bluuebunny/crossref_metadata_2025 huggingface dataset:
Horizontal Transfer of
phnAc
Dioxygenase Genes within One of Two Phenotypically and Genotypically Distinctive Naphthalene-Degrading Guilds from Adjacent Soil Environments
Authors: Wilson Mark S. , Herrick James B. , Jeon Che Ok , Hinman David E. , Madsen Eugene L.
Published: April 2003

Several distinct naphthalene dioxygenases have been characterized to date, which provides the opportunity to investigate the ecological significance, relative distribution, and transmission modes of the different analogs. In this study, we showed that a group of naphthalene-degrading isolates from a polycyclic aromatic hydrocarbon (PAH)-contaminated hillside soil were phenotypically and genotypically distinct from naphthalene-degrading organisms isolated from adjacent, more highly contaminated seep sediments. Mineralization of
14
C-labeled naphthalene by soil slurries suggested that the in situ seep community was more acclimated to PAHs than was the in situ hillside community.
phnAc
-like genes were present in diverse naphthalene-degrading isolates cultured from the hillside soil, while
nahAc
-like genes were found only among isolates cultured from the seep sediments. The presence of a highly conserved
nahAc
allele among gram-negative isolates from the coal tar-contaminated seep area provided evidence for in situ horizontal gene transfer and was reported previously (J. B. Herrick, K. G. Stuart-Keil, W. C. Ghiorse, and E. L. Madsen, Appl. Environ. Microbiol.
63:
2330-2337, 1997). Natural horizontal transfer of the
phnAc
sequence was also suggested by a comparison of the
phnAc
and 16S ribosomal DNA sequences of the hillside isolates. Analysis of metabolites produced by cell suspensions and patterns of amplicons produced by PCR analysis suggested both genetic and metabolic diversity among the naphthalene-degrading isolates of the contaminated hillside. These results provide new insights into the distribution, diversity, and transfer of
phnAc
alleles and increase our understanding of the acclimation of microbial communities to pollutants.
Multiplex Reverse Transcription-PCR for Simultaneous Detection of
Beet Necrotic Yellow Vein Virus
,
Beet Soilborne Virus
, and
Beet Virus Q
and Their Vector
Polymyxa betae
KESKIN on Sugar Beet
Authors: Meunier Alexandre , Schmit Jean-François , Stas Arnaud , Kutluk Nazli , Bragard Claude
Published: April 2003

Three soilborne viruses transmitted by
Polymyxa betae
KESKIN in sugar beet have been described:
Beet necrotic yellow vein virus
(BNYVV), the agent of rhizomania,
Beet soilborne virus
(BSBV), and
Beet virus Q
(BVQ). A multiplex reverse transcription-PCR technique was developed to simultaneously detect BNYVV, BSBV, and BVQ, together with their vector,
P. betae
. The detection threshold of the test was up to 128 times greater than that of an enzyme-linked immunosorbent assay. Systematic association of BNYVV with one or two different pomoviruses was observed. BVQ was detected in samples from Belgium, Bulgaria, France, Germany, Hungary, Italy, Sweden, and The Netherlands but not in samples from Turkey.
Triage for Leiurus quinquestriatus scorpion envenomation in children —is routine ICU hospitalization necessary?
Authors: Ben-Abraham R , Eshel G , Winkler E , Weinbroum A A , Barzilay Z , Paret G
Published: April 2003

(1) Leiurus quinquestriatus scorpion (LQS) envenomtion is a common public health problem with a similar clinical presentation in the Middle East and worldwide: localized reactions occur in up to 97% of the victims. (2) LQS envenomation in children is potentially fatal since the severity of symptoms is weight-dependent. (3) A common policy is to hospitalize all children stung by the LQS egardless of clinical severity in the pediatric intensive care unit (PICU). (4) Seventeen of 18 children treated at two Israeli medical centers during an 8-year period developed mild to moderate clinical manifestations (antivenin was given in the one severe case; all children survived): all 18 had been transferred to an ICU for surveillance. Since patient care in PICUs is far more costly and manpower-intense than in general emergency rooms, we propose that a protocol of 6 h of surveillance in the emergency department is adequate and safe for most children who had been stung by LQS. Only children who develop systemic manifestations should be hospitalized and transferred to the intensive care unit. (5) Further prospective studies should be conducted to define specific subgroups that may benefit from these recommendations.
Developmental toxicity of dimethylacetamide in rabbits following inhalation exposure
Authors: Klimisch H-J , Hellwig J
Published: April 2003

(1) Dimethylacetamide was tested for developmental toxicity after inhalation exposure of pregnant Himalayan rabbits. Fifteen female rabbits per main group were exposed to dimethylacetamide vapours at concentrations of 0, 0.2, 0.7 or 2.0 mg/l (equivalent to 0, 57, 199.5 or 570 ppm) and five female rabbits per satellite group to 0 or 2.0 mg/l 6 h/day from day 7 post-insemination (p.i.) to day 19 p.i. All animals were observed until day 29 p.i. (2) No signs of maternal toxicity were seen in the does of the main groups (body weight and gross pathology) or in the does of the satellite groups (body weight, blood chemistry, histopathological findings of the liver). (3) Fetotoxic effects were caused at a concentration of 0.7 mg/l (e.g., increased skeletal variations) and 2.0 mg/l (e.g., significantly decreased fetal and placental weights, increase in soft tissue and skeletal variations). At 2.0 mg/ 1, there were also signs of a weak teratogenic effect expressed as a marginal, statistically not significant increase in soft tissue malformations (regarding the heart and great vessels). No compound-related effects were observed in the fetuses after exposure to 0.2 mg/l. (4) The highest concentration tested under these conditions (2.0 mg/l) was found to be a no-observable-adverse-effeclevel (NOAEL) for the maternal Himalayan rabbit, whereas 0.2 mg/l was defined as the NOAEL for the developing organism.
Urinary cotinine levels of smokeless tobacco (MaraE powder) users1
Authors: Çok I , Ozturk R
Published: April 2003

Smokeless tobacco is used in various forms in some countries ofthe world. “Mara, otu” is a kind of smokeless tobacco usage in the Southeastern region of Turkey. The use of smokeless tobacco causes nicotine addiction and depen-dence. Moreover this type of smokeless tobacco usage is one of the risk factors for oral cancers and genotoxic da ages for users. Cotinine is widely used as a biomarker of tobacco consumption and intake of nicotine. Therefore, urine samples were collected from people who are using Mara, powder and smoking cigarettes, and passive smokers, and the levels ofcotinine investigated. The purpose ofthis study is to determine the cotinine levels of Mara, powder users and to compare the results with cigarette smokers and passive smokers. Urinary cotinine levels of subjects were determined by using capillary gas chromatography with FID detection. The mean (SD) urinary cotinines have been determined as 6467.35±3198 [μg/g creatinine for 26 Mara, powderusers, 1943.92±1443,ug/gcreatininefor26 cigarette smokers and 198.62±420.82 μg/g creatinine for 26 passive smokers. A significant difference has been found between cotinine levels of Mara powder users and cigarette smokers, which is three times higher in Mara, powder users (p <0.001). The present study suggests that smokeless tobacco poses a threat to public health and it should not be viewed as a safe alternative to cigarettes.
Polycyclic aromatic hydrocarbons in placenta
Authors: Gladen B C , Zadorozhnaja T D , Chislovska N , Hryhorczuk D O , Kennicutt M C , Little R E
Published: April 2003

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 pattern. Placentas from deliveries in autumn or winter had slightly but not significantly higher concentrations. Concentrations were not related to maternal age. There were too few smokers in the sample for meaningful evaluation. No associations were seen between any of the placental PAH concentrations and birth weight of the infant.
Detecting hormesis using a non-parametric rank test
Authors: Deng C , Zhao Q , Shukla R
Published: April 2003

When a dose-response experiment is conducted, the enhanced responses can be observed at low doses. This phenomenon is often called hormesis. The enhanced responses at low doses does not necessarily mean the existence of hormesis. It is important to conduct statistical analyses to determine whether a departure from monotonic relationships is significantly different from the chance occurrence. This paper introduces a non-parametric rank testto detecthormesis. To illustrate the use ofthis method, we apply it to the data from a Whole Effluent Toxicity test. We demonstrate that the occurrence of hormesis can be statistically evaluated by using this non-parametric rank test.
Acute delirium induced by intravenous trimethoprim–sulfamethoxazole therapy in a patient with the Acquired Immunodeficiency Syndrome
Authors: Salkind A R
Published: April 2003

The development of a rash in response to trimethoprim-sulfamethoxazole (TMP-SMX) administration is a fre-quent adverse reaction in people with the acquired immunodeficiency syndrome (AIDS). In contrast, there are no published reports in the English language literature describing TMP-SMX induced delirium in an AIDS patient. This report describes the development of frank delirium in a person with AIDS receiving TMP-SMX. The episode resolved completely within 72 h of withdrawal of the drug.
A long–term follow–up of lung function in survivors of paraquat poisoning
Authors: Yamashita M , Yamashita M , Ando Y
Published: April 2003

1 Respiratory failure is a frequent cause of death in moderate to severe paraquat poisoning, and a tran- sient 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. DL/VA 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 examina- tion, 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.
Preclinical assessments of European Union marketing authorisation applications for aimmunomodulatory biopharmaceuticals
Authors: Liminga U
Published: April 2003

A review of preclinical assessment reports on immuno-modulatory biopharmaceuticals submitted to the Eur-opean Agency for Evaluation of Medicinal Products from 1995 to the middle of 1999 was conducted. Questions regarding the rationale for the preclinical development programmes were often put to the applicants. Effects mediated via changes of the immune function, including risks of reproductive toxicity and tumorigenicity, were of Background: European Union regulatory review process In 1995, the “New System” for authorisation of medicinal products in the European Union (EU) was introduced. At the same time, the European Agency for Evaluation of Medicinal Products (EMEA) was created. The EMEA is the permanent secretariat for the Committee for Proprietary Medicinal Products (CPMP), which is a scientific committee responsible for human medicinal products. Since 1995, it has been possible to submit a single EU marketing authorisation application (MAA) to the EMEA, which is reviewed following a predefined procedure with set time frames. The CPMP has two representatives from each member state and for each MAA, a rapporteur and a co-rapporteur are assigned from this represen-tation. The primary evaluation is performed by assessor teams, consisting of European experts from the national agencies and academia, who are engaged by the rapporteurs. These evaluations are subse-quently commented on by experts from the other member states. Within 120 days of active review time, the CPMP agrees on a “List of Questions,” which is sent to the applicant. The applicant's responses to the “List of Questions” are assessed by both rapporteur teams, and their joint *Correspondence: Dr U Liminga, Medical Products Agency, Box 26, S-751 03, Uppsala, Sweden particular concern. This review indicates the need to further develop methods for safety testing of immunomo-dulatory biopharmaceuticals.
Status of preclinical safety assessment for immunomodulatory biopharmaceuticals
Authors: Green J D , Black L E
Published: April 2003

Scientists from academia, industry, FDA, European and Japanese regulatory groups met to discuss key considera-tions that are central to the safe and expeditious development of novel biologic agents that are thought to act by modulation of the host immune system. In the presentations and case studies, particular attention was given to the current clinical experience with immunosuppressant agents. Many new biologic agents (such as humanized monoclonal antibodies) have been developed to interact in a highly specific manner with their target. However, their pharmacologic properties may be more complex than originally appreciated, impact-ing on clinical trial designs. The goal of preclinical safety assessment should be to provide some assurance that patients will be protected from any unacceptable risks by defining “safe” and “active” doses. For immunomodulatory molecules, particular attention is paid to defining potential for increased risks of lymphoproliferative disorders, oppor-tunistic infections, and immune impairment. To address these issues, a wide variety of preclinical studies, mainly in non-human primates, have been performed for the purpose of assessing the potential risk of drug-induced, human immunotoxicity. Case studies presented at this symposium showed the feasibility of assessing humoral and cell-mediated aspects of the immune system, using antigen and neoantigen challenges, immunohistochemical, and flow cytometric (FACS) methods. In some cases, homologous forms of the biologic agent and “humanized” transgenic models have been used to assess potential clinical risks. These data have been useful in providing some assurance that severe adverse effects would not be induced in patients. Despite these limitations, it is important that industry sponsors provide information to regulatory authorities, the clinical investigator, and patients that provides the best feasible basis for risk assessment, safe clinical trial design, informed consent, and eventually, appropriate labeling. It is recognized that existing preclinical models often have significant limitations. Consequently, the sponsor's and regulatory authority's experienced judgement has deter-mined whether or not the purported benefits of the novel therapeutic agent are balanced by the potential short-and long-term risks. In this field of development, preclinical models often need to reflect recent technology innovations; therefore, these models are not always “validated” in a conventional sense. Experience to date suggests that im-proved methods and approaches are needed as these agents are developed for use in lower or moderate risk patient populations. Consequently, there is an increased need for an industry/regulatory partnership in order to achieve pro-gress in these risk assessment areas.
The PCR assay in the preclinical safety evaluation of nucleic acid medicines
Authors: Haworth R , Pilling A M
Published: April 2003

The polymerase chain reaction (PCR) is a highly efficient gene amplification procedure which is increasingly being applied to the safety assessment of nucleic acid (NA) medicines such as gene therapies and DNA vaccines.

Although clinical experience is limited, a number of potential safety issues exist with these new compounds including toxicity associated with the expression of encoded gene products, autoimmunity due to the induction of anti-DNA antibodies and insertional mutagenesis. PCR enables these questions to be addressed and provides data on mRNA expression, biodistribution and integration.

In this review the use of PCR methodologies in the preclinical safety evaluation of NA medicines is discussed. Particular consideration is given to the issues surrounding the use of PCR in regulatory toxicology, including sensitiv-ity requirements, cross-contamination problems, tissue sampling procedures and good laboratory practice (GLP) compliance. In addition, the use of a PCR-based assay to demonstrate the integration of DNA vector into host DNA is described.

As the use of PCR in the development of NA medicines will undoubtedly increase over the next few years, it is important that pathologists and toxicologists familiarise themselves with the principles and applications of this technique.
Phenytoin poisoning after using Chinese proprietary medicines
Authors: Lau K K , Lai C K , Chan A YW
Published: April 2003

We report a case of poisoning resulting from the use of Chinese proprietary medicines (CPM) containing antic-onvulsants 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.
In vitro metabolism and interaction of cilostazol with human hepatic cytochrome P450 isoforms
Authors: Abbas R , Chow C P , Browder N J , Thacker D , Bramer S L , Fu C J , Forbes W , Odomi M , Flockhart D A
Published: April 2003

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 mM)wasthemostpotentinhibitorof both quinone and hexane hydroxylation. Both the CYP2D6 inhibitor quinidine (0.1 mM) and the CYP2C19 inhibitor omeprazole (10 mM) 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, P50.01) 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 mM 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.
Toxic encephalopathy associated with use of DEET insect repellents: a case analysis of its toxicity in children
Authors: Briassoulis G , Narlioglou M , Hatzis T
Published: April 2003

(1) Respiratory distress and seizures developed in an 18-month-old boy following brief exposure to low-strength (17.6%) N,N-diethyl-m-toluamide (DEET). A review of the literature revealed 17 reports of DEET-induced encephalopathy in children. The objective of this study was to test the hypothesis that the potential toxicity of DEET is high and that available repellents containing DEET, irrespective of their strength, are not safe when applied to children's skin. (2) Although this is a case report, we used the features of published reports of DEET-induced encephalopathy in children to support the diagnosis, since the evidence that the child's illness was caused by DEET was circumstantial. In the following case analysis, clinical reports of children < 16 years old have been reviewed and analyzed in an effort to relate direct DEET toxicity to various clinical, demographic, and toxic compound exposure factors (Fisher's exacttest and logistic regression analysis). (3) DEET-induced encephalopathy in children (56%o girls) followed not only ingestion or repeated and extensive application of repellents, but also a brief exposure to DEET (45%). Of those who reported a dermal exposure, 33% reported an exposure to a product containing DEET <20%. Seizures, the most prominent symptom (72%), were significantly more frequent when DEET solutions were applied to the skin (P < 0.01). Mortality (16.6%) did not correlate significantly with the concentration of the DEET liquid used, duration of skin exposure, pattern of use, age, or sex. (4) Data of this case analysis suggest that repellents containing DEET are not safe when applied to children's skin and should be avoided in children. Additionally, since the potential toxicity of DEETis high, less toxic preparations should be probably substituted forDEET-containingrepellents, whenever possible.
Effects of Vepacide (Azadirachta indica) on asp artate and al anine aminotransferase profiles in a subchronic study with rats
Authors: Rahman M F , Siddiqui M KJ , Jamil K
Published: April 2003

The aim of this study was to ascertain the long-term effects of Vepacide, a neem-based pesticide on biochemical profiles. Albino Wistar rats were treated orally with 80 (low), 160 (medium) and 320 mg/kg (high) doses of Vepacide in coconut oil for 90 days. Control rats received the same volume of the vehicle. Vepacide caused increase of aspartate and alanine aminotransferase in serum, kidney and lung, and these enzymes decreased in liver in both male and female rats when measured after 45 and 90 days of treatment. The two-way analysis of variance (ANOVA) showed that the alterations in these enzymes were dose–and time-dependent. Sexual dimorphism was observed when male rats were compared with female rats (Student t-test at P< 0.05). Positive correlation was observed with regard to these enzymes between serum, kidney and lung, whereas in the case of serum and liver, a negative correlation was recorded. These enzyme profiles elucidate that they increased in serum with simultaneous decrease in liver, indicating necrosis of liver, whereas in other tissues, the level of enzymes increased, showing an adaptive mechanism due to the chemical stress. The affected enzymes were recovered to normal conditions after 28 days of post-treatment (withdrawal study). Due to the Vepacide treatment, lung was more affected followed by liver and kidney. This study has indicated that these enzymes could be useful as biomarkers for the insult of any toxicant. Besides, they can also help in predictive toxicology.
Analysis of single hair by XRF discloses mercury intake
Authors: Toribara T Y
Published: April 2003

Utilizing information obtained from the X-ray fluores-cence linear scanning along a single strand of hair in a recent fatal exposure to dimethylmercury, it was possible to determine the circumstances leading to the fatal result. When the Dartmouth chemistry professor displayed symptoms of mercury toxicity, samples of her urine and blood were found to have considerable amounts of mercury by a commercial laboratory. The Dartmouth medical people immediately started treatment with a chelator on January 29, 1997 to remove the mercury, and sent the first samples of blood, urine and hair taken on January 31, 1997 to our laboratory. Our X-ray fluorescence analysis of a single strand of hair shown in Figure 1 shows a single large peak of intake of mercury confirming the information revealed by examination of her laboratory notebook that she had spilled some dimethylmercury about 5 months previous to the date the hair sample was taken. Figure 2 shows two peaks, the peak closest to the scalp end of the hair shows the effect of the large amount of mercury released by the chelator, part of which appeared in the blood. Utilizing the start of the first increase in the blood level as August 14, 1996, and the second as caused by the chelator on January 29, 1997, a count of the number of 2-mm points measured between the two dates gives an accurate growth of the hair during that time. A close examination of Figure 1 indicates that it required five points, each of 2 mm, along the hair to reach the maximum. This indicates a time period of 10 mm of growth equal to 23 days during which a large concentration of methylmercury was entering the blood as evidenced by the hair concentration. The professor died on June 11, 1997.
Parasuicide by self-injection of an organophosphate insecticide
Authors: Premaratna R , Tilakarathna Y , Fonseka M MD , Gunatilake SB , de Silva HJ
Published: April 2003

Parasuicide by ingestion of organophosphate (OP) insecticides is common in Sri Lanka, but the use of the parateral route to self administer the poison is extremely rare. We report a patient who deliberately injected herself intramuscularly with an OP compound with suicidal intent. The clinical manifestations of OP poisoning were unpredictable and posed a therapeutic problem.
Effect of peroxynitrite on glutaredoxin
Authors: Aykaç-Toker G , Bulgurcuogélu S , Koçak-Toker N
Published: April 2003

Glutaredoxin is an important enzyme in thiol homeostasis. As a thioltransferase, it reduces oxidized thiols. It also has dehydroascorbate reductase (DHAR) activity to reduce dehydroascorbate (DHA) to ascorbic acid. Peroxynitrite (ONOO-) is one of the most active elements of oxidative stress that can be formed wherever nitric oxide and superoxide are produced simultaneously. ONOO- is known to react with free thiols easily. To observe the effect of ONOO- on glutaredoxin, rat liver cytosolic fractions were incubated with 0–250 MONOO -. Thioltransferase activity was found to be decreased as ONOO- concentration increased. The inhibition was not reversible with dithiothreitol (DTT). In cytosol besides glutaredoxin, another enzyme with DHAR activity is also present. In our study, the cytosolic DHAR activity which consisted both enzymes, was also inhibited by ONOO-, but DTT was able to return the activity almost completely.
Metal-induced hormesis requires cPKC dependent glucose transport and lowered respiration
Authors: Damelin L H , Alexander J J
Published: April 2003

Previously, cytotoxicity studies using an 3-(4,5 dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide (MTT)based in vitro toxicity assay found that low concentrations of mercuric, cadmium and cupric chloride (0.7, 1 and 3 μM, respectively) induced hormesis in McCoy cells after 24 h exposure. An investigation of the biochemical events required for the induction of this phenomenon revealed that hormesis was dependent on two simultaneous but independent events, namely, an 11-15% conventional protein kinase C (cPKC)-dependent increase in glucose uptake and a protein synthesis-dependent 19-23% drop in mitochondrial respiration. The inhibition of either event was sufficient to abolish hormesis for all three metal toxicants. Furthermore, an investigation of the energy status of cells prior to and during hormesis revealed an oscillating level of ATP production found to be in phase with mitochondrial respiration, independent of cPKC activated glucose transport and found to coincide with a 16-20% drop in AMP-activated protein kinase activity. These findings suggest that hormesis is not a form of energy compensation but is most likely a reductive burst where an increase in glucose uptake together with a simultaneous reduction in oxygen consumption results in a significant increase in reduction equivalents, which may then be utilized by cells to counteract the effects of oxidative stress induced by heavy metal toxicants.
Factors affecting R6 fungicide toxicity on sea urchin fertilization and early development: Roles of exposure routes and mixture components
Authors: Pagano G , Iaccarino M , De Biase A , Meri S , Warnau M , Oral R , Trieff N M
Published: April 2003

A technical fungicide mixture, R6 and its components, cymoxanil (CYM) and cupric oxychloride (Cu-OCl), were tested by sea urchin bioassays (Paracentrotus lividus and Sphaerechinus granularis). A set of toxicity endpoints was evaluated including both lethal and sublethal effects with the following endpoints: (a) acute embryotoxicity, (b) developmental defects, (c) changes in sperm fertilization success, (d) transmissible damage from sperm to the offspring, and (e) cytogenetic abnormalities. Acute effects on developing embryos were observed as early (prehatch) mortality at R6 levels 25 g/ml. The pesticide mixture R6 was tested at realistic concentrations, ranging from 25 ng/ ml to 2.5 g/ml, and the two components, CYM and CuOCl, were tested, either alone or in mixture, at concentrations equal to their levels in the corresponding R6 solutions. R6 was either dissolved in filtered seawater (water only, W-O), or spiked in ‘‘pristine’’ silt–clay sediment or soil samples before bioassays. Developmental toxicity of R6, following W-O dissolution, displayed a significant dose-related increase of larval malformations and differentiation arrest at concentrations of 750 ng/ml to 2.5 g/ml both in P. lividus and in S. granularis larvae. Developmental toxicity was removed in spiked sediment up to R6 nominal levels (25 g/ml), 10-fold above the embryotoxic R6 levels in W-O exposure. No significant developmental toxicity was exerted by CYM or Cu-OCl (W-O exposure) up to their concentrations equivalent to 2.5 g/ml R6. The laboratory-prepared mixture of CYM and Cu-OCl, in the same concentration range, only resulted in minor effects, as larval retardation, suggesting the presence of toxic impurities (or additional components) in the R6 formulation. When sperm from either P. lividus or S. granularis were exposed to R6 before fertilization, a W-O exposure resulted in a dose-related decrease in fertilization of P. lividus sperm (up to 250 g/ml R6), whereas S. granularis sperm underwent a significant increase of fertilization rate at the highest R6 nominal levels (up to 25 g/ml). Equivalent CYM or Cu-OCl levels were ineffective on sperm fertilization success in both species. The offspring of S. granularis sperm exposed to 25 g/ml R6 showed a significant increase in larval malformations, which were not detected in the offspring of R6-exposed P. lividus sperm. Again, CYM or Cu-OCl was unable to exert any transmissible damage from sperm to the offspring in either species. The present study raises the case of possible discrepancies between toxicity of a technical mixture and of its analytical-grade components, also providing evidence for a loss of pesticide toxicity following dispersion in an environmental matrix such as sediment or soil.
Mechanisms of chromium toxicity, carcinogenicity and allergenicity: Review of the literature from 1985 to 2000
Authors: Dayan A D , Paine A J
Published: April 2003

Laboratory and clinical reports about the pathogenesis of the carcinogenicity and allergenicity of chromium compounds published between 1985 and 2000 have been reviewed as a basis for consideration of the pathogenetic mechanisms involved. There is good evidence from the clinic and the laboratory that Cr[VI] is the ion responsible for most of the toxic actions, although much of the under lying molecular damage may be due to its intracellular reduction to the even more highly reactive and short-lived chemical species Cr[III] and Cr[V]. Exposure to Cr[VI] can result in various point mutations in DNA and to chromosomal damage, as well as to oxidative changes in proteins and to adduct formation. The relative importance of these effects of chromium ions and of the free oxidising radicals they may generate in the body in causing tumours and allergic sensitisation remain to be demonstrated. Biochemical studies of the DNA-damaging effects and of the pathogenesis of the allergic reactions to chromium ions have not kept up with advances in understanding of the molecular basis of the effects of other carcinogens and allergens.
Comments to paper by S. Rattan: applying hormesis in aging research and therapy — a perspective from evolutionary biology
Authors: Hercus M , Loeschcke' V
Published: April 2003

The phenomenon of hormesis is discussed from an evolutionary biology perspective, i.e. in a context of fitness. Some of the evolutionary theories of aging are outlined. The influence of associations between traits and their environmental specificity is highlighted. Questions about consistency of the impact of hormetic agents across life stages are raised and finally the uniformity of definitions across disciplines is shortly discussed.
Experiments, analyses and decisions: hormesis in ecotoxicology
Authors: Bailer A J
Published: April 2003

We have been challenged by Peter Chapman to consider the implication of hormesis for both ecotoxicology and ecological risk assessment. A consideration of his proposal led to the following observations and comments. I echo his comments related to the need for experimental designs and statistical tools that accommodate and address hormesis. I expand on his comments related to the basic question of how adverse responses should be defined for hormetic concentration–response patterns for both individual species and populations. Finally, I reflect on the notion of the implication of incorrectly detecting or not detecting hormesis in an ecosystem.
Neutropenia induced by paraquat poisoning
Authors: Papanikolaou N , Paspatis G , Dermitzakis A , Tzortzakakis E , Charalambous E , Tsatsakis A M
Published: April 2003

Paraquat is a synthetic, nonselective, contact herbicide, which causes injury to tissues following contact. When ingested in sufficient amounts, paraquat has life-threatening effects on the gastrointestinal tract, lungs, kidney, liver, heart and other organs. This is a case report of a 15-year-old girl from an agricultural area who was admitted to hospital for treatment. She presented with dis comfort, nausea and vomiting. She had drunk a small wine glass full of paraquat. After 18 days in the hospital, the girl developed neutropenia. This is the first reported case of paraquat poisoning-induced neutropenia.
Vitamin C ameliorates fluoride-induced embryotoxicity in pregnant rats
Authors: Verma R J , Sherlin D M Guna
Published: April 2003

Oral administration of sodium fluoride (40 mg/kg body weight) from day 6 to 19 of gestation caused, as compared to control, significant reductions in body weight, feed consumption, absolute uterine weight and number of implantations. Significantly higher incidence of skeletal (wavy ribs, 14th rib, <6 sternal centre, dumbell-shaped second and fifth sternebrae, incomplete ossification of skull and thickening of tibia) and visceral (subcutaneous haemorrhage) abnormalities were also observed in NaF-treated dams than that of control. Oral administration of vitamin C (50 mg/kg body weight) and vitamin E (2 mg/0.2 ml olive oil/animal/day) from day 6 to 19 of gestation along with NaF significantly ameliorates NaF-induced reductions in body weight, feed consumption, absolute uterine weight (only with vitamin E treatment) and number of implantations. As compared with NaF-treated alone, the total percentage of skeletal and visceral abnormalities were significantly lowered in fluoride plus vitamin C-treated animals. Vitamin E was less effective. These findings suggest that vitamin C significantly reduced the severity and incidence of fluoride-induced embryotoxicity in rats.
Repeated measurements of aldicarb in blood and urine in a case of nonfatal poisoning
Authors: Tracqui A , Flesch F , Sauder P , Raul J S , Géraut A , Ludes B , Jaeger A
Published: April 2003

A nonfatal case of poisoning involving aldicarb, an extremely toxic carbamate pesticide, is presented. A 39-year-old female ingested an unknown amount of aldicarb, together with alprazolam and sertraline. On admission to ICU (T0), she displayed marked cholinergic symptoms and a deep coma. The patient was given pralidoxime and atropine. Her condition gradually improved on days 2 and 3 and she was discharged at T0+80 h. Aldicarb was assayed by high-performance liquid chromatography on 21 blood and 8 urine samples successively taken during hospitalization. At the same time, serum pseudocholinesterase activity was followed on 21 successive samples. Blood aldicarb level was 3.11 g/mL at T0 and peaked at T0+3.5 h (3.22 g/mL), then followed a two-slope decay with a terminal half-life of ca. 20 h. Aldicarb was detected in all urine samples (peak level: 6.95 g/mL at T0+31.5 h) and was still present at the time of discharge. Serum pseudo-cholinesterase activity remained low (10% of normal) until the 30th hour then rapidly increased and returned to normal after the 60th hour. The patient’s clinical picture closely followed blood aldicarb levels and serum pseudo-cholinesterase activities. To our knowledge, this is the first report of an aldicarb poisoning documented by repeated measurements of the drug in the intoxicated person. Human & Experimental Toxicology (2001) 20, 657–660.
Endocrine changes in patients with acute organophosphate poisoning
Authors: Güven M , Bayram F , Ünlühizarci K , Kelestimur F
Published: April 2003

In critical illness, several drugs and various stressful conditions modify the functions of neurotransmitters which consequently affect the secretion of pituitary hormones. Although the role of neurotransmitters in the regulation of endocrine system is well known, cholinergic actions have been less investigated. In animals, cholinesterase inhibitors were shown to modify the pituitary-thyroid and pituitary-adrenal axes, and to affect prolactin levels. The aim of the present study was to determine the effect of the organophosphate compounds on endocrine system, particularly pituitary hormones. This prospective study was performed in Medical Intensive Care Unit of Erciyes University Medical School Hospital. Twenty-two consecutive patients (ten males and 12 females aged 28+8 years) with organophosphate poisoning were included in the study. ACTH (P50.002), cortisol (P50.0005) and PRL (P50.005) levels were significantly higher during poisoning than after resolution of poisoning. FSH levels were significantly lower during poisoning (P50.05). Sick euthyroid syndrome was determined in seven patients (31.8%). Two of them had low fT3 (with normal fT4 and TSH), two had low fT4 (with normal fT3 and TSH) and three had low TSH (with normal fT3 and fT4) levels. Serum levels of these hormones returned to normal values after resolution of poisoning. The present study demonstrated that organophosphate compounds affected PRL, ACTH and cortisol levels, but did not change LH levels. Organophosphate compounds may result in sick euthyroid syndrome. These conditions may be related to the effects of acetylcholine and direct effect of organophosphate compounds.
Etiological and demographical characteristics of acute adult poisoning in Ankara, Turkey
Authors: Özköse Z , Ayoĝlu F
Published: April 2003

1 The aim of this retrospective study was to evaluate etiological and demographical characteristics of acute adult poisoning patients during 1 year at a university hospital in Ankara, Turkey. 2 Two-hundred and twenty-eight adults (of which 180 were suicidal poisoning cases) were admitted to the emergency center with acute poisonings. This was 0.7% of all emergency admissions. The female-to-male ratio was 3: 1, and the majority of patients (63.6%) were below the age of 25 years. 3 Drugs were the major cause in 75.9% of the cases, followed by inhalation of gases (17.6%), food (2.6%), corrosives (2.2%), pesticides (0.9%), and alcohol (0.9%). Analgesics were the most common cause of drug poisoning (29.7% of all substances). There were no fatalities. 4 It is important to realize that this study is a hospital based study, and hence it may be considered difficult to draw conclusions for the whole population of Turkey. However, we consider that the reason for such a high ratio of analgesic poisoning is probably due to the habit of extensive analgesic prescribing in Ankara, which is thecapitalofTurkey.
Glutathione protection against hydrogen peroxide, tert-butyl hydroperoxide and diamide cytotoxicity in rat hepatoma-derived Fa32 cells
Authors: Dierickx P J , Van Nuffel G , Alvarez I
Published: April 2003

1 Several ozonides, peroxides and aldehydes are formed during ozone therapy, recently introduced in medicine. tert-Butyl hydroperoxide (t-BHP), H2O2 and diamide were investigated as model substrate in rat hepatoma-derived Fa32 cells. 2 The cytotoxicity was measured by the neutral red uptake inhibition assay after 1 h or 24 h treatment. The relative toxicities were quantified by the determination of the NI50. This is the concentration of test compound required to induce an inhibition of 50% in neutral red uptake as compared to the control cells. All test chemicals were more toxic after 24 h than after 1h. 3 The influence of the glutathione (GSH) alteration on the cytotoxicity was measured by treating the cells with 2-oxo-4-thiazolidine carboxylic acid (OTC) or L-buthio-nine sulfoximine (BSO). OTC increased the endogenous GSH content in the cells. BSO pretreatment strongly decreased the NI50 of the three chemicals. OTC pretreatment increased the NI50 of H2O2 but not of t-BHP and diamide. This can be explained by the strong GSH-depletion after 1 h by t-BHP and diamide, which contrasted with a weak GSH-depletion by H2O2 after the same time period. 4 The three test chemicals increased the endogenousGSH content after 24 h. t-BHP and H2O2,butnot diamide, increased the total GSH transferase (GST) activity. Several alterations of the GST subunits were observed. Most striking was the increase of class alpha GST subunits, also for diamide. 5 SinceH2O2 and t-BHP are ozone metabolites thought to be responsible for the therapeutic effects of well-dosed ozone, the results show that Fa32 cells can be used as a valuable alternative model system for studying the effects encountered in human ozone therapy.
Male reproductive toxicity and b-luteinizing hormone gene expression in sexually mature and immature rats exposed to 2-bromopropane
Authors: Wu X , Faqi A S , Yang J , Ding X , Jiang X , Chahoud I
Published: April 2003

1 The reproductive effects of 2-bromopropane (2-BP) in sexually mature and immature male Sprague-Dawley rats were investigated. The animals were randomly divided into three treatment groups and one control group each of which comprised six mature and six immature rats. The treated groups were injected s.c. 200, 600 and 1800 mg/kg of 2-BP on 5 days a week for 5-7 weeks and the control group received the vehicle. 2 The absolute and relative testis weights were significantly reduced in 600 and 1800 mg/kg b.w. dose groups in both mature and immature rats. The absolute epididymis, prostate, seminal vesicle, and pituitary weights and the relative epididymis weights, however, were significant only at the highest dose level used in both mature and immature rats. 3 The sperm concentration and sperm viability in epididymal duct decreased and the percentage of abnormal sperm increased in a dose-dependent manner in both mature and immature rats. Additionally, serum testosterone level was significantly decreased in all dose groups in mature rats, and was significantly reduced only in the group treated with the middle and highest dose in immature rats. 4 In both mature and immature rats treated with 200 and 600 mg/kg, the seminiferous tubules were atrophied and all types of germ cells were decreased in number. At the highest dose level, the effect was more marked showing severely atrophied seminiferous tubules and a complete loss of all types of germ cells. 5 The mating, pregnancy and fertility indices were significantly reduced in the 600 and 1800 mg/kg groups. Additionally, at the highest dose group the number of implantations and viable fetuses per litter were reduced and the resorption rate was increased significantly. 6 In the mature rats, the b-LH gene expression increased significantly in the 1800 mg/kg group when compared to the control group. 7 It can be concluded that 2-BP induces alterations in both neuro-endocrine axis and the reproductive tract under the present experimental conditions. The no observed adverse effect level (NOAEL) in this study could be estimated to be lower than 200 mg/kg/b.w. based on the alteration in testicular morphology as well as on sperm parameters observed at the dose level of 200 mg/kg.
The effect of perfluoroisobutene and phosgene on rat lavage fluid surfactant phospholipids
Authors: Jugg B , Jenner J , Rice P
Published: April 2003

1 This study investigated whether the reactive organohalogen gases perfluoroisobutene (PFIB) and phosgene, which cause death by overwhelming pulmonary oedema, affect the surfactant system or type II pneumocytes of rat lung. 2 The progression and type of pulmonary injury in Porton Wistar-derived rats was monitored over a 48 h period following exposure to either PFIB or phosgene (LCt30) by analyzing the inflammatory cells and protein in bronchoalveolar lavage fluid. Six rat lung phospholipids were measured by high-performance liquid chromatography, following solid phase extraction from lavage fluid. 3 Alterations in the cell population and lung permeability occurred following both gases, indicating that the injury was a permeability-type pulmonary oedema. Changes in the total amount of phospholipid and in the percentage composition of the surfactant were different for the two gases. PFIB produced increases in phosphatidylglycerol and phosphatidylcholine over the first hour, similar to that seen following air exposure, followed by substantial decreases in these phospholipids. Phosgene caused late increases in all phospholipids from 6 h post-exposure. 4 Differences in the response of the surfactant system to exposure to PFIB and phosgene suggest different mechanisms of action at the alveolar surface although the final injurious response is pulmonary oedema for both gases.