As with the previous editions, Introduction to Toxicology, Fourth Edition, continues to chart the evolution of the field of toxicology, from the use of natural toxins by ancient tribes through the developments established by Paracelsus, and progresses through to the current topics in the public interest. For centuries, the study of toxicology has fascinated students. The book begins with basic toxicological principles, including an historical summary, dose-response relationships (NEW chapter), exposure-response relationships (NEW chapter), disposition, and metabolism of xenobiotic toxic substances. Other important new chapters include target organ toxicity, toxicity of carcinogenic agents and new and updated concepts in toxicity testing, and antidotes and treatment of poisonings. In all, nine new or expanded chapters from the third edition are advanced. Current concerns about the effects of therapeutic drugs, carcinogens, industrial toxins, pesticides, and herbicides on human health, animal welfare, and the stability and maintenance of the ecosystem continue to highlight toxicology as an important and growing scientific discipline. Key features: Comprehensive coverage of the field of toxicology which illustrates its importance to and impact on society Uses pertinent examples, tables, and diagrams to aid understanding with learning objectives, summaries, questions, and answers for each chapter Clearly and concisely written and presented concepts for easy comprehension by toxicology, biomedical, and health science students Examines the complex interactions associated with toxicological events Covers the effect of toxins on biological and physiological systems This book successfully condenses the diffuse literature in the field into an accessible and readable text, made easier with the insertion of many tables and figures. It introduces fundamental concepts and builds upon these using topical and relevant historical examples. Its improved format includes learning objectives and summaries of each chapter, as well as questions and answers suitable for self-assessment. This latest edition is an invaluable resource for undergraduate and graduate toxicology students, as well as an introductory text for other health care students and professionals. The book also functions as a comprehensive introductory reference text for environmental scientists, medical biologists and chemists, chemical engineers, and regulatory agencies, with interests in toxicologically related areas.

AbstractXenobiotics, which are absorbed into biological systems by passive diffusion across membranes are usually lipid soluble and not ideally suited for excretion. Indeed very lipophilic substances may remain in the mammalian body for many years. After a xenobiotic has been absorbed, it may undergo biotransformation to products which are rapidly excreted and therefore elimination of the compound from the animal is facilitated. However, biotransformation may also change the biological activity of the substance. Hence, the metabolic fate of the compound can have an important bearing on its toxic potential, the disposition of the compound in the body and the excretion of the compound. The metabolic reactions involved are usually divided into phase 1 and phase 2 reactions, the latter being conjugation reactions. The products of metabolism are usually more water soluble than the original compound. Although usually detoxifying, these reactions, especially phase 1 ones, sometimes increase toxicity.

We have previously reported on the changes in urinary taurine levels in rats following treatment with some hepatotoxic agents and compounds reported to affect protein synthesis. This study follows the time course of the elevation of urinary taurine after treatment of rats with cycloheximide which was maximal 8-12 h after dosing and was dose related. [H-3]-Leucine incorporation into proteins was used as an indicator of protein synthesis. There was a significant reduction in [H-3] leucine incorporation into acid precipitable proteins 8 h but not 24 h after dosing. The reduction in incorporation was negatively correlated with the raised levels of both serum and urinary taurine 8 h after dosing. Liver glutathione was raised both 8 and 24 h after dosing rats and liver taurine was significantly reduced at 8 h. It is suggested that measuring urinary taurine in collections made continuously might provide a simple, non-invasive biomarker for monitoring the effects of xenobiotics or other external stimuli on the status of protein synthesis.

1. Old art, new science: Introduction to toxicology 2. What chemicals do to us and what our bodies do to them: The principles of toxicology 3. Keep taking the medicine, But is it safe Doctor?: chemicals we deliberately swallow 4. Blood, sweat, and tears: Pesticides, poisons man has designed 5. First the cats died: Environmental contaminants 6. Natural born killers: Chemicals nature designs to be poisonous 7. The Mad Hatter and a bad case of acne: Industrial chemicals 8. Under the sink and in the shed: Household poisons 9. Rasputin's revenge: Chemicals used to kill 10. Ginger Jake and Spanish oil: Food contaminants and additives 11. A risky business: The assessment of risk from chemicals Glossary Bibliography Index

The aim of this study was to compare four in vitro cytotoxicity assays and determine their ability to detect early cytotoxic events.Two hepatoma cell lines, namely HTC and HepG2 cells, were exposed to cadmium chloride (0-300 mu M) for 3,5 and 8 h. Following exposure to the toxic metal cytotoxicity was determined with the lactate dehydrogenase leakage assay (LDH), a protein assay, the neutral red assay and the methyl tetrazolium (MTT) assay.In HTC cells no toxicity was observed for any incubation period when the LDH leakage, the MTT and the protein assay were employed whereas the neutral red assay revealed early cytotoxicity starting after incubation of HTC cells with CdCl2 for 3 h. In the case of HepG2 cells the MTT assay reveals cytotoxicity due to CdCl2 exposure after 3 h whereas no such effect is seen with the other three assays. Following 5 h exposure of HepG2 cells to CdCl2, toxicity is observed with the MTT assay at lower concentrations compared to the ones required for detection of toxicity with the LDH leakage and the neutral red assay.In conclusion different sensitivity was observed for each assay with the neutral red and the MTT assay being the most sensitive in detecting cytotoxic events compared to the LDH leakage and the protein assay. (c) 2005 Elsevier Ireland Ltd. All rights reserved.

Biomarkers for neurodegenerative disorders are essential to facilitate disease diagnosis, ideally at early stages, monitor disease progression, and assess response to existing and future treatments. Application of proteomics to the human brain, cerebrospinal fluid and plasma has greatly hastened the unbiased and high-throughput searches for novel biomarkers. There are many steps critical to biomarker discovery, whether for neurodegenerative or other diseases, including sample preparation, protein/peptide separation and identification, as well as independent confirmation and validation. In this review we have summarized current proteomics technologies involved in discovery of biomarkers for neurodegenerative diseases, practical considerations and limitations of several major aspects, as well as the current status of candidate biomarkers revealed by proteomics for Alzheimer and Parkinson diseases.

Cadmium is a toxic metal and no effective antidote exists at present. The aim of this study was to examine whether sulphur amino acids, involved in glutathione synthesis, can modulate cadmium toxicity in vitro. Two hepatoma cell lines (HepG2 and HTC cells) were exposed to cadmium chloride (0-100 microM) for 8h in control media or in media containing 1mM of homocysteine, cysteine or cystathionine. Cell viability was then assessed with the neutral red assay. In order to assess the mechanism by which homocysteine and cysteine modulate cadmium toxicity their ability to scavenge reactive oxygen species was determined as well as the potential to increase intracellular glutathione levels. The ability of the sulphur amino acids to prevent cadmium uptake by HTC and HepG2 cells was also assessed. The results indicate that homocysteine and cysteine protect efficiently both cell lines from cadmium chloride toxicity whereas cystathionine protects efficiently HTC cells but not HepG2 cells. This effect was shown to be dependent on the dose of each amino acid and increased protection from cadmium was observed with increasing concentrations of homocysteine and cysteine. Both amino acids prevented the formation of reactive oxygen species only when they were administered together with cadmium chloride. In addition homocysteine and cysteine did not increase intracellular glutathione levels. The results indicate that the mechanism by which sulphur amino acids protect from cadmium toxicity in vitro is due to the reduced uptake of the metal by the cells possibly by direct binding to the -SH group of the amino acids.

Cadmium coexists with other metals in various products. Releases of cadmium in the environment occur in parallel to the release of other metals including copper, iron and zinc which also have an essential role in human homeostasis as they participate in various biochemical pathways. We studied the interaction of iron, copper, zinc and calcium channel blockers (nifedipine and verapamil) with cadmium chloride in two hepatoma cell lines (HepG2 and HTC cells) in order to determine if these trace elements can affect CdCl(2) uptake and interfere with its toxicity. Both cell lines were initially exposed to CdCl(2) (0-200 microM) for 2h and the uptake of the metal was determined. Cadmium chloride uptake by HepG2 and HTC cells shows an increase with increasing doses of the metal. Cells were also pretreated with 100 uM of FeCl(2) or ZnCl(2) or CuCl(2) or with a nifedipine/verapamil (100 uM) mixture for 2h and then exposed to 200 uM CdCl(2) for 1h in the presence of the trace elements. The uptake of CdCl(2) was determined as well as the membrane integrity (LDH leakage assay), the cell viability (neutral red assay) and cell proliferation (protein assay). Zinc and calcium channel blockers inhibited the uptake of cadmium chloride by both cell lines. On the other hand iron loading resulted in increased uptake of CdCl(2) by both cell lines whereas copper loading increased the uptake of cadmium chloride from HTC cells and inhibited the uptake by HepG2 cells. These findings are of importance when the effects of cadmium on living organisms are examined since co-exposure to cadmium and other metals can occur.

The aim of this study was to investigate the effect of individual sulfur amino acid deprivation in cadmium chloride toxicity. HTC cells were deprived of cystine and/or methionine for 12h and then exposed to CdCl(2) for 12h. HepG2 cells were deprived of cystine for 3 and 5h and exposed to CdCl(2) for 3h. In addition HepG2 cells were deprived of methionine for 12h and then exposed to CdCl(2) for 5 and 12h. Our results indicate that only cystine depletion increased cadmium toxicity in HTC cells but not in HepG2 cells as indicated by the neutral red assay. This effect was due to glutathione depletion as indicated by measurement of intracellular glutathione in HTC cells following deprivation of cystine. Methionine depletion had only a slight effect on the viability of HepG2 cells.

The cytotoxicity of extracts from a widely used species of plant, Moringa stenopetala, was assessed in HEPG2 cells, by measuring the leakage of lactate dehydrogenase (LDH) and cell viability. The functional integrity of extract‐exposed cells was determined by measuring intracellular levels of ATP and glutathione (GSH). The ethanol extracts of leaves and seeds increased significantly (p < 0.01) LDH leakage in a dose‐ and time‐dependent manner. The water extract of leaves and the ethanol extract of the root did not increase LDH leakage. A highly significant (p < 0.001) decrease in HEPG2 viability was found after incubating the cells with the highest concentration (500 µg/mL) of the ethanol leaf and seed extracts. At a concentration of 500 µg/mL, the water extract of leaves increased (p < 0.01), while the ethanol extract of the same plant part decreased (p < 0.01), ATP levels. The root and seed extracts had no significant effect on ATP levels. The ethanol leaf extract decreased GSH levels at a concentration of 500 µg/mL (p < 0.01), as did the ethanol extract of the seeds at 250 µg/mL and 500 µg/mL (p < 0.05). The water extract of the leaves did not alter GSH or LDH levels or affect cell viability, suggesting that it may be non‐toxic, and is consistent with its use as a vegetable. The data obtained from the studies with the ethanol extract of the leaves and seeds from Moringa stenopetala show that they contain toxic substances that are extractable with organic solvents or are formed during the process of extraction with these solvents. The significant depletion of ATP and GSH only occurred at concentrations of extract that caused leakage of LDH. Further investigation with this plant in order to identify the constituents extracted and their individual toxic effects both in vivo and in vitro is warranted. This study also illustrates the utility of cell culture for screening plant extracts for potential toxicity. Copyright © 2005 John Wiley & Sons, Ltd.

Cadmium is a toxic metal and no uniform mechanism of toxicity has so far been proposed. The aim of this study was to investigate the biochemical effects of cadmium chloride in a rat hepatoma cell line (HTC cells) and the cellular events mediating DNA damage.HTC cells were exposed to various concentrations of cadmium chloride for 5 and 8 h and lysosomal damage was assessed with the neutral red assay (NR) and fluorescence microscopy. Mitochondrial integrity was assessed from ATP levels and DNA damage determined with the single cell gel electrophoresis/comet assay. The formation of reactive oxygen species (ROS) was also determined under the same experimental conditions with the dichlorofluorescein assay. Cytotoxicity was assessed with the LDH leakage assay the levels of glutathione were measured and correlated with the other effects.The results indicate that lysosomal damage occurs at a lower concentration of cadmium chloride (20 mu M) than DNA damage (500 mu M) in HTC cells. The latter effect was accompanied by an increase of reactive oxygen species without any significant LDH leakage whereas lysosomal damage was significant as determined by the neutral red assay and confirmed with fluorescence microscopy. The effect of CdCl2 on mitochondria and glutathione levels were observed at concentrations or incubation times higher than the ones required to induce lysosomal damage. The data suggest that DNA damage may be due to the formation of reactive oxygen species. It is possible that cadmium induced lysosomal damage is an earlier event than DNA damage and can mediate other cellular events that lead to cell death. (c) 2005 Elsevier Ltd. All rights reserved.

The acute biochemical effects of the nephrotoxin p-aminophenol (PAP) were studied in detail using a combination of conventional bioanalytical and 1H-NMR spectroscopic methods. Dosing PAP (25–100 mg/kg) to male F344 rats resulted in a dose-related proximal nephropathy with consequent elevations in urinary enzymes, glucose, and urine total protein as shown by conventional methodology. 1H-NMR spectroscopy at 400 MHz of urine from PAP-treated rats also revealed a characteristic glycosuria, with concomitant amino aciduria. The increased excretion of these compounds indicates functional defects in the proximal tubule and reduced solute reabsorption efficiency. In addition, 1H-NMR urinalysis and conventional enzymatic analysis showed a dose-related lactic aciduria. Other changes detected by 1H-NMR included a dose-related reduction in the excretion of citrate (confirmed by a conventional biochemical method) and an increase in the excretion of acetate. The degree of abnormalities shown by 1H-NMR urinalysis agreed well with histopathological observations and conventional biochemical indices of nephrotoxicity. 1H-NMR urinalysis therefore serves to highlight changes in the excretion of low MW urine components not routinely studied by conventional biochemical analysis.

Since the publication of the first edition of Introduction to Toxicology , toxicology has become a more mature science, the number of undergraduate and postgraduate courses has increased and thus the need for a regularly updated introductory text has become more pressing. This third edition caters for this need in a clear and easy-to-read style, featuring:* Up-to-the-minute information* Relevant toxicological examples that reinforce principles* End-of-chapter essay questions* New and redrawn illustrations* Glossary of terms* Extensively revised bibliographyThe fundamental principles of absorption, distribution, metabolism and excretion are described in the introductory chapters, as are the types of exposure and response. In subsequent chapters these are clarified with the use of carefully chosen examples. Among the topics considered are the potential adverse effects of drugs, pesticides, food additives and industrial chemicals.

Urinary creatine has been shown to markedly increase in rats following testicular damage caused by toxicants as diverse as cadmium, 2-methoxyethanol, 1,3-dinitrobenzene, and 2,3,5,6-tetramethylphenylene diamine. More recent findings have shown that urinary creatine is raised in mice exposed to 2-methoxyacetic acid. The most recent studies have revealed that urinary creatine and creatine in interstitial fluid in the testis are raised as early as four hours after dosing with 2-methoxyethanol. Using the testicular toxicants 2-methoxyethanol and cadmium, the authors compared urinary creatine with other markers of testicular damage, such as histopathological assessment of testis by light microscopy, testis weight and lactate dehydrogenase C4 isoenzyme, and testosterone. Urinary creatine was found to be the most sensitive indicator of testicular damage detected by histopathology after both 2-methoxyethanol and cadmium exposure. It is therefore a potentially very useful non-invasive biomarker of male reproductive dysfunction caused by chemicals.