Showing papers in "Human & Experimental Toxicology in 2000"

Chemical hormesis: its historical foundations as a biological hypothesis.

Abstract: Despite the long history of hormesis-related experimental research no systematic effort to describe its early history has been undertaken. The present paper attempts to reconstruct and assess the early history of such research and to evaluate how advances in related scientific fields affected the course of hormesis-related research. The purpose of this paper is not only to satisfy this gap in current knowledge, but also to provide a foundation for the assessment of how the concept of hormetic dose-response relationships may have affected the nature of the bioassay especially with respect to hazard assessment practices within a modern risk assessment framework.

Radiation hormesis: its historical foundations as a biological hypothesis.

Abstract: This paper represents the first systematic effort to describe the historical foundations of radiation hormesis. Spanning the years from 1898 to the early 1940's the paper constructs and assesses the early history of such research and evaluates how advances in related scientific fields affected the course of hormetic related research. The present effort was designed to not only address this gap in current knowledge, but to offer a toxicological basis for how the concept of hormetic dose-response relationships may affect the nature of the bioassay and its role in the risk assessment process.

The marginalization of hormesis.

Abstract: Despite the substantial development and publication of highly reproducible toxicological data, the concept of hormetic dose-response relationships was never integrated into the mainstream of toxicological thought. Review of the historical foundations of the interpretation of the bioassay and assessment of competitive theories of dose-response relationships lead to the conclusion that multiple factors contributed to the marginalization of hormesis during the middle and subsequent decades of the 20th century. These factors include: (a) the close-association of hormesis with homeopathy lead to the hostility of modern medicine toward homeopathy thereby creating a guilt by association framework, and the carry-over influence of that hostility in the judgements of medically-based pharmacologists/ toxicologists toward hormesis; (b) the emphasis of high dose effects linked with a lack of appreciation of the significance of the implications of low dose stimulatory effects; (c) the lack of an evolutionary-based mechanism(s) to account for hormetic effects; and (d) the lack of appropriate scientific advocates to counter aggressive and intellectually powerful critics of the hormetic perspective.

The composition of cigarette smoke: a retrospective, with emphasis on polycyclic components.

Abstract: The difficulties encountered in extrapolating biological activity from cigarette smoke composition provide generally applicable lessons as they are representative of the problems encountered with other complex mixtures. Researchers attempting to assess risk are faced with attempting to interpret data from a number of areas including: tobacco science; smoke/aerosol chemistry specific to tobacco; sophisticated analytical chemistry applications and techniques for trapping, collecting, separating, and quantifying very specific compounds at nanogram to picogram levels; numerous biological testing methodologies; and animal models of tumors and carcinogenesis. Numerous hypotheses have been developed over the past five decades and tested with the technology of the day in attempts to interpret the biological activity of cigarette smoke in relation to the chemistry of this complex mixture. These hypotheses fall into several categories discussed in this review: mechanisms of pyrogenesis of polycyclic aromatic hydrocarbons (PAHs) in tobacco smoke; levels of PAHs in cigarette mainstream smoke (MS) and its tumorigenicity in mouse skin-painting experiments; control of PAH levels in MS; chemical indicators of cigarette smoke condensate (CSC) tumorigenicity; control of levels of MS components partitioned between the vapor phase and particulate phase of MS; tumorigenic threshold limits of CSC and many of its components; tumorigenic aza-arenes in tobacco smoke; MS components reported to be ciliastatic to smokers' respiratory tract cilia; anticarcinogenic tobacco-smoke components. Of 52 hypotheses reviewed in this paper, 15 have excellent data supporting the hypothesis based on today's technology. The remaining 37 hypotheses, although originally plausible, have since become insupportable in light of new and contradictory data generated over the years. Such data were generated sometimes by the original authors of the hypotheses and sometimes by other investigators. The hypotheses presented today are less likely to be supplanted because they are well conceived and have a strong mechanistic basis. The challenge for the future is the generation and interpretation of data relating the chemistry and biological activity associated with the dynamic and complex mixture of tobacco smoke.

Tales of two similar hypotheses: the rise and fall of chemical and radiation hormesis.

Abstract: This paper compares the historical developments of chemical and radiation hormesis from their respective inceptions in the late 1880's for chemical hormesis and early 1900's for radiation hormesis to the mid 1930's to 1940 during which both hypotheses rose to some prominence but then became marginalized within the scientific community. This analysis documents that there were marked differences in their respective temporal developments, and the direction and maturity of research. In general, the formulation of the chemical hormesis hypothesis displayed an earlier, more-extensive and more sophisticated development than the radiation hormesis hypothesis. It was able to attract prestigious researchers with international reputations from leading institutions, to be the subject of numerous dissertations, to have its findings published in leading journals, and to have its concepts incorporated into leading microbiological texts. While both areas became the object of criticism from leading scientists, the intensity of the challenge was greatest for chemical hormesis due to its more visible association with the medical practice of homeopathy. Despite the presence of legitimate and flawed criticism, the most significant limitations of both chemical and radiation hormesis and their respective ultimate undoing were due to their: (1) lack of development of a coherent dose-response theory using data of low dose stimulation from both the chemical and radiation domains; (2) difficulty in replication of low dose stimulatory responses without an adequate study design especially with respect to an appropriate number and properly spaced doses below the toxic threshold; (3) modest degree of stimulation even under optimal conditions which was difficult to distinguish from normal variation; and (4) lack of appreciation of the practical and/or commercial applications of the concepts of low dose stimulation.

Radiation hormesis: the demise of a legitimate hypothesis.

Abstract: This paper examines the underlying factors that contributed to the marginalization of radiation hormesis in the early and middle decades of the 20th century. The most critical factor affecting the demise of radiation hormesis was a lack of agreement over how to define the concept of hormesis and quantitatively describe its dose-response features. If radiation hormesis had been defined as a modest overcompensation to a disruption in homeostasis as would have been consistent with the prevailing notion in the area of chemical hormesis, this would have provided the theoretical and practical means to blunt subsequent legitimate criticism of this hypothesis. A second critical factor undermining the radiation hormesis hypothesis was the generally total lack of recognition by radiation scientists of the concept of chemical hormesis which was markedly more advanced, substantiated and generalized than in the radiation domain. The third factor was that major scientific criticism of low dose stimulatory responses was galvanized at the time that the National Research Council (NRC) was organizing a national research agenda on radiation and the hormetic hypothesis was generally excluded from the future planned research opportunities. Furthermore, the criticisms of the leading scientists of the 1930s which undermined the concept of radiation hormesis were limited in scope and highly flawed and then perpetuated over the decades by other 'prestigious' experts who appeared to simply accept the earlier reports. This setting was then linked to a growing fear of radiation as a cause of birth defects, mutation and cancer, factors all reinforced by later concerns over the atomic bomb. Strongly supportive findings on hormetic effects in the 1940s by Soviet scientists were either generally not available to US scientists or disregarded as part of the Cold War mindset without adequate analysis. Finally, a massive, but poorly designed, US Department of Agriculture experiment in the late 1940s to assess the capacity for low dose plant stimulation by radionuclides failed to support the hormetic hypothesis thereby markedly lessening enthusiasm for research and funding in this area. Thus, the combination of a failed understanding of the hormetic hypothesis and its linkage with a strong chemical hormesis database, flawed analyses by prestigious scientists at the critical stage of scientific research development, reinforced by a Cold War mentality led to marginalization of an hypothesis (i.e., radiation hormesis) that had substantial scientific foundations and generalizability.

Isoniazid- and rifampicin-induced oxidative hepatic injury : protection by N-acetylcysteine

Abstract: The role of N-acetylcysteine (NAC), a glutathione (GSH) precursor, was investigated in protection against isoniazid- (INH) and rifampicin- (RIF) induced oxidative hepatic injury in young Wistar rats. The hepatotoxic dose of INH and RIF was 50 mg kg(-1) day(-1) each and the hepatoprotective dose of NAC was 100 mg kg(-1) day(-1). All drugs were administered intraperitoneally (i.p.) in sterile water (4.0 ml kg(-1) day(-1)) over a period of 3 weeks. Status of oxidative/antioxidative profiles was the mechanistic approach to assess the hepatotoxicity and/or hepatoprotection. The oxidative injury in INH-RIF co-exposed animals was closely associated with significant decline of GSH and related thiols, as well as with compromised antioxidant enzyme system. The oxidative stress was further supported by increased lipid peroxidation observed in these animals. The co-administration of NAC prevented the induction of oxidative stress in INH-RIF co-exposed animals. The amelioration of oxidative stress by NAC was faithfully reflected as normal morphology in these animals, except the presence of mild degree of portal triaditis in one animal co-exposed to INH-RIF and NAC. In contrast, the animals co-exposed to INH-RIF alone showed histological lesions which ranged from intralobular inflammation to patchy necrosis. These results suggest that INH-RIF-induced oxidative injury can be prevented by supporting the cellular antioxidant defense mechanism by NAC.

Epigenetic mechanisms of chemical carcinogenesis.

Abstract: Chemically induced cancer is a multi-step process involving damage to the genome initially followed by clonal expansion of the DNA damaged cell eventually leading to a neoplasm. Chemical carcinogens have been shown to impact at all of the stages of the tumorigenesis process. It has become apparent that chemical and physical agents that induce cancer may do so through several different cellular and molecular mechanisms. Epigenetic (nongenotoxic) chemical carcinogens are those agents that function to induce tumor formation by mechanisms exclusive of direct modification or damage to DNA. These agents appear to modulate cell growth and cell death and exhibit dose response relationships between exposure and tumor formation. The exact and/or exclusive mechanisms by which these agents function have not been established, however, changes in cell growth regulation and gene expression are important to tumor formation. This review focuses on several potential mechanisms and cellular processes that may be involved in nongenotoxic chemical carcinogenesis.

Using an analogous monoclonal antibody to evaluate the reproductive and chronic toxicity potential for a humanized anti-TNFalpha monoclonal antibody.

Abstract: Infliximab (Remicade* ) is a humanized or chimeric (mouse/human) IgGl monoclonal antibody that binds to tumor necrosis alpha (TNFa) with high affinity and specificity.1 Infliximab has been used for the treatment of several chronic autoimmune diseases like Crohn's disease and rheumatoid arthritis.2'3 Nonclinical safety assessment of infliximab has been limited because of its limited species cross-reactivity to only chimpanzee and human TNFa. The potential patient population for infliximab will include males and females of childbearing age. Infliximab will also be administered chronically. To evaluate the potential reproductive and chronic toxicity of infliximab, an analogous anti-TNFa monoclonal antibody that selectively inhibits the functional activity of mouse TNFa was developed.

Repeated acetaminophen dosing in rats : adaptation of hepatic antioxidant system

Abstract: Repeated dosing of acetaminophen (paracetamol) to rats is reported to decrease their sensitivity to its hepatotoxic effects, which are associated with oxidative stress and glutathione depletion. We determined if repeated acetaminophen dosing produced adaptive response of key antioxidant system enzymes. Male rats (Sprague-Dawley, 10 weeks) were given 800, 1200, or 1600 mg/kg/day acetaminophen by oral gavage for 4 days. Liver was assayed for oxidative stress and antioxidant markers: malondialdehyde (MDA), thiobarbituric acid reactive substance (TBARS), total antioxidant status (TAS), glutathione (GSH), glutathione reductase (GR), glutathione peroxidase (GPx), glucose-6-phosphate dehydrogenase (G6PD), catalase (CAT), and superoxide dismutase (SOD), and alanine transaminase (ALT) as a marker of hepatocellular injury. Acetaminophen at 1200/1600 mg/kg decreased GSH 26/47%, GPx 21/26%, CAT 35/28%, SOD 21/12%; and TAS 28/18% (correlated with CAT, r=0.91; SOD, r=0.66; GPx, r=0.45). Despite antioxidant deficiencies, and no TBARS change, MDA decreased 26%/33%/37% at 800/1200/1600 mg/kg, which correlated with increased GR (61%/62%/76%, r=0.77) and G6PD (130%/110%/190%, r=0.78). Both MDA (r=0.68) and G6PD (r=0.71) correlated with hepatic ALT, which decreased 27%/43%/48%, respectively. Resistance to acetaminophen hepatotoxicity produced by repeated exposure is partially attributable to upregulation of hepatic G6PD and GR activity as an adaptive and protective response to oxidative stress and glutathione depletion.

Dose-dependent toxicity of diphenhydramine overdose.

Abstract: BACKGROUND: Diphenhydramine (DPHM) overdose is a frequent cause of acute poisoning. Although its clinical features are well known, information about the dose-dependent toxicity of DPHM is still scarce. The objective of this study was to investigate the dose-dependent toxicity of DPHM in patients with acute DPHM poisoning. METHODS: We have analyzed retrospectively all well-documented cases with DPHM monointoxications reported by physicians to the Swiss Toxicological Information Centre (STIC) between January 1984 and April 1996. In addition, a prospective study focusing on ingested DPHM doses and severity of symptoms was performed between May 1996 and December 1998. RESULTS: The retrospective and prospective studies included 232 and 50 patients with DPHM monointoxications, respectively. In both studies, mild symptoms (somnolence, anticholinergic signs, tachycardia, nausea/vomiting) occurred in 55-64%, moderate symptoms (isolated and spontaneously resolving agitation, confusion, hallucinations and ECG disturbances) in 22-27% and severe symptoms (delirium/psychosis, seizures, coma) in 14-18% of patients. Moderate symptoms occurred above ingested doses of 0.3 g DPHM. For severe symptoms the critical dose limit was 1.0 g DPHM. Although the frequency of delirium/psychosis remained constant or even decreased, coma and seizures were significantly (p1.5-g compared with the 1.0- to 1.5-g-dose group. CONCLUSIONS: These data demonstrate a clear dose-dependent acute toxicity of DPHM. They indicate that only patients with DPHM ingestions above 1.0 g are at risk for the development of severe symptoms and, therefore, should be hospitalized. Thus, the results contribute to the data basis required for a cost effective management of patients with DPHM overdose.

Copper toxicity affects proliferation and viability of human hepatoma cells (HepG2 line).

Abstract: In Wilson's disease and Indian childhood cirrhosis (ICC) copper accumulates in the liver resulting in poor hepatocyte regeneration and fibrosis. An inhibition of hepatocyte proliferation and an increase in cell death could account for these outcomes. To establish how the toxicity of this metal ion impacts upon the proliferation and viability of the HepG2 cells they were cultured in 4-32 microM copper(II) sulphate (CuSO4)). These levels were comparable to the circulatory and tissue concentrations of copper recorded for these two diseases. Specific uptake comparable to levels of copper recorded in the livers of patients with Wilson's disease and ICC was measured in the HepG2 cells. After 48 h acid vesicle function increased from 4 to 32 microM Cu2+ but significantly declined at 64 microM compared to the controls. Lysosomal acid phosphatase showed a concentration dependent decline in activity at 72 h. Cellls exposed to 64 microM Cu2+ had a potential doubling time (Tpot) 21 h longer than the control cells due to a prolonged DNA synthesis phase. At 64 microM Cu2+, increases of necrosis up to 18% were seen whereas comparable levels of apoptotic and necrotic cells (<5%) were seen below this concentration. Chronic exposure over 8 weeks impaired colony-forming efficiency at concentrations of 16 microM Cu2+ and above. This study suggests that when liver cells sequester large amounts of copper, the toxic effects include delayed cell-cycle progression, a gradual loss of replicative capacity, and an increased incidence of cell death.

Polycyclic aromatic hydrocarbons in placenta.

Abstract: Concentrations of chrysene, benz [a I anthracene, benzo [a I -pyrene, benzo [h lfluoranthene, indeno [1,2,3 -c,d] pyrene, dibenz [a,h I anthracene, and benzo [g,h,i] perylene were measured in placentas from 200 women from two cities in Ukraine, Kyiv and Dniprodzerzhinsk. The participants had no special exposures and were chosen from among subjects in an ongoing study of reproductive health. All seven of the polycyclic aromatic hydrocarbons (PAHs) were found in all placentas, with the sole exception of benzo [a I pyrene in one placenta. Chrysene was present at the highest concentrations, with median 1.38 ng/g dry weight. Dibenz[a,h]anthracene and benzo[g,h,ilperylene had the lowest concentrations; each had median 0.73 ng/g dry weight. Concentrations in Kyiv were slightly higher than those in Dniprodzerzhinsk, butthe differencewas significantonlyfor dibenz [a,h I anthracene. Dibenz [a,h] anthracene and benzo[g,h,ijperylene increased significantly with maternal body mass index, but other PAHs showed no such ...

Inhibitory effect of Emblica officinalis on the in vivo clastogenicity of benzo[a]pyrene and cyclophosphamide in mice.

Abstract: Benzo [α] pyrene (B[α]P) and cyclophosphamide (CP) are potent carcinogens/mutagens. Effect of Emblica officinalis extract administration on the in vivo genotoxi-city of B[α]P and CP was studied using bone marrow chromosomal aberration and micronucleus induction tests in mice.Three doses (50,250 and 500mg/kgbodyweight) oftheplant extractwere administered orallyfor 7 consecutive days prior to the administration of single dose of mutagens (B[α]P 125 mg/kg oral; CP 40 mg/kg i.p.).It was found that administration of 250 and 500 mg/kg of E. officinalis extract significantly inhibited the genotoxi-city of B [α] P as well as CP in both the assay systems. Administration of 50 mg/kg of the plant extract had no inhibitory effect.Vitamin C, a major constituent of E. officinalis when administered at dose level of 9 mg/kg b.w. (the approx-imate estimated amount present in the highest dose of plant extract, i.e. 500 mg) for 7 days did inhibit chromosomal aberrations and micronuclei induction, but not in a significant ma...

Preclinical development of keliximab, a Primatized anti-CD4 monoclonal antibody, in human CD4 transgenic mice: characterization of the model and safety studies.

Abstract: The preclinical safety assessment of biopharmaceuticals necessitates that studies be conducted in species in which the products are pharmacologically active. Monoclonal antibodies are a promising class of biopharmaceuticals for many disease indications; however, by design, these agents tend to have limited species cross-reactivity and tend to only be active in primates. Keliximab is a human-cynomolgus monkey chimeric (Primatized) monoclonal antibody with specificity for human and chimpanzee CD4. In order to conduct a comprehensive preclinical safety assessment of this antibody to support chronic treatment of rheumatoid arthritis in patients, a human CD4 transgenic mouse was used for chronic and reproductive toxicity studies and for genotoxic studies. In addition, immunotoxicity studies were conducted in these mice with Candida albicans, Pneumocystis carinii and B16 melanoma cells to assess the effects of keliximab on host resistance to infection and immunosurveillance to neoplasia. The results of these studies found keliximab to be well tolerated with the only effects observed being related to its pharmacologic activity on CD4+ T lymphocytes. The use of transgenic mice expressing human proteins provides a useful alternative to studies in chimpanzees with biopharmaceutical agents having limited species cross-reactivity.

Hormesis: a stress response in cells exposed to low levels of heavy metals.

Abstract: Cytotoxicity studies using a 3-(4,5 dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide (MT)-based in vitro toxicity assay revealed that McCoy cells exposed to low concentrations of mercuric (0.7 yM),cadmium (1 1M) and cupric chloride (3 tIM) exhibited significant increases in cellular activity. This increased activity, previously termed hormesis, coincided with the production ofhigh levels ofthe stress proteins, heat shock protein 70 (Hsp 70) and metallothionein, while the high constitutive expression of these proteins in cadmium-resistant mutant (CRM) cells corresponded to constitutive hormetic activity. Hormesis was found to obey uniform kinetics allowing for a mathematical description of this increased activity. These results suggest that hormetic activity is a specific cellular response, and most likely, a stress response to low but harmful levels of toxic agents and may therefore provide a rapid test for the presence of toxicants at concentrations associated with chronic toxicity.

An assessment of the in vitro toxicology of Clostri di urn perfringens type D ε-toxin in human and animal cells

Abstract: The epithelial Madin Darby canine kidney (MDCK) cell line and 17 human cell lines were examined for sensitivity to Clostridium perfringens type D epsilon-toxin. MDCK cells were confirmed as being sensitive to the toxin. In addition, the Caucasian renal leiomyoblastoma (G-402) human cell line was identified as being epsilon-toxin sensitive. Using the MTS/PMS assay system the concentration of toxin reducing cell culture viability by 50% (LC50) was found to be 2 microg/ml in MDCK cells. The LC50 for G-402 cells was 280 microg/ml. Epsilon-Toxin was found to be rapid acting in MDCK cells exposed to a maximum lethal dose of the toxin (40% loss of viability after a 0.5 h exposure), but slower acting in G-402 cells (40% loss of viability after 1.7 h exposure). Photomicrography of toxin exposed cultures indicated necrotic cell death on exposure to epsilon-toxin. Investigations using an antibody probe indicated that epsilon-toxin could bind to many cell surface proteins in both MDCK, G-402 and a toxin insensitive human cell line (CAKI-2). It has previously been found that the toxin may bind to the cell surface via glycosylated moieties. However, exposing MDCK and G-402 cells to epsilon-toxin in the presence of sialic acid and several different sugars did not reduce the lethal effects of the toxin.

Toxicity of ingested formalin and its management

Abstract: Formaldehyde is a physiological intermediary metabolite taking part in many biological process in the body. It is a constituent of many items of daily use, including foods. It is also used in medicine for treatment of some conditions. A 40% solution of formaldehyde in water is known as formalin. Formalin is irritating, corrosive and toxic and absorbed from all surfaces of the body. Ingestion is rare because of alarming odour and irritant effect but documented in accidental, homicidal or suicidal attempts. Ingestion can lead to immediate deleterious effects on almost all systems of the body including gastrointestinal tract, central nervous system, cardiovascular system and hepato-renal system, causing gastrointestinal hemorrhage, cardiovascular collapse, unconsciousness or convulsions, severe metabolic acidosis and acute respiratory distress syndrome. No specific antidote is available. Treatment of toxicity is supportive care of the various organ systems. Multidisciplinary approach is required for proper management.

Glycyrrhizic acid: the assessment of a no effect level

Abstract: Because from earlier experiments in rats and a pilot study in humans a no-effect level of glycyrrhizic acid could not be established, a second experiment was performed in healthy volunteers. The experiment was performed in females only, because the effects were most marked in females in the pilot study. Doses of 0, 1, 2 and 4 mg glycyrrhizic acid/kg body weight were administered orally for 8 weeks to 39 healthy female volunteers aged 19-40 years. The experiment lasted 12 weeks including an adaptation and a "wash-out" period. A no-effect level of 2 mg/kg is proposed from the results of this study, from which an acceptable daily intake (ADI) of 0.2 mg/kg body weight can be extrapolated with a safety factor of 10. This means consumption of 12 mg glycyrrhizic acid/day for a person with a body weight of 60 kg. This would be equal to 6 g licorice a day, assuming that licorice contains 0.2% of glycyrrhizic acid. The proposed ADI is below the limit advised by the Dutch Nutrition Council of 200 mg glycyrrhizic acid/day. This reflects the relatively mild acute toxicity of glycyrrhizic acid, which is also emphasised by the "generally recognised as safe" (GRAS) status of glycyrrhizic acid in the USA in 1983. However, the long-term effects of a mild chronic intoxication (causing, for example, a mild hypertension), although not immediately lethal, justify special attention to the amount of glycyrrhizic acid used daily.

A long-term follow-up of lung function in survivors of paraquat poisoning.

Abstract: 1. Respiratory failure is a frequent cause of death in moderate to severe paraquat poisoning, and a transient fall in the gas transfer factor may be seen in mild poisoning. 2. The objectives of this study were to detect long-term changes in lung function in survivors of paraquat poisoning. 3. We analyzed 12 survivors retrospectively for age, sex, signs and symptoms, laboratory findings, chest X-ray findings, serum paraquat level, and lung function test. The first and the follow-up lung tests were performed at 3.7+/-1.4 weeks and 3.4+/-1.4 years, respectively. 4. Serum paraquat levels were assayed in all patients and 3/12 were above the Proudfoot's predictive line. Liver dysfunction (GOT > 50) and renal dysfunction (BUN > 30) were noted in 5/12 and 8/12, respectively. D(L)/V(A) was lower than the normal limit in the first study (3.9+/-0.6 L), but increased significantly and returned to the normal range in the follow-up study (4.5+/-0.6 L). %VC was within the normal range in either examination, but significantly decreased in the follow-up. %TLC was within the normal range in the first study (87+/-13%), but significantly decreased below the normal limit in the follow-up (81+/-13%). 5. These results indicate that survivors of paraquat poisoning may be left with a restrictive type of pulmonary dysfunction and suggest that a long-term follow-up of lung function may be necessary for survivors of paraquat poisoning.

Assessment of thyroid function in pesticide formulators.

Abstract: Thirty male pesticide formulators exposed to the dust and liquid formulation of endosulfan, quinalphos, chlorpyriphos, monocrotophos, lindane, parathion, phorate, and fenvalerate and 20 comparable control subjects from the same area of study were examined for the evaluation of thyroid function tests. The level of TSH was elevated (about 28%) in pesticide formulators as compared to a control group, but the increase was statistically insignificant. Based on the individual TSH measurement, 3 of 30 formulators had isolated elevated levels of TSH and seem to have acquired sub-clinical hypothyroidism; five had TSH values slightly elevated to the upper boarder line (4.03 muIU/ml); and the majority of formulators (N= 22) had TSH values in the normal range varying from 1.29 to 3.9 muIU/ml. Total T3 was suppressed significantly (P< 0.01) in formulators, while marginal decrease (about 7%) was noticed in T4 level. This study indicated thyroid function impairment in few pesticide formulators.

Effects of R-(+)- and S-(-)-limonene on the respiratory tract in mice.

Abstract: The effects of airborne R-(+)- and S-(-)-limonene were studied in conscious BALB/c mice by continuous monitoring respiratory rate (f), tidal volume (VT) and mid-expiratory flow rate (VD) during an ...

Amitraz poisoning in children.

Abstract: Amitraz is an acaricide and insecticide indicated for the treatment of generalized demodicosis in dogs and for the control of ticks and mites in cattle and sheep. There is little information available in the human literature about the toxicology of the product. In this study, the clinical and laboratory features of amitraz poisoning in 11 children are presented. The age range of the patients was 2-1/2 to 6 years. Accidental ingestion of an improperly stored liquid pesticide was determined in all patients. Unconsciousness (100%), drowsiness (100%), and myosis (84%) were the most common abnormal signs; 45%, 27%, and 18% of patients had bradycardia, respiratory insufficiency, and hypotension, respectively. All of the patients were treated with atropine, gastric lavage, activated charcoal, and supportive care. Although the patients had a prompt response to therapy, three patients required multiple doses of atropine during a 24-h period. This study revealed that clinical poisoning by oral route emerged within 30-90 min and that central nervous system (CNS) depression, which is the most important sign, resolved within 8-1/2-14 h. All cases were discharged.

In vitro metabolism and interaction of cilostazol with human hepatic cytochrome P450 isoforms.

Abstract: 1. Cilostazol (OPC-13013) undergoes extensive hepatic metabolism. The hydroxylation of the quinone moiety of cilostazol to OPC-13326 was the predominant route in all the liver preparations studies. The hydroxylation of the hexane moiety to OPC-13217 was the second most predominant route in vitro. 2. Ketoconazole (1 microM) was the most potent inhibitor of both quinone and hexane hydroxylation. Both the CYP2D6 inhibitor quinidine (0.1 microM) and the CYP2C19 inhibitor omeprazole (10 microM) failed to consistently inhibit metabolism of cilostazol via either of these two predominant routes. 3. Data obtained from a bank of pre-characterized human liver microsomes demonstrated a stronger correlation (r2=0.68, P < 0.01) between metabolism of cilostazol to OPC-13326 and metabolism of felodipine, a CYP3A probe, that with probes for any other isoform. Cimetidine demonstrated concentration-dependent competitive inhibition of the metabolism of cilostazol by both routes. 4. Kinetic data demonstrated a Km value of 101 microM for cilostazol, suggesting a relatively low affinity of cilostazol for CYP3A. While recombinant CYP1A2, CYP2D6 and CYP2C19 were also able to catalyze formation of specific cilostazol metabolites, they did not appear to contribute significantly to cilostazol metabolism in whole human liver microsomes.

Disruption of the reproductive system and reproductive performance by administration of nonylphenol to newborn rats.

Abstract: A number of alkylphenolic compounds are used in a variety of commercial products and have been shown in in vitro studies to be weakly estrogenic, but few in vivo data are available addressing this ...

Cholinesterase activities determination in frozen blood samples: an improvement to the occupational monitoring in developing countries.

Abstract: 1. Studies were carried out on rural workers in Brazil to determine the decrease in the activity of plasma butyrylcholinesterase (BChE), erythrocyte cholinesterase (AChE) associated with exposure to organophosphorus pesticides (OP). The goal of this work is to help prevent injury to these workers. 2. In developing countries the distance between area of pesticide use and reference laboratories is a drawback for analytical techniques, since cholinesterase activity determinations require fresh blood samples. Field methodologies can be a useful alternative to laboratory tests, however they are not as sensitive as those found in laboratories. 3. The modification of Ellman's Method presented in this paper allows blood samples to be frozen and maintain enzymatic stability: 7 days for AChE and 3 days for BChE. The proposed method is also more sensitive than Ellman's Method Modified by Magnotti (EMMM). 4. The results suggest that the Ellman Method Modified by Oliveira-Silva (EMMOS) is valid for monitoring procedures. This method represents an important contribution to the process of monitoring OP exposures, since the evaluations no longer have to be conducted near the site of OP use.

Does caloric restriction induce hormesis

Abstract: The question of whether caloric restriction (CR) is hormetic is addressed in terms of two common defini-tions of the term. In terms of the older definition, i.e., a growth-stimulatory effect when lower doses of a compound which resulted in growth inhibition at higher doses, CR is better characterized as a co-hormetic (i.e., a paradigm which at relatively “low doses,” in combina-tion with some stimulus, will evince increased growth (proliferation) and at higher “doses” will inhibit this increased proliferation) rather than a hormetic agent. Mechanisms such as cellular selection of cellular subpopulations, increases in receptor efficiency, and preservation of cellular proliferative potential can inter-act with agents and produce increased growth as long as the CR is not too severe. In terms of a broader definition, i.e., nonmonotonic dose-response behavior of a compound for any adverse response, CR appears to be hormetic, both as a result of body weight (BW) loss and other potential mechanisms. The impact o...

Phenytoin poisoning after using Chinese proprietary medicines.

Abstract: We report a case of poisoning resulting from the use of Chinese proprietary medicines (CPM) containing anticonvulsants phenytoin, carbamazepine and valproate. The manufacturer's information leaflets did not mention any of these prescription drugs. As a consequence, the patient was admitted comatose due to severe phenytoin poisoning. We are not aware of any reported case of severe poisoning due to CPM adulterated with anticonvulsants and this is possibly the first case.

Cholinergic and noncholinergic brain biomarkers of insecticide exposure and effects.

Abstract: The objective of this investigation was to determine the distribution of cholinergic and noncholinergic biomarkers in discrete brain regions (cortex, stem, striatum, hippocampus, and cerebellum) of rats treated with dimethyl sulfoxide (DMSO, controls), and insecticides such as carbofuran (CARB, 1.5 mg/kg, sc), or methyl parathion (MPTH, 5 mg/kg, ip). Both insecticides produced characteristic signs of anticholinesterase nature within 5-7 min after injection. In controls, analyses of the brain regions revealed a wide variability in the values of cholinergic (acetylcholinesterase, AChE) and noncholinergic (creatine kinase, CK; and lactic dehydrogenase, LDH, and their isoenzymes) biomarkers. The highest activities of AChE and LDH were found in the striatum (1661+/-23 micromol/g/h and 57,720+/-478 IU/l, respectively) and lowest in the cerebellum (118+/-6 micromol/g/h) and 39,480+/-918 IU/l, respectively). However, the activity of CK was found highest in the cerebellum (742,560+/-798 IU/l) and lowest in the hippocampus (353,400+/-11,696 IU/l). Each brain region showed a characteristic profile of CK and LDH isoenzymes. Among the CK isoenzymes, activity of CK-BB was highest (77.5-89.3%), followed by CK-MM (6.7-15.6%), and least CK-MB (0-6.9%). The cerebellum had no CK-MB activity. In all brain regions, CK-MM isoenzyme had only the CK-MM3 subform. Among the LDH isoenzymes, activity of LDH-4 was highest in all brain regions (23-40%), except the cerebellum in which LDH-1 was highest (29%). Compared to the brain, control serum contained very little CK and LDH activity, but serum had three distinct CK and five distinct LDH isoenzymes. Unlike brain regions, serum had three CK-MM subforms. Each insecticide induced characteristic alterations in brain biomarkers. AChE activity was maximally inactivated in cortex (90. 6%) with CARB, and in cerebellum (95.3%) with MPTH. With either insecticide, the least inhibition of AChE occurred in the striatum. Unlike AChE, carboxylesterase (CarbE) did not show brain regional variability in controls, and its activity was uniformly inhibited in all brain regions by CARB and comparatively greater by MPTH. CARB- or MPTH-induced characteristic alterations in CK, LDH, and their isoenzymes in the brain, which were also reflected in serum, as a result of their leakage from the brain by increased permeability due to depletion of ATP (38-57% and 33-47%, respectively) and phosphocreatine (PCr, 23-42% and 56-65%, respectively).

Astrocyte phenotype and prevention against oxidative damage in neurotoxicity.

Abstract: Astrocytes possess a potent array of protective systems. These are chiefly targeted against oxidised products and radicals, which are frequently present in increased amounts following exposure of nervous tissue to a range of toxic insults. Following exposure to the toxic chemicals astrocytes commonly respond by alteration in phenotype with upregulation of a large number of molecules, including those controlling the protective systems. This article summarizes evidence, largely obtained from in vitro studies, which supports the concept that some of the changes in astrocyte phenotype are associated with increased protection against the cytotoxicity caused by the oxidative damage that results from exposure to range of neurotoxicants.