Adriana Oller - Academia.edu (original) (raw)

Papers by Adriana Oller

Regulatory Toxicology and Pharmacology, 2022

Bioelution tests measure in vitro the release of metal ion in surrogate physiological conditions ... more Bioelution tests measure in vitro the release of metal ion in surrogate physiological conditions (termed "bioaccessibility") and estimate the potential bioavailability relative to that of a known reference metal substance. Bioaccessibility of cobalt ion from twelve cobalt substances was tested in three artificial lung fluids (interstitial, alveolar and lysosomal) to gather information about the substances' fate and potential bioavailability in the respiratory tract after inhalation. The results can be used as one line of evidence to support grouping and read-across for substances lacking in vivo data, and where in vivo testing is not readily justifiable. Strong differences were observed in the dissolution behaviour of the substances in the different fluids, with the cobalt substances generally being less soluble in neutral pH fluids and more soluble in the acidic pH fluid. The resulting database, presented with its strengths and limitations, was used to support the formulation of an initial grouping of these cobalt substances into three categories.

The appropriate assessment of the human health hazards of complex inorganic materials is required... more The appropriate assessment of the human health hazards of complex inorganic materials is required to ensure their adequate risk management. This requires that the collection of data fulfils information requirements outlined in different chemicals management systems and identifies gaps in the knowledge of the material. Toxicity data on complex inorganic materials allowing to fulfil these human health information requirements and derive dose–responses/effect levels are usually scarce. Although testing could be theoretically envisaged to complete data gaps, the number of complex inorganic materials to be assessed would have significant implications for animal welfare and represent a disproportionate burden. For some materials like the Unknown or Variable composition, Complex reaction products or Biological materials (UVCBs), the variability will also prevent selecting a representative sample. The assessment will therefore often be based on the constituents of the complex materials. Thi...

Journal of Immunotoxicology, 2021

Nickel (Ni) in ambient air may vary regionally with contributions from both natural processes and... more Nickel (Ni) in ambient air may vary regionally with contributions from both natural processes and anthropogenic activities. Exposure to Ni compounds in ambient air above a certain level is associated with acute adverse effects, such as upper respiratory tract irritation, pneumonitis, and chronic adverse effects, such as respiratory cancer. Inhalation reference exposure standards are enacted in different jurisdictions to minimize exposures to ambient Ni above levels that can elicit adverse effects. This paper reports a guideline-/GLP-compliant study designed for setting inhalation exposure standards to protect from immunological effects associated with acute exposure to Ni. Female CD-1 mice were exposed via whole-body inhalation to aerosolized nickel chloride hexahydrate for 24-hr at nominal (vs. mean analyzed) concentrations of 20 (16), 50 (44) and 100 (81) mg Ni/m 3. Host T-cell antibody immunological responses to intravenously-injected sheep red blood cells were then measured ex vivo in an Antibody-Forming Cell (AFC) assay. Exposure to the Ni substance significantly decreased spleen cell levels by 33%, but this was within biological variability for outbred mice. No concurrent decreases in spleen, thymus, or body weights were noted. No immunosuppression was observed with the Ni substance in the context of Total Spleen Activity [IgM AFC/spleen (Â 10 3)] and Specific Activity [IgM AFC/spleen cells (Â 10 6)]. Significant concentration-independent increases in Total Spleen Activity and Specific Activity seen with the nickel chloride hexahydrate were normal and within biological variability for outbred mice. In contrast, cyclophosphamide (positive control) significantly decreased spleen cell numbers, spleen and thymus weights, and abolished Specific Activity and Total Spleen Activity. Based on results here, an NOAEC of 81 mg Ni/m 3 for immunosuppressive effects from inhaled nickel chloride hexahydrate was identified. It is hoped this value can be used to derive a reference standard for human exposure to ambient Ni.

Journal of Cell Science, 1989

Oxygen, although essential to the growth of mammalian cells in vitro and in vivo, has been widely... more Oxygen, although essential to the growth of mammalian cells in vitro and in vivo, has been widely reported to be toxic at concentrations at or above the oxygen concentration in culture medium equilibrated with air (approximately 200 microM). We were therefore surprised to note that a diploid human B-cell line (TK6) was able to proliferate normally while exposed to 380 microM-oxygen. This observation was extended to Vero (African Green monkey kidney) cells, and Sp2/0-derived murine transfectomas producing antibody. Using an experimental system with a high capacity for oxygen transfer, we determined the growth rates of the three cell lines at controlled oxygen concentrations ranging from 80 microM to 910 microM. Each of these cell types was able to grow normally at oxygen concentrations up to 360–380 microM. At oxygen concentrations above 380 microM, a significant increase in the apparent doubling times of the cells was observed. No adverse effect of oxygen on TK6 cell survival was se...

Genetics, 1994

We have previously isolated mutants of Escherichia coli that replicate their DNA with increased f... more We have previously isolated mutants of Escherichia coli that replicate their DNA with increased fidelity. These mutants have a mutation in the dnaE gene, encoding the alpha subunit of DNA polymerase III. They were isolated in a mismatch-repair-defective mutL background, in which mutations can be considered to represent uncorrected DNA replication errors. In the present study we analyze the effect of one of these alleles, dnaE911, on spontaneous mutagenesis in a mismatch-repair-proficient background. In this background, spontaneous mutations may be the sum of uncorrected replication errors and mutations resulting from other pathways. Hence, the effect of the dnaE allele may provide insights into the contribution of uncorrected DNA replication errors to spontaneous mutation. The data show that dnaE911 decreases the level of Rifr, lacI and galK mutations in this background by 1.5-2-fold. DNA sequencing of 748 forward mutants in the lacI gene reveals that this effect has a clear specifi...

Regulatory Toxicology and Pharmacology, 2020

The oral bioaccessibility of copper alloys and pure metals was assessed using in vitro methods wi... more The oral bioaccessibility of copper alloys and pure metals was assessed using in vitro methods with synthetic saliva and gastric fluid. The metal-specific migration rates from polished alloy surfaces are higher in gastric (pH 1.5) than in saliva fluid (pH 7.2). In both media, migrations are higher for lead than for other metals. The bioaccessible metal concentrations in massive copper alloys, after 2 h in gastric fluid, was only <0.01%-0.18%, consistent with the low surface reactivity of copper alloys (defined as 1 mm spheres). The average metal-specific migrations of cobalt, copper, nickel and lead from most of the tested copper alloys in gastric media are comparable to the ones from their pure metals. The data further show that the bioaccessibility of metals in massive copper alloys primarily depends on the bioelution medium, the exposed surface area and the composition of the alloy. The tested copper alloys show only limited evidence for influence of alloy surface microstructure. This is contrary to findings for other alloys such as stainless steel. Additional investigations on other copper alloys could allow to further refine these conclusions. These findings are useful for establishing the hazard and risk profile of copper alloys following oral exposure.

Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, 2020

Nickel metal is a naturally occurring element used in many industrial and consumer applications. ... more Nickel metal is a naturally occurring element used in many industrial and consumer applications. Human epidemiological data and animal cancer bioassays indicate that nickel metal is not likely to be a human carcinogen. Yet, nickel metal is classified as a suspected human carcinogen (CLP) and possibly carcinogenic to humans (IARC). There are no reliable studies on the potential for nickel metal to induce gene and micronucleus (MN) mutations. To fill these datagaps and increase our understanding of the mechanisms underlying the lack of nickel metal carcinogenicity, gene and micronucleus mutation studies were conducted with nickel metal powder (N36F) in V79 Chinese Hamster cells following OECD 476 and 487 guidelines, respectively, under GLP. Gene mutation at the hprt locus was tested, with and without metabolic activation, after 4-h treatment with 0.05-2.5 mM nickel metal powder. Cytokinesis-block MN frequency following exposure to 0.25-1.5 mM nickel metal was tested after 4-h treatment, with and without metabolic activation, followed by a 24-h treatment without metabolic activation. In the gene mutation assay, there were modest increases in hprt mutants observed at some test concentrations, not exceeding 2.2-fold, which were either within the historical control values and/or showed no concentration-response trend. The positive controls showed increases of at least 7-fold. Likewise, no increases in the MN frequency exceeding 1.5-fold were observed with nickel metal, with no concentration-response trends. Taking these results together, it can be concluded that nickel metal is non-mutagenic and does not cause gene nor chromosomal mutations.

Risk Management of Complex Inorganic Materials, 2018

Abstract Complex inorganic materials have specific (eco-) toxic properties conveyed by the metals... more Abstract Complex inorganic materials have specific (eco-) toxic properties conveyed by the metals they are containing. The main principles governing the mechanisms of the toxicity of metals can therefore be applied when assessing complex inorganic materials, particularly in relation to the rate and extent to which these materials can produce soluble (bio)available ionic and other metal-bearing species (e.g. metal complexes). This chapter describes the key mechanistic aspects to consider when managing the human health and environmental risks of such materials, such as bioavailability, speciation, particle size, essentiality, or natural background. It also describes briefly the endpoints requiring the consideration of metal specificities when assessing the underlying mechanisms of toxicity.

Inorganics, 2019

Nickel (Ni) metal and Ni compounds are widely used in applications like stainless steel, alloys, ... more Nickel (Ni) metal and Ni compounds are widely used in applications like stainless steel, alloys, and batteries. Nickel is a naturally occurring element in water, soil, air, and living organisms, and is essential to microorganisms and plants. Thus, human and environmental nickel exposures are ubiquitous. Production and use of nickel and its compounds can, however, result in additional exposures to humans and the environment. Notable human health toxicity effects identified from human and/or animal studies include respiratory cancer, non-cancer toxicity effects following inhalation, dermatitis, and reproductive effects. These effects have thresholds, with indirect genotoxic and epigenetic events underlying the threshold mode of action for nickel carcinogenicity. Differences in human toxicity potencies/potentials of different nickel chemical forms are correlated with the bioavailability of the Ni2+ ion at target sites. Likewise, Ni2+ has been demonstrated to be the toxic chemical speci...

American Journal of Analytical Chemistry, 2018

Bioelution, the measuring of in vitro metal ion release from metals or metal compounds in simulat... more Bioelution, the measuring of in vitro metal ion release from metals or metal compounds in simulated body fluids, can be used as a tool to measure bioaccessibility of metals and metal compounds, and as such provide an estimate of their bioavailability. Comparable bioelution results can allow grouping of substances within a "metal" family. By referring to toxicity data on a metal substance (reference substance) within the group, predictions on the hazard of the other substances in the group can be established. This paper discusses how bioelution testing of metals and metal compounds can be used as an alternative to animal testing for obtaining basic information on their potential toxicity, while allowing compliance with strict information requirements. Two human health hazard endpoints are used to illustrate how bioelution can become part of a testing programme and in particular, target the requirement for new studies and minimise the need for animal testing. In these cases, it is shown how bioelution can be used to predict the hazard of several indium compounds as a first screening.

Mutation Research/Environmental Mutagenesis and Related Subjects, 1989

Long term-low dose mutation assays offer a means to study the genetic effects of environmental mu... more Long term-low dose mutation assays offer a means to study the genetic effects of environmental mutagens at concentrations relevant to human exposure. These assays involve continuous induction of mutants, serial dilution of cultures and sampling to determine the mutant fraction as a function of time and mutagen concentration. An arithmetic model for the expected variance among identically treated cultures is presented. This model provides means to calculate a predicted variance of the mutant fractions and mutation rates in typical long term-low dose experiments. We have calculated the expected variances of the mutant fraction with this model and compared them to the observed variances among 4 independent experiments in which human lymphoblastoid cells were treated for 5, 10, 15 and 20 days with a non-toxic concentration of the mutagen 4-aminobiphenyl. Mutations at the HPRT locus were measured by determining the 6-thioguanine-resistant mutant fraction. The expected and observed variances of the mutant fractions are in close agreement. This model is adequate to predict the variance of the mutant fraction and should be useful in experimental design and objective evaluation of long term-low dose mutation assays. Microbial and mammalian in vivo and in vitro carcinogenicity and mutagenicity assays generally employ relatively high exposure levels over short periods of time. However, human exposure is usu

Regulatory Toxicology and Pharmacology, 2017

Nickel (Ni) is in the earth's crust and can be found in environmental compartments such as water,... more Nickel (Ni) is in the earth's crust and can be found in environmental compartments such as water, soil, and air, as well as food. This paper presents an assessment of the oral nickel toxicity data in support of non-cancer health-based oral exposure limits or toxicity reference values (TRVs). This paper derives TRVs for three populations of interest: adults, toddlers, and people who have been dermally sensitized to nickel. The adult/lifetime TRV of 20 µg Ni/kg-day is based on post-implantation loss/perinatal mortality in a 2-generation reproductive study in rats. Several recent assessments by regulatory agencies have used the same study and endpoint, but the dose-response modeling conducted here was more appropriate for the study design. Toxicokinetic data from rats and humans indicate that the applied uncertainty factors are very conservative. Because the endpoint relates to fetal exposure and is not relevant to toddlers, a toddler TRV was derived based on decreased body weight in young rats; this TRV was also 20 µg Ni/kg-day. A separate TRV of 4 µg Ni/kg in addition to Ni in food was derived for protection of nickel-sensitized populations from flare-up of dermatitis, based on studies of single exposures in humans under conditions that maximize oral absorption.

Toxicology and applied pharmacology, Jan 15, 2014

To provide insights into the mode of action for Ni3S2 lung carcinogenicity by examining gene expr... more To provide insights into the mode of action for Ni3S2 lung carcinogenicity by examining gene expression changes in target cells after inhalation exposure. Gene expression changes were determined in micro-dissected lung broncho-alveolar cells from Fischer 344 rats following inhalation of Ni3S2 at 0.0, 0.04, 0.08, 0.15, and 0.60 mg/m(3) (0.03, 0.06, 0.11, and 0.44 mgNi/m(3)) for one and four weeks (6h/day, 5 days/week). Broncho-alveolar lavage fluid evaluation and lung histopathology provided evidence of inflammation only at the two highest concentrations, which were similar to those tested in the 2-year bioassay. The number of statistically significant up- and down-regulated genes decreased markedly from one to four weeks of exposure, suggesting adaptation. Cell signal pathway enrichment at both time-points primarily reflected responses to toxicity, including inflammatory and proliferative signaling. While proliferative signaling was up-regulated at both time points, some inflammator...

Inhalation toxicology, 2014

Nickel (Ni) in ambient air is predominantly present in the form of oxides and sulfates, with the ... more Nickel (Ni) in ambient air is predominantly present in the form of oxides and sulfates, with the distribution of Ni mass between the fine (particle aerodynamic diameter < 2.5 µm; PM2.5) and coarser (2.5-10 µm) size-selected aerosol fractions of PM10 dependent on the aerosol's origin. When deriving a long-term health protective reference concentration for Ni in ambient air, the respiratory toxicity and carcinogenicity effects of the predominant Ni compounds in ambient air must be considered. Dosimetric adjustments to account for differences in aerosol particle size and respiratory tract deposition and/or clearance among rats, workers, and the general public were applied to experimentally- and epidemiologically-determined points of departure (PODs) such as no(low)-effect concentrations, for both cancer and non-cancer respiratory effects. This approach resulted in the derivation of threshold-based PM10 size-selected equivalent concentrations (modified PODs) of 0.5 µg Ni/m(3) bas...

Bioelution assays are fast, simple alternatives to in vivo testing. In this study, the intraand i... more Bioelution assays are fast, simple alternatives to in vivo testing. In this study, the intraand inter-laboratory variability in bioaccessibility data generated by bioelution tests were evaluated in synthetic fluids relevant to oral, inhalation, and dermal exposure. Using one defined protocol, five laboratories measured metal release from cobalt oxide, cobalt powder, copper concentrate, Inconel alloy, leaded brass alloy, and nickel sulfate hexahydrate. Standard deviations of repeatability (s r) and reproducibility (s R) were used to evaluate the intra-and inter-laboratory variability, respectively. Examination of the s R :s r ratios demonstrated that, while gastric and lysosomal fluids had reasonably good reproducibility, other fluids did not show as good concordance between laboratories. Relative standard deviation (RSD) analysis showed more favorable reproducibility outcomes for some data sets; overall results varied more between-than withinlaboratories. RSD analysis of s r showed good within-laboratory variability for all conditions except some metals in interstitial fluid. In general, these findings indicate that absolute bioaccessibility results in some biological fluids may vary between different laboratories. However, for most applications, measures of relative bioaccessibility are needed, diminishing the requirement for high inter-laboratory reproducibility in absolute metal releases. The inter-laboratory exercise suggests that the degrees of freedom within the protocol need to be addressed.

Toxicology Letters, 2010

late the composition and characteristics of the samples to their toxicity.

Toxicology and Applied Pharmacology, 1997

Man (ICNCM) was formed (as a joint effort between indus-Appl. Pharmacol. 143, 152-166. try, scien... more Man (ICNCM) was formed (as a joint effort between indus-Appl. Pharmacol. 143, 152-166. try, scientists and regulators) to gather the most pertinent The early epidemiological data indicated different carcinogenic available epidemiological data related to exposure to the risks from inhalation of different nickel compounds, but it was various nickel compounds encountered in the nickel-producnot clear what characteristics governed the intrinsic carcinogenic ing industry. The results from this effort were published in hazard of the various nickel compounds. Based on the earlier 1990 (ICNCM Report, 1990). These epidemiological data results, all soluble and insoluble nickel compounds were assumed clearly indicated different inhalation carcinogenic risks for to have the same carcinogenic mechanism albeit different potendifferent classes of nickel compounds, but it was not clear cies. Recent in vivo and in vitro studies challenged this assumption. from these data, or the animal data that preceded this study, In this paper an attempt is made to integrate the most relevant what characteristics governed the intrinsic carcinogenic hazhuman, animal, and in vitro data into a general model that can ard of the various nickel compounds or their potency. help understand the different carcinogenic potentials of the vari-In addition, the lack of a biological model that could be ous nickel compounds. In this perspective, it is recognized that used to integrate and explain all the available data has led there are two main components that could contribute to the development of lung cancer via exposure to certain nickel compounds. in many instances to a lack of consensus in the interpretation The first component corresponds to the heritable changes (genetic of the carcinogenicity of any given nickel compound. For or epigenetic) derived from the direct or indirect actions of nickel example, in 1990 the International Agency for Research on compounds. The second component may be the promotion of cell Cancer (IARC) classified soluble nickel as ''group 1'' (conproliferation elicited by certain nickel compounds. The different firmed human carcinogen), whereas in 1991 the Directorate contributions of three nickel compounds to these two components General XI (DGXI) of the Commission of European Comare presented. This paper emphasizes the importance of recognizmunities (CEC) classified soluble nickel sulfate as ''category ing the individuality of the different nickel species in reaching 3'' (possible human carcinogen), and recently the American regulatory decisions and the fact that different risk assessment Conference of Governmental Industrial Hygienists (ACGIH) considerations may apply for compounds that appear to produce has proposed a ''category A4'' 2 (not classifiable as human immortality and cancer by genetic/epigenetic mechanisms (like carcinogen) for these soluble compounds. nickel subsulfide), compounds that may present a threshold for the induction of tumors in rats (like high-temperature nickel oxide), or Some of the difficulties encountered in establishing the compounds that may only have an enhancing effect on carcinogecarcinogenic hazard for the different nickel compounds, tonicity (like nickel sulfate). ᭧ 1997 Academic Press gether with a brief summary of the most relevant data, are presented below. Human Data I. BACKGROUND AND INTRODUCTION The difficulties in interpreting the epidemiological data Regulatory and nonregulatory agencies have been trying originate from the presence of mixed exposures not only for many years to consider the issue of speciation in making to different nickel compounds, but in some cases to other pronouncements regarding the carcinogenic potential of inorganic compounds as well (ICNCM Report, 1990). In nickel compounds. In 1986, speciation was brought to the addition, the exposure data were sparse and very little speciaforefront by the EPA with the advent of the Nickel Health

Regulatory Toxicology and Pharmacology, 2010

Inhalation animal studies usually employ homogeneous aerosols of small particle diameter. By cont... more Inhalation animal studies usually employ homogeneous aerosols of small particle diameter. By contrast, workers are usually exposed to coarser and more heterogeneous aerosols. The particle size distribution of an aerosol will determine the deposited fraction of inhaled particles in the various regions of the respiratory tract in rodents and humans. The deposited, and subsequently retained, doses in these regions correlate closely with long-term toxic effects. Yet, differences in deposited doses between animals and humans due to particle size differences of aerosols have not been consistently taken into account in risk assessment. This paper describes an approach to calculate equivalent human concentrations (EHC) for respiratory tract effects after inhalation using workplace particle size information. Worker&amp;amp;amp;amp;amp;#39;s exposure to the EHC results in the same deposited dose in the respiratory tract as achieved in animals exposed to the experimental particle size distribution. Example data for nickel compounds demonstrate that exposure levels used in the rat studies are equivalent to 4-11-fold higher levels of human workplace exposures. This approach is equally applicable to other metal/inorganic particulates that exert adverse effects on the respiratory tract after inhalation. Dosimetric extrapolation should be a first step in the derivation of limit values based on animal local respiratory effects.