Lang Tran - Academia.edu (original) (raw)

Papers by Lang Tran

Regulatory Toxicology and Pharmacology Rtp, Dec 1, 2010

Fullerenes have gained considerable attention due to their anti-oxidant and radical scavenging pr... more Fullerenes have gained considerable attention due to their anti-oxidant and radical scavenging properties. Their current applications include targeted drug delivery, energy application, polymer modifications and cosmetic products. The production of fullerenes and their use in consumer products is expected to increase in future.

Inhalation Toxicology, Feb 1, 2008

We previously demonstrated the importance of the surface area burden as the key dose metric in th... more We previously demonstrated the importance of the surface area burden as the key dose metric in the elicitation of inflammation in rat lungs by low-solubility, low-toxicity particles (LSLTP). We have now explored the dosimetry of LSLTP in vitro using epithelial cell interleukin (IL)-8 gene expression as a surrogate for potential of particles to cause inflammation. The proximal alveolar region (PAR) of the lung has been identified as a key site for the retention of respirable particles, as it receives high deposition but has slow clearance compared to the larger airways. For these reasons, a few days after exposure to particles the residual dose is concentrated in the PAR region. Re-expressing our rat lung data as particle surface area burden per unit of PAR surface area we obtained a threshold value for onset of inflammation of 1 cm(2)/cm(2). We carried out dose responses in vitro for onset of IL-8 gene expression with the same particles as we had used in vivo. When we expressed the in vitro dose as surface area dose per unit A549cell culture surface area, we obtained a threshold of 1 cm(2)/cm(2). This concordance between proinflammatory effects in vivo (PMN in BAL) and in vitro (epithelial IL-8 gene expression) confirms and supports the utility of the particle surface area metric and the importance of the PAR. These studies also open the way for future in vitro approaches to studying proinflammatory effects of a range of toxic particles based on sound dosimetry that complements animal use in particle toxicology.

Journal of toxicology and environmental health. Part B, Critical reviews, 2016

ENPRA was one of the earlier multidisciplinary European Commission FP7-funded projects aiming to ... more ENPRA was one of the earlier multidisciplinary European Commission FP7-funded projects aiming to evaluate the risks associated with nanomaterial (NM) exposure on human health across pulmonary, cardiovascular, hepatic, renal, and developmental systems. The outputs from this project have formed the basis of this review. A retrospective interpretation of the findings across a wide range of in vitro and in vivo studies was performed to identify the main highlights from the project. In particular, focus was placed on informing what advances were made in the hazard assessment of NM, as well as offering some suggestions on the future of "nanotoxicology research" based on these observations, shortcomings, and lessons learned from the project. A number of issues related to the hazard assessment of NM are discussed in detail and include use of appropriate NM for nanotoxicology investigations; characterization and dispersion of NM; use of appropriate doses for all related investigati...

The Handbook of Environmental Chemistry, 2016

Journal of Physics Conference Series

European Journal of Nanomedicine, 2015

ABSTRACT In October of 2014, a meeting jointly organized by the EU Nanosafety Cluster and the COS... more ABSTRACT In October of 2014, a meeting jointly organized by the EU Nanosafety Cluster and the COST Action TD 1204, was held on the beautiful island of Ortygia in Syracuse (Sicily). The meeting was specifically conceived to give the opportunity to young researchers in the field of nanotoxicology to present and discuss the results of their research. Presentations were divided into eight sessions over 2 days, reflecting the eight working groups of the Nanosafety Cluster. This report gives a description of the meeting activities and a summary of the data presented there.

Wiley interdisciplinary reviews. Nanomedicine and nanobiotechnology

Nanotechnology has become the focus of a large amount of scientific, political, and financial int... more Nanotechnology has become the focus of a large amount of scientific, political, and financial interest. Limited information on the exposure to nanomaterials is available, with only a few occupational exposure studies having been performed. While laboratory animal studies on the biological effects of some nanomaterials have been published, no epidemiological studies have been reported to date. This lack of data on exposure and human health effects hinders risk assessment of these materials. As the use of nanomaterials increases rapidly, it is of vital importance that the risk assessment community understands the complexities of the issues surrounding the manufacture, use and disposal of nanomaterials, the potential of environmental and occupational exposure to human populations, as well as adverse health outcomes. For this to happen, it is in many ways necessary for the scientific community to also understand what questions risk assessors need to ask, and what research will best answ...

Environmental and Human Health Impacts of Nanotechnology, 2009

The Toxicology of Carbon Nanotubes, 2012

Nanotoxicology, 2014

Substantial limitations and uncertainties hinder the exposure assessment of engineered nanomateri... more Substantial limitations and uncertainties hinder the exposure assessment of engineered nanomaterials (ENMs). The present deficit of reliable measurements and models will inevitably lead in the near term to qualitative and uncertain exposure estimations, which may fail to support adequate risk assessment and management. Therefore it is necessary to complement the current toolset with user-friendly methods for near-term nanosafety evaluation. This paper proposes an approach for relative exposure screening of ENMs. For the first time, an exposure model explicitly implements quantitative weight of evidence (WoE) methods and utilizes expert judgment for filling data gaps in the available evidence-base. Application of the framework is illustrated for screening of exposure scenarios for nanoscale titanium dioxide, carbon nanotubes and fullerenes, but it is applicable to other nanomaterials as well. The results show that the WoE-based model overestimates exposure for scenarios where expert judgment was substantially used to fill data gaps, which suggests its conservative nature. In order to test how variations in input data influence the obtained results, probabilistic Monte Carlo sensitivity analysis was applied to demonstrate that the model performs in stable manner. © Informa UK, Ltd. This provisional PDF corresponds to the article as it appeared upon acceptance. Fully formatted PDF and full text (HTML) versions will be made available soon.

Nanotoxicology, 2011

In assessing hazard for human health posed by newly engineered nanomaterials (ENM), approaches su... more In assessing hazard for human health posed by newly engineered nanomaterials (ENM), approaches such as Weight of Evidence (WOE) and expert judgment are required to develop conclusions about the hazard of ENM. This is because all factors affecting hazard are not currently well defined and are often subject to different interpretation. Here we report the application of a WOE procedure to assess the potential of ENM to cause harm for human health, by integrating and combining physicochemical properties of NM and toxicity data obtained within the EU-funded Particle Risk project. The procedure was applied to carbon black (CB), single-walled carbon nanotubes (SWNT), C60 fullerene and quantum dots (QD) ENM tested during the Particle Risk project. The results show that some of the investigated ENM present a relatively higher hazardousness level on the basis of the integration of their physicochemical properties and toxicological effects, and that their hazard may be ranked as follow: QD >> C60 > SWNT > CB. This case study shows the utility of WOE approach to obtain a hazard ranking of ENM.

Critical Reviews in Toxicology, 2010

Carbon nanotubes (CNTs) possess many unique electronic and mechanical properties and are thus int... more Carbon nanotubes (CNTs) possess many unique electronic and mechanical properties and are thus interesting for numerous novel industrial and biomedical applications. As the level of production and use of these materials increases, so too does the potential risk to human health. This study aims to investigate the feasibility and challenges associated with conducting a human health risk assessment for carbon nanotubes based on the open literature, utilising an approach similar to that of a classical regulatory risk assessment. Results indicate that the main risks for humans arise from chronic occupational inhalation, especially during activities involving high CNT release and uncontrolled exposure. It is not yet possible to draw definitive conclusions with regards the potential risk for long, straight multi-walled carbon nanotubes to pose a similar risk as asbestos by inducing mesothelioma. The genotoxic potential of CNTs is currently inconclusive and could be either primary or secondary. Possible systemic effects of CNTs would be either dependent on absorption and distribution of CNTs to sensitive organs or could be induced through the release of inflammatory mediators. In conclusion, gaps in the data set in relation to both exposure and hazard do not allow any definite conclusions suitable for regulatory decision-making. In order to enable a full human health risk assessment, future work should focus on the generation of reliable occupational, environmental and consumer exposure data. Data on toxicokinetics and studies investigating effects of chronic exposure under conditions relevant for human exposure should also be prioritised.

Critical Reviews in Toxicology, 2011

In 1987 the International Agency for Research on Cancer (IARC) classified crystalline silica (CS)... more In 1987 the International Agency for Research on Cancer (IARC) classified crystalline silica (CS) as a probable carcinogen and in 1997 reclassified it as a Group 1 carcinogen, i.e., that there was sufficient evidence for carcinogenicity in experimental animals and sufficient evidence for carcinogenicity in humans. The Working Group noted that "carcinogenicity in humans was not detected in all industrial circumstances studied, carcinogenicity may be dependent on inherent characteristics of the crystalline silica or on external factors affecting its biological activity or distribution of its polymorphs. " This unusual statement that the physicochemical form of the CS influences its carcinogenicity is well understood at the toxicological level and arises as a consequence of the fact that CS activity depends on the reactivity of the CS surface, which can be blocked by a number of agents. We reviewed the literature on CS genotoxicity that has been published since the 1997 monograph, with special reference to the mechanism of CS genotoxicity. The mechanism of CS genotoxicity can be primary, a result of direct interaction of CS with target cells, or indirect, as a consequence of inflammation elicited by quartz, where the inflammatory cell-derived oxidants cause the genotoxicity. The review revealed a number of papers supporting the hypothesis that the CS genotoxic and inflammatory hazard is a variable one. In an attempt to attain a quantitative basis for the potential mechanism, we carried out analysis of published data and noted a 5-fold greater dose required to reach a threshold for genotoxic effects than for proinflammatory effects in the same cell line in vitro. When we related the calculated threshold dose at the proximal alveolar region for inflammation in a published study with the threshold dose for genotoxicity in vitro, we noted that a 60-120-fold greater dose was required for direct genotoxic effects in vitro. These data strongly suggests that inflammation is the driving force for genotoxicity and that primary genotoxicity of deposited CS would play a role only at very high, possibly implausible, exposures and deposited doses. Although based on rat studies and in vitro studies, and therefore with caveats, the analysis supports the hypothesis that the mechanism of CS genotoxicity is via inflammation-driven secondary genotoxicity. This may have implications for setting of the CS standard in workplaces. During the writing of this review (in May 2009), IARC undertook a review of carcinogenic substances, including CS. The Working Group met to reassess 10 separate agents including CS. This was not a normal monograph working group published as a large single monograph, but was published as a two-page report. This review group reaffirmed the carcinogenicity of "silica dust, crystalline in the form of quartz or cristobalite" as a Group 1 agent, with the lung as the sole tumor site. Of special relevance to the present review is that the cited "established mechanism events" for CS are restricted to the words "impaired particle clearance leading to macrophage activation and persistent inflammation. " The lack of mention of direct genotoxicity is in line with the conclusions reached in the present review.

Annals of Occupational Hygiene, 2002

Following the classification of quartz as a human carcinogen by the IARC, many standardsetting co... more Following the classification of quartz as a human carcinogen by the IARC, many standardsetting committees are currently trying to convert this hazard into their national or EU standards. Since human data to set a safe exposure limit for quartz are limited, we hypothesized that lung burden data on quartz in coal miners' lungs after lifetime exposure could be used to set a non-carcinogenic lung burden of quartz, and that this might be valid for other groups occupationally exposed to quartz. A review of data shows that lungs of coal miners with simple coal workers' pneumoconiosis (sCWP) typically contain up to 30 g of dust, and in one specific study lung burdens between 0.7 and 1.7 g of quartz were associated with macules only, and no sCWP. Assuming independent actions of coal and quartz and no clearance of quartz, and sCWP as a prerequisite for lung cancer due to quartz exposure in coal mine dust, a simple kinetic approach was applied. A no observed adverse effect level (NOAEL) for quartz of between 0.03 and 0.13 mg/m 3 (40 yr exposure) is derived, but it is concluded that more refined physiologically based pharmacokinetic modelling is needed for a better estimate, also including interindividual differences in lung clearance. Considering the independent effects of, and the well-known interaction between coal and quartz, these data could be important to other workplaces with usual mixed-dust exposure.

Environment International, 2016

Commercialization of nanotechnologies entails a regulatory requirement for understanding their en... more Commercialization of nanotechnologies entails a regulatory requirement for understanding their environmental, health and safety (EHS) risks. Today we face challenges to assess these risks, which emerge from uncertainties around the interactions of manufactured nanomaterials (MNs) with humans and the environment. In order to reduce these uncertainties, it is necessary to generate sound scientific data on hazard and exposure by means of relevant frameworks and tools. The development of such approaches to facilitate the risk assessment (RA) of MNs has become a dynamic area of research. The aim of this paper was to review and critically analyse these approaches against a set of relevant criteria. The analysis concluded that none of the reviewed frameworks were able to fulfill all evaluation criteria. Many of the existing modelling tools are designed to provide screening-level assessments rather than to support regulatory RA and risk management. Nevertheless, there is a tendency towards developing more quantitative, higher-tier models, capable of incorporating uncertainty into their analyses. There is also a trend towards developing validated experimental protocols for material identification and hazard testing, reproducible across laboratories. These tools could enable a shift from a costly case-by-case RA of MNs towards a targeted, flexible and efficient process, based on grouping and read-across strategies and compliant with the 3R (Replacement, Reduction, Refinement) principles. In order to facilitate this process, it is important to transform the current efforts on developing databases and computational models into creating an integrated data and tools infrastructure to support the risk assessment and management of MNs.

Toxicol Sci, 2008

The aryl hydrocarbon receptor (AhR) is required for the toxicity of 2,3,7,8-tetrachlorodibenzo-p-... more The aryl hydrocarbon receptor (AhR) is required for the toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and so the AhR of CRL:WI and CRL:WI(Han) rats was characterized. Western blot showed AhR proteins of~110 and~97 kDa in individual rats from both strains. The AhR cDNA from a CRL:WI(Han) rat with thẽ 110-kDa protein revealed a sequence that was identical to that of the CRL:WI and SD rat. However, cloning of the AhR from a rat with the~97-kDa protein revealed a point mutation, and five variants encoding two C-terminally truncated variants of the AhR protein, arising from a point mutation in the intron/exon junction and consequent differential splicing. These C-terminally truncated variants were expressed and shown to give rise to a protein of~97 kDa; the recombinant AhR bound TCDD with an affinity that was not statistically different from the full-length protein. A single-nucleotide polymorphism assay was developed, and showed that both alleles were represented in a Hardy-Weinberg equilibrium in samples of CRL:WI and CRL:WI(Han) populations; both alleles are abundant. Rats from two studies of TCDD developmental toxicity were genotyped, and the association with toxicity investigated using statistical analysis. There was no plausible evidence that the AhR allele had a significant effect on the toxic endpoints examined. These data show that the two AhR alleles are common in two strains of Wistar rat, and that the AhR alleles had no effect on TCDD-induced developmental toxicity in two independent studies.

Toxicology and Applied Pharmacology, 2010

Nanoparticles (NPs) are being used within diverse applications such as medicines, clothing, cosme... more Nanoparticles (NPs) are being used within diverse applications such as medicines, clothing, cosmetics and food. In order to promote the safe development of such nanotechnologies it is essential to assess the potential adverse health consequences associated with human exposure. The liver is recognised as a target site for NP toxicity, due to NP accumulation within this organ subsequent to injection, inhalation or instillation. The uptake of fluorescent polystyrene carboxylated particles (20 nm or 200 nm diameter) by hepatocytes was determined using confocal microscopy; with cells imaged…