How does defamiliarization relate to that which it assumes to be familiar? This chapter explores this question in the context of toxicity, an often invisible and imperceptible power, with the aid of two case studies from landscape art. Wout Berger’ s work Giflandschap (Poisoned Landscape, 1992) is exemplary of the ways in which defamiliarization has been a useful aesthetic strategy for artists to make toxicity’ s presence in the everyday tangible. But if toxicity (also outside artistic contexts) always has to be discovered or remembered anew, as Lawrence Buell (Toxic Discourse. Critical Inquiry 24(3): 639–665, 1998) already pointed out, how can we learn to live with toxicity and to understand its ongoing, pervasive presence? Can defamiliarization actually stay with the toxic trouble at hand (Haraway, Staying with the Trouble: Making Kin in the Chthulucene. Durham: Duke University Press, 2016)? Through a second case study, Alexandra Navratil’ s Silbersee (2015), this chapter explores the possibilities of getting intimate with toxicity instead. Ultimately, it suggests that in the context of toxicity, it can be generative to make the strange familiar again.
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From the article: Abstract Sub-chronic toxicity studies of 163 non-genotoxic chemicals were evaluated in order to predict the tumour outcome of 24-month rat carcinogenicity studies obtained from the EFSA and ToxRef databases. Hundred eleven of the 148 chemicals that did not induce putative preneoplastic lesions in the sub-chronic study also did not induce tumours in the carcinogenicity study (True Negatives). Cellular hypertrophy appeared to be an unreliable predictor of carcinogenicity. The negative predictivity, the measure of the compounds evaluated that did not show any putative preneoplastic lesion in de sub-chronic studies and were negative in the carcinogenicity studies, was 75%, whereas the sensitivity, a measure of the sub-chronic study to predict a positive carcinogenicity outcome was only 5%. The specificity, the accuracy of the sub-chronic study to correctly identify non-carcinogens was 90%. When the chemicals which induced tumours generally considered not relevant for humans (33 out of 37 False Negatives) are classified as True Negatives, the negative predictivity amounts to 97%. Overall, the results of this retrospective study support the concept that chemicals showing no histopathological risk factors for neoplasia in a sub-chronic study in rats may be considered non-carcinogenic and do not require further testing in a carcinogenicity study.
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From the article: "To enable selection of novel chemicals for new processes, there is a recognized need for alternative toxicity screening assays to assess potential risks to man and the environment. For human health hazard assessment these screening assays need to be translational to humans, have high throughput capability, and from an animal welfare perspective be harmonized with the principles of the 3Rs (Reduction, Refinement, Replacement). In the area of toxicology a number of cell culture systems are available but while these have some predictive value, they are not ideally suited for the prediction of developmental and reproductive toxicology (DART). This is because they often lack biotransformation capacity, multicellular or multi- organ complexity, for example, the hypothalamus pituitary gonad (HPG) axis and the complete life cycle of whole organisms. To try to overcome some of these limitations in this study, we have used Caenorhabditis elegans (nematode) and Danio rerio embryos (zebrafish) as alternative assays for DART hazard assessment of some candidate chemicals being considered for a new commercial application. Nematodes exposed to Piperazine and one of the analogs tested showed a slight delay in development compared to untreated animals but only at high concentrations and with Piperazine as the most sensitive compound. Total brood size of the nematodes was also reduced primarily by Piperazine and one of the analogs. In zebrafish Piperazine and analogs showed developmental delays. Malformations and mortality in individual fish were also scored. Significant malformations were most sensitively identified with Piperazine, significant mortality was only observed in Piperazine and only at the higest dose. Thus, Piperazine seemed the most toxic compound for both nematodes and zebrafish. The results of the nematode and zebrafish studies were in alignment with data obtained from conventional mammalian toxicity studies indicating that these have potential as developmental toxicity screening systems. The results of these studies also provided reassurance that none of the Piperazines tested are likely to have any significant developmental and/or reproductive toxicity issues to humans when used in their commercial applications."
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PURPOSE: To determine the impact of late radiation-induced toxicity on health-related quality of life (HRQoL) among patients with prostate cancer.PATIENTS AND METHODS: The study sample was composed of 227 patients, treated with external beam radiotherapy. Common Terminology Criteria for Adverse Events version 3.0 were used to grade late genitourinary and gastrointestinal toxicity. The European Organization for Research and Treatment of Cancer Quality of life Questionnaire C30 (EORTC QLQ-C30) was used to assess HRQoL at baseline, and 6, 12 and 24 months after completion of radiotherapy. Statistical analysis was performed using a multivariate analysis of variance (MANOVA).RESULTS: Urinary incontinence and rectal discomfort significantly affected HRQoL. The impact of urinary incontinence on HRQoL was most pronounced 6 months after radiotherapy and gradually decreased over time. The impact of rectal discomfort on HRQoL was predominant at 6 months after radiotherapy, decreased at 12 months and increased again 2 years after radiotherapy. No significant impact on HRQoL was observed for any of the other toxicity endpoints, or non-toxicity related factors such as hormonal therapy, radiotherapy technique or age.CONCLUSION: Urinary incontinence and rectal discomfort have a significant impact on HRQoL. Prevention of these side effects may likely improve quality of life of prostate cancer patients after completion of treatment.
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Introduction: To reduce continuously increasing costs in drug development, adverse effects of drugs need to be detected as early as possible in the process. In recent years, compound-induced gene expression profiling methodologies have been developed to assess compound toxicity, including Gene Ontology term and pathway over-representation analyses. The objective of this study was to introduce an additional approach, in which literature information is used for compound profiling to evaluate compound toxicity and mode of toxicity. Methods: Gene annotations were built by text mining in Medline abstracts for retrieval of co-publications between genes, pathology terms, biological processes and pathways. This literature information was used to generate compound-specific keyword fingerprints, representing over-represented keywords calculated in a set of regulated genes after compound administration. To see whether keyword fingerprints can be used for assessment of compound toxicity, we analyzed microarray data sets of rat liver treated with 11 hepatotoxicants. Results: Analysis of keyword fingerprints of two genotoxic carcinogens, two nongenotoxic carcinogens, two peroxisome proliferators and two randomly generated gene sets, showed that each compound produced a specific keyword fingerprint that correlated with the experimentally observed histopathological events induced by the individual compounds. By contrast, the random sets produced a flat aspecific keyword profile, indicating that the fingerprints induced by the compounds reflect biological events rather than random noise. A more detailed analysis of the keyword profiles of diethylhexylphthalate, dimethylnitrosamine and methapyrilene (MPy) showed that the differences in the keyword fingerprints of these three compounds are based upon known distinct modes of action. Visualization of MPy-linked keywords and MPy-induced genes in a literature network enabled us to construct a mode of toxicity proposal for MPy, which is in agreement with known effects of MPy in literature. Conclusion: Compound keyword fingerprinting based on information retrieved from literature is a powerful approach for compound profiling, allowing evaluation of compound toxicity and analysis of the mode of action. © 2007 Future Medicine Ltd.
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Human exposure to polybrominated diphenyl ethers (PBDEs) can occur via ingestion of indoor dust, inhalation of PBDE-contaminated air and dust-bound PBDEs. However, few studies have examined the pulmonary toxicity of particle-bound PBDEs, mainly due to the lack of an appropriate particle-cell exposure system. In this study we developed an in vitro exposure system capable of generating particle-bound PBDEs mimicking dusts containing PBDE congeners (PBDEs 35, 47 and 99) and delivering them directly onto lung cells grown at an air–liquid interface (ALI). The silica particles and particles-coated with PBDEs ranged in diameter from 4.3 to 4.5 μm and were delivered to cells with no apparent aggregation. This experimental set up demonstrated high reproducibility and sensitivity for dosing control and distribution of particles. All exposure of cells to PBDE-bound particles significantly decreased cell viability and induced reactive oxygen species generation in A549 and NCI-H358 cells. In male Sprague-Dawley rats exposed via intratracheal insufflation (0.6 mg/rat), particle-bound PBDE exposures induced inflammatory responses with increased recruitment of neutrophils to the lungs compared to sham-exposed rats. The present study clearly indicates the potential of our exposure system for studying the toxicity of particle-bound compounds.Abstract of the paper published by Elsevier. The whole paper can be obtained via: http://www.sciencedirect.com/science/article/pii/S0300483X14000067#
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Toxicity outcomes derived in vitro do not always reflect in vivo toxicity values, which was previously observed for a series of phenols tested in the embryonic stem cell test (EST). Translation of in vitro data to the in vivo situation is therefore an important, but still limiting step for the use of in vitro toxicity outcomes in the safety assessment of chemicals. The aim of the present study was to translate in vitro embryotoxicity data for a series of phenols to in vivo developmental toxic potency values for the rat by physiologically based kinetic (PBK) modelling-based reverse dosimetry. To this purpose, PBK models were developed for each of the phenols. The models were parameterised with in vitro-derived values defining metabolism and transport of the compounds across the intestinal and placental barrier and with in silico predictions and data from the literature. Using PBK-based reverse dosimetry, in vitro concentration–response curves from the EST were translated into in vivo dose–response curves from which points of departure (PoDs) were derived. The predicted PoDs differed less than 3.6-fold from PoDs derived from in vivo toxicity data for the phenols available in the literature. Moreover, the in vitro PBK-based reverse dosimetry approach could overcome the large disparity that was observed previously between the in vitro and the in vivo relative potency of the series of phenols. In conclusion, this study shows another proof-of-principle that the in vitro PBK approach is a promising strategy for non-animal-based safety assessment of chemicals.
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Lasiocarpine and riddelliine are pyrrolizidine alkaloids (PAs) known to cause liver toxicity. The aim of this study was to predict the inter-species and inter-ethnic human differences in acute liver toxicity of lasiocarpine and riddelliine using physiologically based kinetic (PBK) modelling based reverse dosimetry of in vitro toxicity data. The concentration–response curves of in vitro cytotoxicity of lasiocarpine and riddelliine defined in pooled human hepatocytes were translated to in vivo dose–response curves by PBK models developed using kinetic data obtained from incubations with pooled tissue fractions from Chinese and Caucasian individuals, providing PBK models for the average Chinese and average Caucasian, respectively. From the predicted in vivo dose–response curves, the benchmark dose lower and upper confidence limits for 5% effect (BMDL5 and BMDU5) were derived and subsequently compared to those previously obtained in rat to evaluate inter-species differences. The inter-species differences amounted to 2.0-fold for lasiocarpine and 8.2-fold for riddelliine with humans being more sensitive than rats. The inter-ethnic human differences varied 2.0-fold for lasiocarpine and 5.0-fold for riddelliine with the average Caucasian being more sensitive than the average Chinese. In conclusion, the present study provides the proof-of-principle to predict inter-species and inter-ethnic differences in in vivo liver toxicity for PAs by an alternative testing strategy integrating in vitro cytotoxicity data with PBK modelling-based reverse dosimetry.
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BACKGROUND & AIMS: We studied whether low pre-treatment muscle mass, measured with CT at thoracic (T4) or lumbar level (L3) associates with early termination of chemotherapy related to toxicity in head and neck cancer (HNC) patients.METHODS: This was a retrospective chart and image review. Adult HNC patients treated with (surgery and) platinum-based chemo-radiotherapy were included if a pre-treatment CT scan at T4 or L3 level was available. Muscle mass was evaluated by assessment of skeletal muscle index (SMI; cm2/m2). T4 and L3 SMI measurements were corrected for deviation from their respective means and were merged into one score for SMI difference (cm2/m2). All cases were assessed for presence of toxicity-related unplanned early termination of chemotherapy ('early termination'). Univariate and multivariate logistic regression models were used to investigate associations between pooled SMI and early termination.RESULTS: 213 patients (age: 57.9 ± 10.3 y, male: 77%, T4 image: 45%) were included. A significant association between SMI as a continuous variable and early termination was found, both in the univariate analysis (p = 0.007, OR = 0.96 [0.94-0.99]) and the multivariate analysis (p = 0.021, OR 0.96 [0.92-0.99]). The multivariate models identified potential associations with type of chemotherapy, presence of co-morbidity, a combination of (former) smoking and alcohol consumption, and sex.CONCLUSION: Lower muscle mass was robustly associated with higher odds of early termination of chemotherapy in HNC patients. Further prospective studies are required to tailor the care for patients with low muscle mass and to avoid early termination of chemotherapy.
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Summary: Xpaths is a collection of algorithms that allow for the prediction of compound-induced molecular mechanisms of action by integrating phenotypic endpoints of different species; and proposes follow-up tests for model organisms to validate these pathway predictions. The Xpaths algorithms are applied to predict developmental and reproductive toxicity (DART) and implemented into an in silico platform, called DARTpaths.
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