Check out our New Publishers' Select for Free Articles

Archives of Toxicology (v.73, #8-9)

Peroxisome proliferators: mechanisms of adverse effects in rodents and molecular basis for species differences by Ruth A. Roberts (pp. 413-418).

Peroxisome proliferators (PPs), such as diethylhexylphthalate (DEHP), constitute a diverse class of chemicals with many therapeutic, industrial and environmental applications. In rodents, PPs are nongenotoxic hepatocarcinogens, raising concerns regarding the potential of PPs to harm human health. However, humans differ from rodents in their response to PPs and the weight of evidence supports the supposition that PPs do not pose a carcinogenic risk to humans. The effects of PPs in the rodent are mediated by peroxisome proliferator activated receptor α (PPARα). PPARα predominates in the liver whereas another isoform PPARγ predominates in adipose tissue and in the immune system. This tissue-specific pattern of PPARα expression is consistent with a role for PPARα but not PPARγ or PPARβ in PP-induced rodent hepatocarcinogenesis. Humans, marmosets and guinea-pigs appear refractory or less responsive to the adverse liver effects of PPs. However, humans give a therapeutic response to the fibrate PPs via an alteration in lipid metabolism mediated by PPARα. Such marked species differences may be explained by quantity of PPARα and/or the quality of the PPARα-mediated response. The lower expression of full-length functional PPARα in humans could be attributed to the presence of a truncated, inactive form of PPARα, which appears to be present in most individuals examined to date. In addition, there are species differences in sequence and responsiveness of the acyl CoA oxidase (ACO) gene promoter, suggesting that even in the presence of sufficient PPARα, the human equivalent of rodent genes associated with peroxisome proliferation may remain inactive.

Keywords: Key words Species differences; Diethylhexylphthalate (DEHP); Peroxisome proliferators; PPARα

Modulation of tumor necrosis factor α expression in mouse brain after exposure to aluminum in drinking water by Masashi Tsunoda; Raghubir P. Sharma (pp. 419-426).

Aluminum, a known neurotoxic substance and a ground-water pollutant, is a possible contributing factor in various nervous disorders including Alzheimer's disease. It has been hypothesized that cytokines are involved in aluminum neurotoxicity. We investigated the alterations in mRNA expression of tumor necrosis factor α (TNFα), interleukin-1β (IL-1β), and interferon γ (IFNγ), cytokines related to neuronal damage, in cerebrum and peripheral immune cells of mice after exposure to aluminum through drinking water. Groups of male BALB/c mice were administered aluminum ammonium sulfate in drinking water ad libitum at 0, 5, 25, and 125 ppm aluminum for 1 month. An additional group received 250 ppm ammonium as ammonium sulfate. After treatment, the cerebrum, splenic macrophages and lymphocytes were collected. The expression of TNFα mRNA in cerebrum was significantly increased among aluminum-treated groups compared with the control, in a dose-dependent manner. Other cytokines did not show any aluminum-related effects. In peripheral cells, there were no significant differences of cytokine mRNA expressions among treatment groups. Increased expression of TNFα mRNA by aluminum in cerebrum may reflect activation of microglia, a major source of TNFα in this brain region. Because the aluminum- induced alteration in cytokine message occurred at aluminum concentrations similar to those noted in contaminated water, these results may be relevant in considering the risk of aluminum neurotoxicity in drinking water.

Keywords: Key words Aluminum; Drinking water contaminant; Neurotoxicity; TNFα; Reverse-transcription (RT)-PCR

Real-time PCR-analysis of the cytochrome P450 1B1 codon 432-polymorphism by T. Brüning; J. Abel; B. Koch; K. Lorenzen; V. Harth; S. Donat; A. Sachinidis; H. Vetter; H. M. Bolt; Y. Ko (pp. 427-430).

The aim of the present study was to develop and validate a rapid assay for genotyping of CYP1B1 codon 432-polymorphism. The described method is a single tube assay and combines both rapid-cycle polymerase chain reaction (PCR) with real-time monitoring by amplification and generation of the melting profiles of an allele-specific fluorescent probe. With this method 300 samples were analysed from healthy, unrelated Germans. Genotype frequency determined for the mutated allele CYP1B1*2 was 0.40. The results show that genotyping of CYP1B1 codon 432-polymorphism with a real-time fluorescence PCR method is a rapid and reliable assay for the analysis of large numbers of samples.

Keywords: Key words CYP1B1; Light-Cycler

The influence of cytochrome P450 1A1 and glutathione S-transferase M1 genotypes on biomarker levels in coke-oven workers by G. Brescia; L. Celotti; E. Clonfero; H. G. Neumann; A. Forni; V. Foà; M. Pisoni; G. M. Ferri; G. Assennato (pp. 431-439).

The present study has the aim of evaluating gene-environment interaction on the levels of different biomarkers in coke-oven workers exposed to PAH. In order to assess whether the levels of some biomarkers (PAH-DNA adducts, nitro-PAH adducts to Hb and MN frequency) could be modulated by the genetic metabolic polymorphisms for CYP1A1 and GSTM1, we analysed in 76 coke-oven workers and 18 controls the CYP1A1 (MspI and Ile/Val sites) and the GSTM1 genotypes by a PCR assay. In individuals with shared set-up of CYP1A1 or GSTM1 genotypes, we analysed how the specified biomarkers correlated with total PAH exposure (urinary levels of 1-hydroxypyrene) both by a stratified analysis and logistic regression modelling. Statistically significant (P = 0.03 and P = 0.01) higher percentages of the more susceptible GSTM1− subjects compared to the GSTM1+ subjects and of the more susceptible CYP1A1 Ile/Val individuals compared to the CYP1A1 Ile/Ile individuals were detected for high levels of PAH-DNA adducts in the high exposure group (namely high levels of 1-OHP). A statistically significant association was observed between increased PAH-DNA adduct levels and the more susceptible GSTM1- genotype (P.O.R. = 4.18, P = 0.03) in a logistic regression modelling and a significant interaction between PAH exposure and GSTM1-genotype was found for PAH-DNA adducts. No effect of these metabolic genotypes was observed for MN frequency and nitro-PAH adducts to Hb. In conclusion, a gene-environment interaction between PAH exposure and two metabolic genotypes involved in activation (CYP1A1) and detoxification (GSTM1) of PAHs, respectively, has been identified.

Keywords: Key words CYP1A1; GSTM1; Polymorphism; Biomarkers; Coke-oven workers

Species differences in induction of hepatic enzymes by BM 17.0744, an activator of peroxisome proliferator-activated receptor alpha (PPARα) by Kirstin Meyer; Alfred Völkl; Richard Endele; Hans-Frieder Kühnle; Johannes Pill (pp. 440-450).

BM 17.0744, a new anti-diabetic and lipid-lowering agent, leads also to strong hepatomegaly and carnitine acetyl transferase (CAT) increase in the liver of rats, a phenomenon known from fibrates. For information on the relevance of changes in liver of rats to other species, we investigated the effects of BM 17.0744 on lipids and selected marker enzymes related to β-oxidation in rats, dogs and guinea-pigs, so-called high and low responders to peroxisome proliferators. To examine selectivity other enzymes were also determined, e.g. esterase, urate oxidase (UOX) and cytochrome c oxidase (CYT.C.OX.). Lowering of triglycerides and cholesterol in blood serum and/or liver was observed in pharmacological dose range in the three species tested. In dogs and guinea-pigs, liver and kidney weights were unaffected even in dogs in medium and high dose groups with high systemic exposure and severe toxicity. In male Sprague-Dawley rats treatment with 1.5, 3, 6 and 12.5 mg/kg per day BM 17.0744 selectively elevated the activities of CAT and acyl-CoA oxidase (AOX) by ≤200 and 20-fold, respectively. Administration of BM 17.0744 to Beagle dogs (1.5, 4, 12 mg/kg per day) and guinea-pigs (3 and 12 mg/kg per day) enhanced the activities of CAT and AOX dose-dependently by a factor of two to three only. Immunoblotting revealed a drug-specific enhancement of the amount of β-oxidation enzymes in rats, which is in accord with the rapid and coordinated transcriptional activation shown in Northern dot blot analysis. Nuclear run-on assays demostrated a real transcriptional activation. BM 17.0744 activates peroxisome proliferator-activated receptor α (PPARα), which could be shown by transactivation assays. The stimulation of PPARα by BM 17.0744 was stronger than that of the known ligands WY 14.643 and ETYA. Activation of PPARγ can be excluded. Taken collectively, the data demonstrate an enhancement of the β-oxidation system by BM 17.0744 paralleled by lipid-lowering in all species investigated. The activation of the nuclear factor PPARα may explain the changes in liver and the metabolic effects on the molecular level. The lack of an increase in liver and kidney weights and the relatively moderate enhancement of activities of β-oxidation-related enzymes in dogs and guinea-pigs indicate that the excessive response observed in rats is not applicable to other, predominantly non-rodent, species. On the basis of these data and the experience with fibrates a specific risk for humans is not expected.

Keywords: Key words BM 17.0744; β-Oxidation pathway; Peroxisomes; Peroxisome proliferators; Species differences

Suppression of apoptosis and induction of DNA synthesis in vitro by the phthalate plasticizers monoethylhexylphthalate (MEHP) and diisononylphthalate (DINP): a comparison of rat and human hepatocytes in vitro by Susan C. Hasmall; Neil H. James; Neil Macdonald; Douglas West; Stephan Chevalier; Sabina C. Cosulich; Ruth A. Roberts (pp. 451-456).

Diethylhexylphthalate (DEHP) and diisononylphthalate (DINP) are plasticizers with many important commercial, industrial and medical applications. However, both DEHP and DINP are rodent peroxisome proliferators (PPs), a class of compounds that cause rodent liver tumours associated with peroxisome proliferation, induction of hepatic DNA synthesis and the suppression of apoptosis. Despite these effects in the rodent, humans appear to be nonresponsive to the adverse effects of PPs. Previously, we have shown that the fibrate hypolipidaemic peroxisome proliferator, nafenopin, induced DNA synthesis and suppressed apoptosis in rat but not in human hepatocytes. In this work, we have examined species differences in the response of rat and human hepatocytes to DEHP and DINP in vitro. In rat hepatocytes in vitro, both DINP and MEHP (a principle metabolite of DEHP and the proximal peroxisome proliferator) caused a concentration-dependent induction of DNA synthesis and suppression of both spontaneous and transforming growth factor β1 (TGFβ1)-induced apoptosis. Similarly, both MEHP and DINP caused a concentration-dependent induction of peroxisomal β-oxidation although the response to DINP was less robust. In contrast to the pleiotropic response noted in rat hepatocytes, neither DINP nor MEHP caused an induction of β-oxidation, stimulation of DNA synthesis and suppression of apoptosis in human hepatocytes cultured from three separate donors. These data provide evidence for species differences in the hepatic response to the phthalates DEHP and DINP, confirming that human hepatocytes appear to be refractory to the hepatocarcinogenic effects of PPs first noted in rodents.

Keywords: Key words Apoptosis; Diethylhexylphthalate (DEHP); Diisononylphthalate (DINP); DNA synthesis; Peroxisome proliferation

Mechanism of enhanced lipid peroxidation in the liver of Long-Evans cinnamon (LEC) rats by Hideki Yamomoto; Kyogo Hirose; Yayoi Hayasaki; Makihiko Masuda; Akio Kazusaka; Shoichi Fujita (pp. 457-464).

The Long-Evans Cinnamon (LEC) rat is a mutant strain of rats that accumulate copper (Cu) in the liver in much the same way as individuals who suffer from Wilson's disease (WD) and has been suggested as a model for this disease. Lipid peroxidation (LPO) is considered to be involved in the toxic action of Cu in the livers of LEC rats. We investigated the mechanism of LPO in the livers of LEC rats showing apparent signs of hepatitis. Several-fold higher LPO levels were observed in post-mitochondrial supernatant (S-9) fraction of livers from hepatitic LEC rats than in those from Wistar rats. To mimic living cells, we introduced NADPH-generating system (NADPH-gs) into the S-9 incubation system. Thus was ensured a constant supply of NADPH to vital enzymes that may be directly or indirectly involved in the generation and/or elimination of reactive oxygen species (ROSs), such as glutathione reductase (GSSG-R), which require NADPH for their reactions. The levels of LPO in liver S-9 from hepatitic LEC rats were further increased by incubating liver S-9 at 37 °C in the presence of NADPH-gs. This increase was inhibited by EDTA, butylated hydroxytoluene (BHT), and catalase (CAT), suggesting that some metal, most likely the accumulated Cu, and ROSs derived from hydrogen peroxide (H₂O₂) are involved in the increased levels of LPO in the livers of hepatitic LEC rats. The requirement of NADPH-gs for enhanced LPO in the livers of hepatitic LEC rats indicates the consumption of NADPH during reactions leading to LPO. It is known that H₂O₂, and consequently hydroxyl radical are generated during Cu–catalyzed glutathione (GSH) oxidation. The cyclic regeneration of GSH from GSSG by NADPH-dependent GSSG-R in the presence of NADPH-gs may cause sustained generation of hydroxyl radical in the presence of excess free Cu. The generation of H₂O₂ in S-9 fraction of livers from hepatitic LEC rats was observed to be significantly higher than that in S-9 fraction of livers from non-hepatitic LEC rats and Wistar rats. Moreover, in addition to the reported decrease in glutathione peroxidase (GPX) activity, we found that CAT activity was markedly decreased in LEC rats with hepatitis. The increased generation of H₂O₂ with reduced activities of GPX and CAT may result in cellular accumulation of H₂O₂ in the liver of hepatitic LEC rats. Taken altogether, it is suggested that the accumulated H₂O₂ undergoes the Fenton-type reaction with also accumulated free Cu, thus generating hydroxyl radical in the livers of hepatitic LEC rats and increasing LPO levels in these animals.

Keywords: Key words Long-Evans cinnamon (LEC) rats; Copper; Lipid peroxidation; Hepatitis; Hydroxyl radical

Evaluation of acute and chronic hepatotoxic effects exerted by anabolic-androgenic steroid stanozolol in adult male rats by Luis D. Boada; Manuel Zumbado; Santiago Torres; Antonio López; Bonifacio N. Díaz-Chico; Juan J. Cabrera; Octavio P. Luzardo (pp. 465-472).

Stanozolol (ST) is a 17α-alkyl anabolic-androgenic steroid (17α-AAS) often misused by athletes and bodybuilders. The use of anabolic-steroids by sportsmen and teenagers has increased dramatically, thus raising the question about their hepatotoxicity, specially those such as ST which are orally administered. Previously, we have reported diverse in vivo effects exerted by this steroid and published the existence of a highly specific ST-binding site in male rat liver microsomes. The existence of this binding site, the reported hepatic effects exerted in humans, and the very limited information about its potential hepatotoxicity led us to treat adult male rats acutely and chronically with ST and study different parameters that could indicate liver damage: serum levels of transaminases, concentration of monooxygenase enzymes in liver, liver membrane lipid peroxidation products, liver histopathology, and cell cycle/ploidy status of liver cells. In our study, no changes in serum transaminases or lipid peroxidation levels were obtained. However, acute stanozolol treatment significantly decreased the levels of cytochrome P450 (Cyt. P450) and cytochrome b₅ (Cyt. b₅) during the first 48 h of treatment, while subsequently, at 72 and 96 h, these microsomal enzymes underwent a significant increase in their levels. In sharp contrast with this response to acute treatment, the content of these two enzymes during chronic treatment showed an important decrease. Interestingly, acutely and chronically ST-treated livers showed slight to moderate inflammatory or degenerative lesions in centrilobular hepatocytes. Flow cytometric analysis demonstrated that both acute and chronic ST treatment were capable of increasing the percentage of S-phase fraction (%SPF) of liver cells. These findings taken together clearly show that this steroid is capable of altering the liver capacity for metabolizing xenobiotics and indicate that high doses of ST could exert a proliferative effect on liver cells. Such data should be considered in risk evaluations for this compound.

Keywords: Key words Stanozolol; Hepatotoxicity; Monooxygenase enzymes; Cell cycle; S-phase

Comparative evaluation of benzodiazepines for control of soman-induced seizures by John H. McDonough Jr; Joseph McMonagle; Tracy Copeland; Dean Zoeffel; Tsung-Ming Shih (pp. 473-478).

This study evaluated the ability of six benzodiazepines to stop seizures produced by exposure to the nerve agent soman. Guinea pigs, previously prepared with electrodes to record electroencephalographic (EEG) activity, were pretreated with pyridostigmine (0.026 mg/kg, i.m.) 30 min before challenge with soman (56 μg/kg, s.c.) and then treated 1 min after soman exposure with atropine (2.0 mg/kg, i.m.) and pralidoxime chloride (2-PAM Cl; 25 mg/kg, i.m.). All animals developed seizures following this treatment. Benzodiazepines (avizafone, clonazepam, diazepam, loprazolam, lorazepam, and midazolam) were given i.m. 5 or 40 min after seizure onset. All benzodiazepines were effective in stopping soman-induced seizures, but there were marked differences between drugs in the rapidity of seizure control. The 50% effective dose (ED₅₀) values and latencies for anticonvulsant effect for a given benzodiazepine were the same at the two times of treatment delay. Midazolam was the most potent and rapidly acting compound at both treatment times. Since rapid seizure control minimizes the chance of brain damage, use of midazolam as an anticonvulsant may lead to improved clinical outcome in the treatment of nerve agent seizures.

Keywords: Key words Seizure; Benzodiazepine; Nerve agent; Soman; Anticonvulsant

Determination of urinary thymidine glycol using affinity chromatography, HPLC and post-column reaction detection: a biomarker of oxidative DNA damage upon kidney transplantation by Ricarda Thier; Thomas Brüning; Kristin Kocher; Meinolf Blaszkewicz; Vassilios Makropoulos; Anders Sundberg; Hermann M. Bolt (pp. 479-484).

Reactive oxygen species are generated during ischaemia-reperfusion of tissue. Oxidation of thymidine by hydroxyl radicals (HO) leads to the formation of 5,6-dihydroxy-5,6-dihydrothymidine (thymidine glycol). Thymidine glycol is excreted in urine and can be used as biomarker of oxidative DNA damage. Time dependent changes in urinary excretion rates of thymidine glycol were determined in six patients after kidney transplantation and in six healthy controls. A new analytical method was developed involving affinity chromatography and subsequent reverse-phase high-performance liquid chromatography (RP-HPLC) with a post-column chemical reaction detector and endpoint fluorescence detection. The detection limit of this fluorimetric assay was 1.6 ng thymidine glycol per ml urine, which corresponds to about half of the physiological excretion level in healthy control persons. After kidney transplantation the urinary excretion rate of thymidine glycol increased gradually reaching a maximum around 48 h. The excretion rate remained elevated until the end of the observation period of 10 days. Severe proteinuria with an excretion rate of up to 7.2 g of total protein per mmol creatinine was also observed immediately after transplantation and declined within the first 24 h of allograft function (0.35 ± 0.26 g/mmol creatinine). The protein excretion pattern, based on separation of urinary proteins on sodium dodecyl sulphate-polyacrylamide gel electrophorosis (SDS-PAGE), as well as excretion of individual biomarker proteins, indicated nonselective glomerular and tubular damage. The increased excretion of thymidine glycol after kidney transplantation may be explained by ischaemia-reperfusion induced oxidative DNA damage of the transplanted kidney.

Keywords: Key words Thymidine glycol; DNA damage; Reactive oxygen species; Renal ischaemia; Kidney transplantation

Protective effects of polyphenols against cadmium-induced glomerular mesangial cell myocontracture by M. P. Barrouillet; A. Moiret; J. Cambar (pp. 485-488).

The main objective of this work was to determine the ability of polyphenols (procyanidoloic oligomers; PCO) to diminish the contracture of CdCl₂-induced mesangial cells (smooth muscle cell type). Glomeruli were isolated by passing rat renal cortex pulp through calibrated sieves followed by a culture step for outgrowth of cells. PCO lethality was measured by microassay (Neutral Red uptake). This study has revealed an absence of PCO toxicity during exposure for 24 h and for concentrations ranging from 0.031 to 1‰ (w/v) on rat renal mesangial cells. We observed a lack of cytotoxicity response for the PCO mixture dissolved in medium. Quantitative assessments of the planar cell surface area (PCSA) were performed with an accurate automatized image analyser. The use of isolated cultured mesangial cells permits us to evaluate by quantitative morphometric analysis the contracture elicited either with CdCl₂ salts alone or by previous incubation with a non-lethal dose of PCO. When renal mesangial cells were exposed for 10 min to the PCO mixture, the Cd-mediated myocontracturant response of the mesangial cells was totally abolished. These results suggest that polyphenols could be effective against renal damages induced by cadmium.

Keywords: Key words Cadmium; Polyphenols; Glomerular mesangial cells; Cell cultures; Myocontracture

Differential substrate behaviours of ethylene oxide and propylene oxide towards human glutathione transferase theta hGSTT1–1 by Ricarda Thier; Frederike A. Wiebel; Hermann M. Bolt (pp. 489-492).

The transformation of ethylene oxide (EO), propylene oxide (PO) and 1-butylene oxide (1-BuO) by human glutathione transferase theta (hGSTT1–1) was studied comparatively using `conjugator' (GSTT1+ individuals) erythrocyte lysates. The relative sequence of velocity of enzymic transformation was PO > EO » 1-BuO. The faster transformation of PO compared to EO was corroborated in studies with human and rat GSTT1–1 (hGSTT1–1 and rGSTT1–1, respectively) expressed by Salmonella typhimurium TA1535. This sequence of reactivities of homologous epoxides towards GSTT1–1 contrasts to the sequence observed in homologous alkyl halides (methyl bromide, MBr; ethyl bromide, EtBr; n-propyl bromide, PrBr) where the relative sequence MeBr » EtBr >PrBr is observed. The higher reactivity towards GSTT1–1 of propylene oxide compared to ethylene oxide is consistent with a higher chemical reactivity. This is corroborated by experimental data of acid-catalysed hydrolysis of a number of aliphatic epoxides, including ethylene oxide and propylene oxide and consistent with semi-empirical molecular orbital modelings.

Keywords: Key words Ethylene oxide; Propylene oxide; Butylene oxide; Methyl bromide; Glutathione transferase theta

The acute pathology of fatty acid anilides and linoleic diester of 3-phenylamino-1,2-propanediol in mice: possible implication as aetiologic agents for the toxic oil syndrome by Susanne A. Bell; Christian Sander; Inge Kuntze; René Chatelain (pp. 493-495).

Two groups of compounds, the fatty acid anilides and the mono- and diester of 3-phenylamino-1,2-propanediol (PAP) are suspected as aetiologic agents for the toxic oil syndrome (TOS). Intraperitoneal administration of oleoyl and linoleoyl anilides in mice caused severe weight loss followed by death in 50% of the animals and histopathological changes mainly to the lungs. Linoleic diester of PAP led to weight loss, haemorrhage, congestion and emphysema in the lungs and an increase in blood eosinophilia. Although not producing the full spectrum of symptoms the effects of the substances resemble the acute human disease. Possibly, the two groups of substances led together to the full spectrum of disease manifestations seen in TOS.

Keywords: Key words Toxic oil syndrome (TOS); Mice; Fatty acid anilides; Oleoyl anilide; Linoleoyl anilide

Itai-itai disease is not associated with polymorphisms of the estrogen receptor α gene by Hisahide Nishio; Chiyo Hayashi; Myeong Jin Lee; Hitoshi Ayaki; Ryoji Yamamoto; Ruriko Ninomiya; Naoko Koizumi; Kimiaki Sumino (pp. 496-498).

Itai-itai (or ouch-ouch) disease is a syndrome accompanied by bone mineral disorders, and which may be related to oral cadmium exposure. Itai-itai predominantly affects postmenopausal women with a history of multiple childbirths. Recently, it has been reported that polymorphisms of the estrogen receptor α (ERα) gene are associated with postmenopausal reduction of bone mineral density in Japanese women. However, estrogen receptors have never been studied in itai-itai disease. In this study, we examined the genotypic distributions of PvuII and XbaI restriction fragment length polymorphisms (RFLPs) of the ERα gene in patients with itai-itai disease and compared them with those of control subjects. The RFLPs are represented here as Pp (PvuII) and Xx (XbaI); the capital and small letters signify the absence and presence of restriction sites, respectively. The genotypic distributions of the patient group were: PP, 14.8%; Pp, 55.6%; pp, 29.6%; XX, 7.4%; Xx, 29.6%; and xx, 63.0%. These distributions were similar to those observed for the control groups, hence no pattern of genotypic distribution was observed that could be related to itai-itai disease. We conclude that RFLPs of the ERα gene may not be associated with itai-itai disease.

Keywords: Key words Itai-itai disease; Cadmium; Estrogen receptor; Restriction fragment length polymorphism

International course on Laboratory Animal Science – Utrecht, The Netherlands May 15–26, 2000 (pp. 499-499).

Sections

Personal tools

Archives of Toxicology (v.73, #8-9)

Sections

Personal tools

Local resources

Archives of Toxicology (v.73, #8-9)