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Archives of Toxicology (v.87, #1)

Role of heat shock proteins in stress response and carcinogenesis by C. Cadenas; R. Marchan; H. M. Bolt (pp. 1-2).

Transcription factors controlling responses to toxic chemicals by P. Godoy; R. Reif (pp. 3-4).

Developmental neurotoxicity testing with human embryonic stem cell-derived in vitro systems: the novel FP7 ESNATS tests are available by H. M. Bolt (pp. 5-6).

Toxicogenomics for transcription factor-governed molecular pathways: moving on to roles beyond classification and prediction by Melvin E. Andersen; Patrick D. McMullen; Sudin Bhattacharya (pp. 7-11).

Stress response pathways, toxicity pathways and adverse outcome pathways by Paul Jennings (pp. 13-14).

A new twist to an old tale: novel insights into the differential toxicities of acetaminophen and its regioisomer N-acetyl-meta-aminophenol (AMAP) by J. Gerry Kenna (pp. 15-18).

Heat shock proteins and heat shock factor 1 in carcinogenesis and tumor development: an update by Daniel R. Ciocca; Andre Patrick Arrigo; Stuart K. Calderwood (pp. 19-48).

Heat shock proteins (HSP) are a subset of the molecular chaperones, best known for their rapid and abundant induction by stress. HSP genes are activated at the transcriptional level by heat shock transcription factor 1 (HSF1). During the progression of many types of cancer, this heat shock transcriptional regulon becomes co-opted by mechanisms that are currently unclear, although evidently triggered in the emerging tumor cell. Concerted activation of HSF1 and the accumulation of HSPs then participate in many of the traits that permit the malignant phenotype. Thus, cancers of many histologies exhibit activated HSF1 and increased HSP levels that may help to deter tumor suppression and evade therapy in the clinic. We review here the extensive work that has been carried out and is still in progress aimed at (1) understanding the oncogenic mechanisms by which HSP genes are switched on, (2) determining the roles of HSF1/HSP in malignant transformation and (3) discovering approaches to therapy based on disrupting the influence of the HSF1-controlled transcriptome in cancer.

Keywords: Heat shock proteins; Heat shock factor; Cancer; Carcinogenesis; Drug resistance; Apoptosis; Metastasis; Prognosis

An overview of transcriptional regulation in response to toxicological insult by Paul Jennings; Alice Limonciel; Luca Felice; Martin O. Leonard (pp. 49-72).

The completion of the human genome project and the subsequent advent of DNA microarray and high-throughput sequencing technologies have led to a renaissance in molecular toxicology. Toxicogenomic data sets, from both in vivo and in vitro studies, are growing exponentially, providing a wealth of information on regulation of stress pathways at the transcriptome level. Through such studies, we are now beginning to appreciate the diversity and complexity of biological responses to xenobiotics. In this review, we aim to consolidate and summarise the major toxicologically relevant transcription factor-governed molecular pathways. It is becoming clear that different chemical entities can cause oxidative, genotoxic and proteotoxic stress, which induce cellular responses in an effort to restore homoeostasis. Primary among the response pathways involved are NFE2L2 (Nrf2), NFE2L1 (Nrf1), p53, heat shock factor and the unfolded protein response. Additionally, more specific mechanisms exist where xenobiotics act as ligands, including the aryl hydrocarbon receptor, metal-responsive transcription factor-1 and the nuclear receptor family of transcription factors. Other pathways including the immunomodulatory transcription factors NF-κB and STAT together with the hypoxia-inducible transcription factor HIF are also implicated in cellular responses to xenobiotic exposure. A less specific but equally important aspect to cellular injury controlled by transcriptional activity is loss of tissue-specific gene expression, resulting in dedifferentiation of target cells and compromise of tissue function. Here, we review these pathways and the genes they regulate in order to provide an overview of this growing field of molecular toxicology.

Keywords: Transcriptomics; Xenobiotic; Nuclear receptors; Transcription factor; Mitochondria; Differentiation

Recent trend in risk assessment of formaldehyde exposures from indoor air by Gunnar Damgård Nielsen; Søren Thor Larsen; Peder Wolkoff (pp. 73-98).

Studies about formaldehyde (FA) published since the guideline of 0.1 mg/m³ by the World Health Organization (WHO) in 2010 have been evaluated; critical effects were eye and nasal (portal-of-entry) irritation. Also, it was considered to prevent long-term effects, including all types of cancer. The majority of the recent toxicokinetic studies showed no exposure-dependent FA–DNA adducts outside the portal-of-entry area and FA–DNA adducts at distant sites were due to endogenously generated FA. The no-observed-adverse-effect level for sensory irritation was 0.5 ppm and recently reconfirmed in hypo- and hypersensitive individuals. Investigation of the relationship between FA exposure and asthma or other airway effects in children showed no convincing association. In rats, repeated exposures showed no point mutation in the p53 and K-Ras genes at ≤15 ppm neither increased cell proliferation, histopathological changes and changes in gene expression at 0.7 ppm. Repeated controlled exposures (0.5 ppm with peaks at 1 ppm) did not increase micronucleus formation in human buccal cells or nasal tissue (0.7 ppm) or in vivo genotoxicity in peripheral blood lymphocytes (0.7 ppm), but higher occupational exposures were associated with genotoxicity in buccal cells and cultivated peripheral blood lymphocytes. It is still valid that exposures not inducing nasal squamous cell carcinoma in rats will not induce nasopharyngeal cancer or lymphohematopoietic malignancies in humans. Reproductive and developmental toxicity are not considered relevant in the absence of sensory irritation. In conclusion, the WHO guideline has been strengthened.

Keywords: Indoor air guideline; Formaldehyde; World Health Organization; Sensory irritation; Asthma; Cancer

Recent trend in risk assessment of formaldehyde exposures from indoor air by Gunnar Damgård Nielsen; Søren Thor Larsen; Peder Wolkoff (pp. 73-98).

Keywords: Indoor air guideline; Formaldehyde; World Health Organization; Sensory irritation; Asthma; Cancer

Size of TiO₂ nanoparticles influences their phototoxicity: an in vitro investigation by Sijing Xiong; Saji George; Zhaoxia Ji; Sijie Lin; Haiyang Yu; Robert Damoiseaux; Bryan France; Kee Woei Ng; Say Chye Joachim Loo (pp. 99-109).

To uncover the size influence of TiO₂ nanoparticles on their potential toxicity, the cytotoxicity of different-sized TiO₂ nanoparticles with and without photoactivation was tested. It was demonstrated that without photoactivation, TiO₂ nanoparticles were inert up to 100 μg/ml. On the contrary, with photoactivation, the toxicity of TiO₂ nanoparticles significantly increased, which correlated well with the specific surface area of the particles. Our results also suggest that the generation of hydroxyl radicals and reactive oxygen species (ROS)-mediated damage to the surface-adsorbed biomolecules could be the two major reasons for the cytotoxicity of TiO₂ nanoparticles after photoactivation. Higher ROS generation from smaller particles was detected under both biotic and abiotic conditions. Smaller particles could adsorb more proteins, which was confirmed by thermogravimetric analysis. To further investigate the influence of the generation of hydroxyl radicals and adsorption of protein, poly (ethylene-alt-maleic anhydride) (PEMA) and chitosan were used to coat TiO₂ nanoparticles. The results confirmed that surface coating of TiO₂ nanoparticles could reduce such toxicity after photoactivation, by hindering adsorption of biomolecules and generation of hydroxyl radical (·OH) during photoactivation.

Keywords: Titanium dioxide nanoparticles; Phototoxicity; Cytotoxicity; Nanotoxicity; Surface coating

The risky cocktail: what combination effects can we expect between ecstasy and other amphetamines? by Diana Dias da Silva; Helena Carmo; Elisabete Silva (pp. 111-122).

The recreational and illicit use of amphetaminic designer compounds, specially 3,4-methylenedioxymethamphetamine (MDMA; Ecstasy), is of concern worldwide. Such psychostimulating drugs are frequently present as complex mixtures in ‘rave’ pills, making concomitant polysubstance use a common trend. However, the understanding of possible combination effects with these substances is still scarce. The present study was aimed at predicting the cytotoxic effects of mixtures of four amphetaminic derivatives: MDMA, methamphetamine, 4-methylthioamphetamine and d-amphetamine in a human hepatoma cell line. Concentration–response curves for all single-mixture components were recorded by the MTT assay. Data obtained for individual agents were then used to compute the additivity expectations for mixtures of definite composition, using the pharmacological models of concentration addition (CA) and independent action. By comparing the predicted calculations with the experimentally observed effects, we concluded that CA accurately predicts the combination of amphetamines, which act together to generate additive effects over a large range of concentrations. Notably, we observed substantial mixture effects even when each drug was present at low concentrations, which individually produced unnoticeable effects. Nonetheless, for all tested mixtures, a small deviation from additivity was observed towards higher concentrations, particularly at high effect levels. A possible metabolic interaction, which could explain such deviation, was investigated, and it was observed that at higher mixture concentrations increased MDMA metabolism could be contributing to divergences from additivity. In conclusion, the present work clearly demonstrates that potentially harmful interactions among amphetaminic drugs are expected when these drugs are taken concomitantly.

Keywords: 3,4-methylenedioxymethamphetamine (ecstasy, MDMA); Amphetamine-related toxicity; Hepatocytes; Combination effects; Concentration addition (CA); Independent action (IA)

Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach by Anne K. Krug; Raivo Kolde; John A. Gaspar; Eugen Rempel; Nina V. Balmer; Kesavan Meganathan; Kinga Vojnits; Mathurin Baquié; Tanja Waldmann; Roberto Ensenat-Waser; Smita Jagtap; Richard M. Evans; Stephanie Julien; Hedi Peterson; Dimitra Zagoura; Suzanne Kadereit; Daniel Gerhard; Isaia Sotiriadou; Michael Heke; Karthick Natarajan; Margit Henry; Johannes Winkler; Rosemarie Marchan; Luc Stoppini; Sieto Bosgra; Joost Westerhout; Miriam Verwei; Jaak Vilo; Andreas Kortenkamp; Jürgen Hescheler; Ludwig Hothorn; Susanne Bremer; Christoph van Thriel; Karl-Heinz Krause; Jan G. Hengstler; Jörg Rahnenführer; Marcel Leist; Agapios Sachinidis (pp. 123-143).

Developmental neurotoxicity (DNT) and many forms of reproductive toxicity (RT) often manifest themselves in functional deficits that are not necessarily based on cell death, but rather on minor changes relating to cell differentiation or communication. The fields of DNT/RT would greatly benefit from in vitro tests that allow the identification of toxicant-induced changes of the cellular proteostasis, or of its underlying transcriptome network. Therefore, the ‘human embryonic stem cell (hESC)-derived novel alternative test systems (ESNATS)’ European commission research project established RT tests based on defined differentiation protocols of hESC and their progeny. Valproic acid (VPA) and methylmercury (MeHg) were used as positive control compounds to address the following fundamental questions: (1) Does transcriptome analysis allow discrimination of the two compounds? (2) How does analysis of enriched transcription factor binding sites (TFBS) and of individual probe sets (PS) distinguish between test systems? (3) Can batch effects be controlled? (4) How many DNA microarrays are needed? (5) Is the highest non-cytotoxic concentration optimal and relevant for the study of transcriptome changes? VPA triggered vast transcriptional changes, whereas MeHg altered fewer transcripts. To attenuate batch effects, analysis has been focused on the 500 PS with highest variability. The test systems differed significantly in their responses (<20 % overlap). Moreover, within one test system, little overlap between the PS changed by the two compounds has been observed. However, using TFBS enrichment, a relatively large ‘common response’ to VPA and MeHg could be distinguished from ‘compound-specific’ responses. In conclusion, the ESNATS assay battery allows classification of human DNT/RT toxicants on the basis of their transcriptome profiles.

Keywords: Methylmercury; Valproic acid; Transcription factor; Reproductive toxicity; Alternative testing strategies

Assessment of immunotoxicity and genotoxicity in workers exposed to low concentrations of formaldehyde by Sevtap Aydın; Hande Canpınar; Ülkü Ündeğer; Dicle Güç; Mustafa Çolakoğlu; Ayşe Kars; Nurşen Başaran (pp. 145-153).

Formaldehyde (FA), which is an important chemical with a wide commercial use, has been classified as carcinogenic to humans by International Research on Cancer (IARC). The genotoxic and carcinogenic potential of FA has been documented in mammalian cells and in rodents. A recent evaluation by the E.U. Scientific Committee for Occupational Exposure Limits (SCOEL) anticipated that an 8-h time-weighted average exposure to 0.2 ppm FA would not be irritating and not genotoxic in humans. In order to verify this prediction, a field study was performed that aimed at evaluating immune alterations and genetic damage in peripheral lymphocytes of workers in medium density fiberboard plants exposed to a level of FA equivalent to the OEL recommended by SCOEL (0.2 ppm). Subsets of peripheral lymphocytes, immunoglobulins (IgG, IgA, IgM), complement proteins, and tumor necrosis factor-alpha (TNF-α) levels were evaluated. DNA damage of the workers was assessed by the Comet assay. The absolute numbers and the percentages of T lymphocytes and of natural killer cells, and the levels of TNF-α were higher than the controls, whereas IgG and IgM levels were found to be lower in workers. Other examined immunological parameters were not different from those of the controls. There was no increased DNA damage in the workers compared to controls.

Keywords: Formaldehyde; Lymphocytes; Serum immunoglobulins; Complements proteins; TNF alpha; DNA damage; Occupational exposure

AMAP, the alleged non-toxic isomer of acetaminophen, is toxic in rat and human liver by Mackenzie Hadi; Sanja Dragovic; Rachel van Swelm; Bram Herpers; Bob van de Water; Frans G. M. Russel; Jan N. M. Commandeur; Geny M. M. Groothuis (pp. 155-165).

N-acetyl-meta-aminophenol (AMAP) is generally considered as a non-toxic regioisomer of the well-known hepatotoxicant acetaminophen (APAP). However, so far, AMAP has only been shown to be non-toxic in mice and hamsters. To investigate whether AMAP could also be used as non-toxic analog of APAP in rat and human, the toxicity of APAP and AMAP was tested ex vivo in precision-cut liver slices (PCLS) of mouse, rat and human. Based on ATP content and histomorphology, APAP was more toxic in mouse than in rat and human PCLS. Surprisingly, although AMAP showed a much lower toxicity than APAP in mouse PCLS, AMAP was equally toxic as or even more toxic than APAP at all concentrations tested in both rat and human PCLS. The profile of proteins released into the medium of AMAP-treated rat PCLS was similar to that of APAP, whereas in the medium of mouse PCLS, it was similar to the control. Metabolite profiling indicated that mouse PCLS produced the highest amount of glutathione conjugate of APAP, while no glutathione conjugate of AMAP was detected in all three species. Mouse also produced ten times more hydroquinone metabolites of AMAP, the assumed proximate reactive metabolites, than rat or human. In conclusion, AMAP is toxic in rat and human liver and cannot be used as non-toxic isomer of APAP. The marked species differences in APAP and AMAP toxicity and metabolism underline the importance of using human tissues for better prediction of toxicity in man.

Keywords: Acetaminophen (APAP); N-acetyl-meta-aminophenol (AMAP); Precision-cut liver slices; Species difference; Toxicity; Drug metabolism

Protection by chrysin, apigenin, and luteolin against oxidative stress is mediated by the Nrf2-dependent up-regulation of heme oxygenase 1 and glutamate cysteine ligase in rat primary hepatocytes by Chin-Shiu Huang; Chong-Kuei Lii; Ai-Hsuan Lin; Yu-Wen Yeh; Hsien-Tsung Yao; Chien-Chun Li; Tsu-Shing Wang; Haw-Wen Chen (pp. 167-178).

Chrysin, apigenin, and luteolin are flavones that differ in their number of hydroxyl groups in the B ring. In this study, we investigated the protection by chrysin, apigenin, and luteolin against tert-butyl hydroperoxide (tBHP)-induced oxidative stress and the possible mechanisms involved in rat primary hepatocytes. Chrysin, apigenin, and luteolin dose-dependently up-regulated the protein expression of heme oxygenase 1 (HO-1) and glutamate cysteine ligase (GCL) catalytic (GCLC) and modifier subunit (GCLM) and increased the intracellular glutathione (GSH) content and the ratio of GSH to oxidized GSH. Among the flavones studied, chrysin showed the greatest induction of HO-1, GCLC, and GCLM protein expression and GSH content. Cellular reactive oxygen species production induced by tBHP was attenuated by pretreatment with chrysin, apigenin, and luteolin (P < .05), and this protection was reversed by the GCL inhibitor l-buthionine-S-sulfoximine and the HO-1 inhibitor zinc protoporphyrin. Chrysin, apigenin, and luteolin activated extracellular signal-regulated protein kinase 2 (ERK2), nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear translocation, nuclear Nrf2–antioxidant responsive element (ARE) binding activity, and ARE-dependent luciferase activity. Both ERK2 and Nrf2 siRNAs attenuated chrysin-induced HO-1, GCLC, and GCLM protein expression. Taken together, these results suggest that chrysin, apigenin, and luteolin inhibit tBHP-induced oxidative stress by up-regulating HO-1, GCLC, and GCLM gene transcription via the ERK2/Nrf2/ARE signaling pathways in rat primary hepatocytes.

Keywords: Extracellular signal-regulated protein kinase 2 (ERK2); Flavones; Heme oxygenase 1 (HO-1); Glutamate cysteine ligase (GCL); Nuclear factor erythroid 2-related factor 2 (Nrf2)

Genotoxic damage in the oral mucosa cells of subjects carrying restorative dental fillings by Giuseppa Visalli; Barbara Baluce; Sebastiano La Maestra; Rosanna Tindara Micale; Luciano Cingano; Silvio De Flora; Angela Di Pietro (pp. 179-187).

A large proportion of the population carries restorative dental fillings containing either classic Hg-based amalgams and/or the more frequently used methacrylates. Both Hg- and resin-based materials have been shown to be released into the buccal cavity and to be spread systemically. In addition, they induce toxic and genotoxic alterations in experimental test systems. Using the comet assay, we previously demonstrated that circulating lymphocytes of subjects with dental fillings have an increased DNA damage. Here, we analyzed the oral mucosa cells of 63 young subjects of both genders, by using both the comet assay and the micronucleus (MN) test and by monitoring cell death markers. The results obtained show that both amalgams and resin-based composite fillings can induce genotoxic damage in human oral mucosa cells, as convincingly and dose-dependently inferred from the results of the MN test and, more marginally, from comet assay data. Lifestyle variables, also including alcohol intake and smoking habits, did not affect the genotoxic response and did not act as confounding factors. Thus, we provide unequivocal evidence for the genotoxicity of both amalgams and resin-based dental fillings in humans not only by testing circulating lymphocytes but also by analyzing oral mucosa cells. These findings are of particular relevance due to the circumstance that subjects with restorative materials are exposed continuously and for long periods of time.

Keywords: Dental fillings; Oral mucosa cells; Comet assay; Micronucleus test

The impact of FANCD2 deficiency on formaldehyde-induced toxicity in human lymphoblastoid cell lines by Xuefeng Ren; Zhiying Ji; Cliona M. McHale; Jessica Yuh; Jessica Bersonda; Maycky Tang; Martyn T. Smith; Luoping Zhang (pp. 189-196).

Formaldehyde (FA), a major industrial chemical and ubiquitous environmental pollutant, has recently been classified by the International Agency for Research on Cancer as a human leukemogen. The major mode of action of FA is thought to be the formation of DNA–protein cross-links (DPCs). Repair of DPCs may be mediated by the Fanconi anemia pathway; however, data supporting the involvement of this pathway are limited, particularly in human hematopoietic cells. Therefore, we assessed the role of FANCD2, a critical component of the Fanconi anemia pathway, in FA-induced toxicity in human lymphoblast cell models of FANCD2 deficiency (PD20 cells) and FANCD2 sufficiency (PD20-D2 cells). After treatment of the cells with 0–150 μM FA for 24 h, DPCs were increased in a dose-dependent manner in both cell lines, with greater increases in FANCD2-deficient PD20 cells. FA also induced cytotoxicity, micronuclei, chromosome aberrations, and apoptosis in a dose-dependent manner in both cell lines, with greater increases in cytotoxicity and apoptosis in PD20 cells. Increased levels of γ-ATR and γ-H2AX in both cell lines suggested the recognition of FA-induced DNA damage; however, the induction of BRCA2 was compromised in FANCD2-deficient PD20 cells, potentially reducing the capacity to repair DPCs. Together, these findings suggest that FANCD2 protein and the Fanconi anemia pathway are essential to protect human lymphoblastoid cells against FA toxicity. Future studies are needed to delineate the role of this pathway in mitigating FA-induced toxicity, particularly in hematopoietic stem cells, the target cells in leukemia.

Keywords: DNA–protein cross-links; Micronuclei; Chromosome aberrations; Apoptosis; DNA damage and repair; Fanconi anemia

Isolation and characterization of two new non-hemorrhagic metalloproteinases with fibrinogenolytic activity from the mapanare (Bothrops colombiensis) venom by María E. Girón; Alexis Rodríguez-Acosta; Ana María Salazar; Elda E. Sánchez; Jacob Galán; Carlos Ibarra; Belsy Guerrero (pp. 197-208).

Colombienases are acidic, low molecular weight metalloproteinases (Mr of 23,074.31 Da colombienase-1 and 23,078.80 Da colombienase-2; pI of 6.0 and 6.2, respectively) isolated from Bothrops colombiensis snake venom. The chromatographic profile in RP-HPLC and its partial sequence confirmed its high homogeneity. Both colombienases present fibrino(geno)lytic activity, but did not show any hemorrhagic, amidolytic, plasminogen activator or coagulant activities, and no effect on platelet aggregation induced by collagen or ADP. Both enzymes were strongly active on fibrinogen Aα chains followed by the Bβ chains, and colombienases-2, at high doses, also degraded the γ chains. This activity was stable at temperatures ranging between 4 and 37 °C, with a maximum activity at 25 °C, and at pHs between 7 and 9. The homology demonstrated by the comparison of sequences, with zinc-dependent metalloproteinases, as well as the metal chelant effects on, confirmed that the colombienases were metalloproteinases, particularly to α-fibrinogenases belonging to the P-I class of SVPMs (20–30 kDa), which contain only the single-domain proteins. The biological characteristics of the colombienases confer a therapeutic potential, since they contain a high fibrino(geno)lytic activity, devoid of hemorrhagic activity. These metalloproteinases might be explored as thrombolytic agents given that they dissolve fibrin clots or prevent their formation.

Keywords: Bothrops colombiensis ; Colombienases; Fibrinolytic activity; Fibrinogenolytic activity; Metalloproteinases; Hemostasis

Multi-cell type human liver microtissues for hepatotoxicity testing by S. Messner; I. Agarkova; W. Moritz; J. M. Kelm (pp. 209-213).

Current 2-dimensional hepatic model systems often fail to predict chemically induced hepatotoxicity due to the loss of a hepatocyte-specific phenotype in culture. For more predictive in vitro models, hepatocytes have to be maintained in a 3-dimensional environment that allows for polarization and cell–cell contacts. Preferably, the model will reflect an in vivo-like multi-cell type environment necessary for liver-like responses. Here, we report the characterization of a multi-cell type microtissue model, generated from primary human hepatocytes and liver-derived non-parenchymal cells. Liver microtissues were stable and functional for 5 weeks in culture enabling, for example, long-term toxicity testing of acetaminophen and diclofenac. In addition, Kupffer cells were responsive to inflammatory stimuli such as LPS demonstrating the possibility to detect inflammation-mediated toxicity as exemplified by the drug trovafloxacin. Herewith, we present a novel 3D liver model for routine testing in 96-well format capable of reducing the risk of unwanted toxic effects in the clinic.

Keywords: 3-dimensional; Spheroids; Kupffer cells

Erratum to: The human bitumen study hits the headlines by C. Van Thriel; R. Marchan (pp. 215-216).

New results on formaldehyde: the 2nd International Formaldehyde Science Conference (Madrid, 19–20 April 2012) by Hermann M. Bolt; Peter Morfeld (pp. 217-222).

The toxicology and epidemiology of formaldehyde were discussed on the 2nd International Formaldehyde Science Conference in Madrid, 19–20 April 2012. It was noted that a substantial amount of new scientific data has appeared within the last years since the 1st conference in 2007. Progress has been made in characterisation of genotoxicity, toxicokinetics, formation of exogenous and endogenous DNA adducts, controlled human studies and epidemiology. Thus, new research results are now at hand to be incorporated into existing evaluations on formaldehyde by official bodies.

Keywords: Formaldehyde; Toxicity; Genotoxicity; Carcinogenicity; Epidemiology; Regulation

Acknowledgements to referees (pp. 223-224).

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Archives of Toxicology (v.87, #1)