water (CB). Inflammation was measured as pulmonary influx of neutrophils into bronchoalveolar fluid, and DNA damage as DNA strand breaks in BAL cells by comet assay. Inflammation was observed for all nanomaterials (except 38-nm TiO2) in all dispersion media. For CB, inflammation was dispersion medium dependent. Increased levels of DNA strand breaks for CB were observed only in water, 2% serum and 10% BAL fluid in 0.9% NaCl. No dispersion medium-dependent effects on genotoxicity were observed for TiO2, whereas CNT in 2% serum induced higher DNA strand break levels than in 0.05% serum albumin. In conclusion, the dispersion medium was a determinant of CB-induced inflammation and genotoxicity. Water seemed to be the best dispersion medium to mimic CB inhalation, exhibiting DNA strand breaks with only limited inflammation. The influence of dispersion media on nanomaterial toxicity should be considered in the planning of intratracheal investigations.

Perfluorononanoic acid in combination with 14 chemicals exerts low-dose mixture effects in rats.

Humans are simultaneously exposed to several chemicals that act jointly to induce mixture effects. At doses close to or higher than no-observed adverse effect levels, chemicals usually act additively in experimental studies. However, we are lacking knowledge on the importance of exposure to complex real-world mixtures at more relevant human exposure levels. We hypothesised that adverse mixture effects occur at doses approaching high-end human exposure levels. A mixture (Mix) of 14 chemicals at a combined dose of 2.5 mg/kg bw/day was tested in combination with perfluorononanoic acid (PFNA) at doses of 0.0125 (Low PFNA), 0.25 (Mid PFNA) and 5 (High PFNA) mg/kg bw/day by oral administration for 14 days in juvenile male rats. Indication of a toxicokinetic interaction was found, as simultaneous exposure to PFNA and the Mix caused a 2.8-fold increase in plasma PFNA concentrations at Low PFNA. An increase in testosterone and dihydrotestosterone plasma concentrations was observed for Low PFNA + Mix. This effect was considered non-monotonic, as higher doses did not cause this effect. Reduced LH plasma concentrations together with increased androgen concentrations indicate a disturbed pituitary-testis axis caused by the 15-chemical mixture. Low PFNA by itself increased the corticosterone plasma concentration, an effect which was normalised after simultaneous exposure to Mix. This combined with affected ACTH plasma concentrations and down-regulation of 11ß HSD mRNA in livers indicates a disturbed pituitary-adrenal axis. In conclusion, our data suggest that mixtures of environmental chemicals at doses approaching high-end human exposure levels can cause a hormonal imbalance and disturb steroid hormones and their regulation. These effects may be non-monotonic and were observed at low doses. Whether this reflects a more general phenomenon that should be taken into consideration when predicting human mixture effects or represents a rarer phenomenon remains to be shown.

Perinatal exposure to mixtures of anti-androgenic chemicals causes proliferative lesions in rat prostate.

BACKGROUND: Elevated levels of endogenous or exogenous estrogens during fetal life can induce permanent disturbances in prostate growth and predispose to precancerous lesions. Recent studies have indicated that also early anti-androgen exposure may affect prostate cancer risk. METHODS: We examined the influence of perinatal exposure to mixtures of anti-androgenic and estrogenic chemicals on prostate development. Wistar rats were exposed from gestation day 7 to postnatal day 22 to a mixture of 8 anti-androgenic compounds (AAMix), a mixture of four estrogenic compounds (EMix), or paracetamol or a mixture of all 13 compounds (TotalMix) in mixture ratios reflecting human exposure levels. RESULTS: Ventral prostate weights were reduced by the TotalMix and AAMix in pre-pubertal rats. Histological changes in prostate appeared with increasing age and indicated a shift from the normal age-dependent epithelial atrophy towards hyperplasia. These lesions showed similarities to pre-cancerous lesions in humans. Increased proliferation was observed already in pre-puberty and it was hypothesized that this could be associated with reduced ERß signaling, but no clear conclusions could be made from gene expression studies on ERß-related pathways. The influences of the estrogenic chemicals and paracetamol on prostate morphology were minor, but in young adulthood the estrogen mixture reduced ventral prostate mRNA levels of Igf1 and paracetamol reduced the mRNA level ofPbpc3. CONCLUSIONS: Mixtures of endocrine disrupters relevant for human exposure was found to elicit persistent effects on the rat prostate following perinatal exposure, suggesting that human perinatal exposure to environmental chemicals may increase the risk of prostate cancer later in life.

Toxicological risk assessment of elemental gold following oral exposure to sheets and nanoparticles - A review.

Elemental gold is used as a food coloring agent and in dental fillings. In addition, gold nanoparticles are gaining increasing attention due to their potential use as inert carriers for medical purposes. Although elemental gold is considered to be inert, there is evidence to suggest the release of gold ions from its surface. Elemental gold, or the released ions, is, to some extent, absorbed in the gastrointestinal tract. Gold is distributed to organs such as the liver, heart, kidneys and lungs. The main excretion route of absorbed gold is through urine. Data on the oral toxicity of elemental gold is limited. The acute toxicity of elemental gold seems to be low, as rats were unaffected by a single dose of 2000mg nanoparticles/kg of body weight. Information on repeated dose toxicity is very limited. Skin rashes have been reported in humans following the ingestion of liquors containing gold. In addition, gold released from dental restorations has been reported to increase the risk of developing gold hypersensitivity. Regarding genotoxicity, in vitro studies indicate that gold nanoparticles induce DNA damage in mammalian cells. In vivo, gold nanoparticles induce genotoxic effects in Drosophila melanogaster; however, genotoxicity studies in mammals are lacking. Overall, based on the literature and taking low human exposure into account, elemental gold via the oral route is not considered to pose a health concern to humans in general.

Evidence from pharmacology and pathophysiology suggests that chemicals with dissimilar mechanisms of action could be of bigger concern in the toxicological risk assessment of chemical mixtures than chemicals with a similar mechanism of action.

Mathematical models have been developed for the toxicological risk assessment of chemical mixtures. However, exposure data as well as single chemical toxicological data are required for these models. When addressing this data need, it could be attractive to focus on chemicals with similar mechanisms of action, similar modes of action or with common target organs. In the European Union, efforts are currently being made to subgroup chemicals according to this need. However, it remains to be determined whether this is the best strategy to obtain data for risk assessment. In conditions such as cancer or HIV, it is generally recognised that pharmacological combination therapy targeting different mechanisms of action is more effective than a strategy where only one mechanism is targeted. Moreover, in diseases such as acute myocardial infarction and congestive heart failure, several organ systems concomitantly contribute to the pathophysiology, suggesting that a grouping based on common target organs may also be inefficient. A better option may be to prioritise chemicals on the basis of potency and risk of exposure. In conclusion, there are arguments to suggest that we should concomitantly consider all targets that a chemical can affect in the human body and not merely a subset.

Oral toxicity of silver ions, silver nanoparticles and colloidal silver--a review.

Orally administered silver has been described to be absorbed in a range of 0.4-18% in mammals with a human value of 18%. Based on findings in animals, silver seems to be distributed to all of the organs investigated, with the highest levels being observed in the intestine and stomach. In the skin, silver induces a blue-grey discoloration termed argyria. Excretion occurs via the bile and urine. The following dose-dependent animal toxicity findings have been reported: death, weight loss, hypoactivity, altered neurotransmitter levels, altered liver enzymes, altered blood values, enlarged hearts and immunological effects. Substantial evidence exists suggesting that the effects induced by particulate silver are mediated via silver ions that are released from the particle surface. With the current data regarding toxicity and average human dietary exposure, a Margin of Safety calculation indicates at least a factor of five before a level of concern to the general population is reached.

Toxicity and biokinetics following pulmonary exposure to aluminium (aluminum): A review.

During the manufacture and use of aluminium (aluminum), inhalation exposure may occur. We reviewed the pulmonary toxicity of this metal including its toxicokinetics. The normal serum/plasma level based on 17 studies was 5.7 ± 7.7µg Al/L (mean ± SD). The normal urine level based on 15 studies was 7.7 ± 5.3µg/L. Bodily fluid and tissue levels during occupational exposure are also provided, and the urine level was increased in aluminium welders (43 ± 33µg/L) based on 7 studies. Some studies demonstrated that aluminium from occupational exposure can remain in the body for years. Excretion pathways include urine and faeces. Toxicity studies were mostly on aluminium flakes, aluminium oxide and aluminium chlorohydrate as well as on mixed exposure, e.g. in aluminium smelters. Endpoints affected by pulmonary aluminium exposure include body weight, lung function, lung fibrosis, pulmonary inflammation and neurotoxicity. In men exposed to aluminium oxide particles (3.2µm) for two hours, lowest observed adverse effect concentration (LOAEC) was 4mg Al2O3/m3 (= 2.1mg Al/m3), based on increased neutrophils in sputum. With the note that a similar but not statistically significant increase was seen during control exposure. In animal studies LOAECs start at 0.3mg Al/m3. In intratracheal instillation studies, all done with aluminium oxide and mainly nanomaterials, lowest observed adverse effect levels (LOAELs) started at 1.3mg Al/kg body weight (bw) (except one study with a LOAEL of ~0.1mg Al/kg bw). The collected data provide information regarding hazard identification and characterisation of pulmonary exposure to aluminium.

Orthogonal assay and QSAR modelling of Tox21 PPARγ antagonist in vitro high-throughput screening assay.

Disruption of signalling mediated by the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) is associated with risk of cancer, metabolic diseases, and endocrine disruption. The purpose of this study was to identify environmental chemicals acting as PPARγ antagonists. Data from the Tox21 PPARγ antagonism assay were replicated using a reporter system in HEK293 cells. Two quantitative structure-activity relationship (QSAR) models were developed, and five REACH-registered substances predicted positive were tested in vitro. Reporter assay results were consistent with Tox21 data since all conflicting results could be explained by assay interference. QSAR models showed good predictive performance, and follow-up experiments revealed two PPARγ antagonists out of three non-interfering chemicals. In conclusion, the developed QSAR models and follow-up experiments are important steps in the discovery of potential endocrine- and metabolism-disrupting chemicals.