bluuebunny/crossref_metadata_2025_split huggingface dataset:
Review of the Safety Assessment of Polychlorinated Biphenyls (PCBs) with Particular Reference to Reproductive Toxicity
Authors: Battershill Jon M. 
Published: December 2008

1 The methods used to evaluate the toxicological effects of PCBs in animals have been reviewed. 2 The data show that Toxic Equivalency Factors (TEFs) could be developed to assess the potential toxicity of PCB mixtures for certain specific target organ effects (such as the liver and immune system) but would be inappropriate for other effects (e.g. thyroid function and neurochemical effects). More data on a wider range of individual PCB congeners and a method for systematically balancing toxicodynamic and toxicokinetic data are required before the TEF approach can be fully evaluated. 3 With the exception of the teratogenic effects seen in mice and the anti-oestrogenic effects reported in in vitro studies, there are insufficient data on individual PCB congeners to evaluate the structure-activity relationships for the effects of PCBs on reproduction. The data also show that individual PCBs may have opposing effects on a particular aspect of reproduction (for example individual PCB congeners may have either oestrogenic or anti-oestrogenic effects). Studies with individual PCB congeners have shown both enhancement and antagonism of the teratogenic effects of 2,3,7,8-tetrachloro dibenzo-p-dioxin (TCDD) in the mouse. It is not possible to use TEFs to evaluate the reproductive effects of PCBs. 4 The mechanism(s) responsible for the effects of PCBs on postnatal neurobehavioural development in rodents and monkeys have not been elucidated. At least two groups of PCBs which might be responsible for the observed effects have been identified in this review, one affecting the dopaminergic system and the other group affecting thyroid hormone levels. Considerably more research would be required before the TEF approach could be applied to the effects of PCBs on postnatal neurobehavioural development. This would include research on an appropriate animal model to determine whether the critical toxicological mechanism is mediated through the Ah receptor. 5 The reproductive toxicity of complex PCB mixtures such as those found in foods will depend on the identities and relative proportions of individual PCB congeners in the mixture. It is not possible to give an accurate estimate of a NOAEL or LOAEL from the reproduction studies using commercial PCB mixtures which could be readily applied to the safety assessment of PCBs present as contaminants in food. 6 It is concluded that the data presented in this paper support the hypothesis that there is no satisfactory method derived from the available studies in laboratory animals for evaluating the potential risk of adverse effects on reproduction posed by contamination of foods with PCBs.
Elimination of Antipyrine and its Metabolites in Interferon Treated Hepatitis C
Authors: Sieck Jens O. , El-Yazigi Adnan , Ali Hatim , Døssing Martin , Saour Jalal , Raines Dale A. , Ernst Peter 
Published: December 2008

1 To study the effect of interferon on hepatic drug metabolism in chronic hepatitis C, we examined nine patients before and at the end of 6 months of interferon treatment. 2 Routine liver function was determined together with the salivary clearance of antipyrine and the 48 h urinary excretion of the main metabolites of antipyrine: 4-hydroxyantipyrine, 3-hydroxymethylantipyrine and norantipyrine before and after 6 months of interferon treatment. 3 Liver pathology, routine liver function, and antipyrine metabolism remained unchanged after patients were treated for 6 months with interferon for a histologically advanced but clinically compensated chronic hepatitis C.
Development of a Rabbit Model to Investigate the Effects of Acute Nitrogen Dioxide Intoxication
Authors: Meulenbelt J. , van Bree L. , Dormans J.A.M.A. , Boink A.B.T.J. , Sangster B. 
Published: December 2008

1 In previous studies a rat inhalation model was developed to investigate the effects of intervention after acute NO2 exposure. The object of the present study was to investigate whether acute NO2 intoxication induced comparable effects in rabbits as it does in rats. Where the effects of intervention in both species are similar, then the conclusions drawn from these studies may have more relevance for the treatment of man. 2 Biochemical variables in bronchoalveolar lavage and supernatant from lung homogenate, which may be relevant for the evaluation of lung injury and repair, were investigated and compared with histology. 3 After NO 2 exposure for 10 min, the pulmonary effects observed became more pronounced with increasing NO2 concentrations (0, 125, 175, 250, 400, 600 or 800 ppm) [1 ppm NO2 is 1.88 mg m-3]. The effects in rabbits were found to be broadly comparable with those in rats. 4 To achieve severe lung injury in rabbits without mortality, enabling investigations of the effects of intervention over several days, exposure to a NO2 concentration of 600 ppm for 10 min was most appropriate, while a concentration of 175 ppm NO2 was needed to attain comparable effects in rats. 5 The repair phase starts later, namely at 3 days after exposure in rats, compared to 5 days in rabbits.
Evaluation of the Genetic Toxicity of the Peroxisome Proliferator and Carcinogen Methyl Clofenapate, Including Assays Usin Muta TM Mouse and Big Blue™ Transgenic Mice
Authors: Lefevre P.A. , Tinwell H. , Galloway S.M. , Hill R. , Mackay J.M. , Elcombe C.R. , Foster J. , Randall V. , Callander R.D. , Ashby J. 
Published: December 2008

The rodent liver carcinogen and hepatic peroxisome proliferator methylclofenapate (MCP) has been evaluated for genetic toxicity in a range of in vitro and rodent genotoxicity assays. It gave a negative response in each of the following assays: mutagenicity to S.typhimurium and E.coli (± S9 mix, plate and pre-incubation assays), clastogenicity to cultured human lymphocytes and CHO cells (± S9 mix), a mouse bone marrow micronucleus assay (24h and 48h sampling), a rat liver assay for UDS in vivo (12h sampling), assays for lac I (Big Blue™) and lac Z (Muta™ Mouse) mutations in the liver of transgenic mice, and an assay of the ability of MCP to modify the mutagenicity to the liver of dimethylnitrosamine in both transgenic mutation assays. The micronucleus and UDS assays were conducted using a single administration of MCP at its maximum tolerated dose, while the transgenic assays were conducted using nine daily administrations of MCP at its cancer bioassay dose level. These nine daily administrations were shown to double the weight of the liver of non-transgenic, Big Blue™ and Muta™ Mice, as well as leading to a dramatic proliferation of peroxisomes (electron microscopy) in the livers of each strain. These changed parameters had returned to control levels when the mutation analyses were conducted (10 days after the final dose of MCP). Despite the liver enlargement observed following MCP administration, no evidence of mitotic activity was observed in treated livers, although an increased number of cells were undergoing replicative DNA synthesis during the final 3 days of the 9 days of administration (BUdR assessment of S-phase). Liver biochemistry parameters (ALT, AST, AP, CK, GGT and albumin) were unaffected by the chronic (9 day) administration of MCP indicating an absence of hepatic toxicity, These combined observations favour a non-genotoxic mechanism of action for the hepatic carcinogenicity of MCP. The clastogenicity in vitro of the peroxisome proliferator Wyeth 14,643 has been confirmed in CHO cells, but it is noted that this chemical is more soluble than is MCP. In particular, at the highest dose level at which MCP could be tested, Wy 14,643 was also nonclastogenic.
Metabolic basis for high paracetamol dosage without hepatic injury: a case study
Authors: Tredger J. Michael , Thuluvath Paul , Williams Roger , Murray-Lyon Iain M. 
Published: December 2008

1 Studies of paracetamol metabolism were performed in a 58-year-old female with rheumatoid arthritis who had consumed 15-20 g paracetamol daily for 5 years with out developing liver damage and data were compared with results in seven normal volunteers.2 After a test dose of 2 g paracetamol, the formation of paracetamol sulphate and glucuronide conjugates detected in plasma from the patient was delayed by around 2 h relative to values in normal volunteers and the proportion of sulphate conjugates excreted in urine was 1.5 to 2 times those in normal volunteers (52% vs 26-35% of dose, respectively). The fractional metabolite clearance of paracetamol to glutathione-derived conju gates (0.28 ml min-1kg-1) in our patient was > 30% lower than in normal females.3 A combination of slow paracetamol absorption, enhanced detoxication of paracetamol (by sulphation) and reduced metabolism to potentially cytotoxic metabolites may have reduced the risk of liver damage in this patient. The latter may have reflected pharmaco- genetic deficiencies in cytochrome P450 isoenzymes per sisting despite chronic alcohol consumption (40—60 g per day) or resulted from inhibition of paracetamol acti vation by concomitant ingestion of aminophylline.
Accumulation of hexachlorobenzene in humans: a long standing risk
Authors: To-Figueras J. , Barrot C. , Rodamilans M. , Gómez-Catalán J. , Torra M. , Brunet M. , Sabater F. , Corbella J. 
Published: December 2008

1 Hexachlorobenzene (HCB) internal dose in the general population of Barcelona (Spain) was estimated after new indications of the carcinogenicity of this chemical in humans were recently reported. Hospital blood bank facilities and randomly selected volunteers were used for HCB analyses in serum ( n=100) and cerumen ( n=25). Other main organochlorine residues often found in human tissues and blood (pp'DDE, β-HCH,) were also determined. 2 HCB serum levels currently found (Range 0.7-19.7 ng ml-1; X ± s.d.: 4.13 ± 3.61; GM: 3.05) were compared to those found in a similar survey made in 1986 on the same population. The serum HCB levels showed a sig nificant decrease ( P<0.001) when compared to the for mer results and correlated with age ( P<0.001) suggest ing a progressive preponderance of a stable blood-adi pose equilibrium with fewer variations due to recent and variable intake of the chemical. 3 Cerumen analyses revealed detectable concentrations of HCB in all samples (Range: 160-4790 ng g -1 in extractable lipid basis) and confirmed the suitability of this matrix to assess the body burden of residues accumulated in adipose and lipid-rich tissues. The set of results shows that, although HCB exposure has been reduced, the overall population under study still accumulates significant amounts of this possible car cinogen.
Lead poisoning from Asian traditional remedies in the West Midlands - report of a series of five cases
Authors: Bayly G.R. , Braithwaite R.A. , Sheehan T.M.T. , Dyer N.H. , Grimley C. , Ferner R.E. 
Published: December 2008

1 Traditional remedies are an unusual, but recognised cause of lead poisoning. Only two cases have previously been reported in this country. 2 We report a series of five cases of lead poisoning due to traditional remedies in the West Midlands. All devel oped typical clinical features. 3 Blood lead and zinc protoporphyrin (ZPP) concentra tions were elevated 2-10 times the upper limit of nor mal. The remedies contained up to 60% lead by weight. One also contained traces of mercury, another arsenic, and a third aluminium and tin. 4 Confirmation of the medicines as the cause of the poi soning was made in one patient by measurement of lead isotopic ratios. 5 The present morbidity from traditional remedies may be far greater than is realised, and will continue until such time as the supply of harmful preparations can be effec tively limited. There needs to be increased awareness of their dangers amongst doctors and the communities at risk. This will best be achieved by appropriately targeted education.
The risk of aspiration in Dettol poisoning: a retrospective cohort study
Authors: Chan Thomas Y.K. , Critchley Julian A.J.H. , Lau Joseph T.F. 
Published: December 2008

1 To determine if the risk of aspiration is increased in 'Dettol' (4.8% chloroxylenol, pine oil and isopropyl alco hol) poisoning and the factors that may be responsible, a study was made of 89 patients and 89 matched control subjects with other forms of poisoning admitted to the Prince of Wales Hospital, Hong Kong. 2 Aspiration was more common in patients with Dettol poisoning (8% vs 3%, P = 0.16). There were more control subjects with drowsiness at presentation (54% vs 24%, P < 0.0001), but the use of gastric lavage (88% vs 64%, P < 0.001) and the occurrence of vomiting (62% vs 17%, P < 0.0001) were more common in patients with Dettol poisoning. 3 Our findings suggest that Dettol poisoning may be asso ciated with an increased risk of aspiration. This increase in risk may be related to the use of gastric lavage and the common occurrence of vomiting in patients with Dettol poisoning.
Blood lead levels in North Carolina painters
Authors: Ennever Fanny K , Zaccaro Daniel J , Fernando Reshan A , Jones Bradley T 
Published: December 2008

1 Blood lead levels were examined in 127 housepainters in North Carolina between April and September, 1993. Each participant filled out a questionnaire and gave a blood sample. The questionnaire covered the individual's work history, concentrating on paint-removal activities and personal protection, and also covered potential non- occupational sources of lead exposure. Blood samples were analysed for lead content using atomic absorption spectroscopy. 2 The geometric mean blood lead level was 0.33 μmol L-1 (6.8 jg dL-1). No blood lead samples were found to exceed the occupational standard of 1.93 μmol L-1 (40 μg dL-1). The three highest samples had levels between 0.97 and 1.45 μmol L-1 (20 and 30 μg dL-1); this represented 2.4% of the study sample. 3 No statistical association was found between blood lead levels in these painters and their painting activities, including using dust masks for personal protection. 4 Current painting practices in this group of North Carolina painters do not appear to elevate blood lead lev els above the occupational standard.
Renal filtration and excretion of aluminium in the rat: dose-response relationships and effects of aluminium speciation
Authors: Lote CJ , Wood JA , Thewles A. , Freeman M. 
Published: December 2008

The known toxicity of aluminium, and the toxicity of agents (such as desferrioxamine) used to remove alumini um from the body, has prompted us to investigate whether there may be ways of enhancing aluminium excretion by exploiting the normal renal handling of aluminium. Aluminium (as sulphate or citrate) was administered intravenously to conscious rats at doses ranging from 25 μg (0.93 μmol) to 800 μg (29.6 μmol) aluminium, and alu minium excretion was monitored over the following 2 h. Measurements of the filterability of aluminium from the rat plasma, and the glomerular filtration rate (inulin clearance), enabled us to calculate the filtered load of alu minium, and hence determine aluminium reabsorption. At all doses of administered aluminium, that adminis tered as sulphate was excreted less effectively than that administered as citrate. This difference was attributable to the much greater filterability of aluminium administered as citrate. However, for any given filtered load, the excre tion of aluminium administered as citrate was not signifi cantly different (in either fractional or absolute terms) from the excretion of aluminium administered as sulphate. It seems likely that, following aluminium sulphate administration, the filtered aluminium may be an alumini um citrate form which is then reabsorbed in the same way as aluminium administered as citrate. It is thus apparent that aluminium removal from the body could be further enhanced if it were possible to pre vent the tubular reabsorption of the aluminium species which is so effectively filtered following aluminium citrate administration.
Evaluation of the generation of genotoxic and cytotoxic metabolites of benzo[a]pyrene, aflatoxin B1, naphthalene and tamoxifen using human liver microsomes and human lymphocytes
Authors: Wilson AS , Tingle MD , Kelly MD , Park BK 
Published: December 2008

1 The ability of model stable epoxides and metabolites generated by human liver microsomes from benzo[a]pyrene, aflatoxin B1, naphthalene and tamoxifen to produce cytotoxicity and genotoxicity in human periph eral lymphocytes has been investigated.2 The stable epoxides 1,1,1 trichloropropene-2,3-oxide (100μM) and trans stilbene oxide (100μM) as well as metabolites generated from aflatoxin B1(30μM) and naph thalene (100μM) by an extracellular metabolising system were toxic to isolated resting mononuclear leucocytes (MNLs), whereas glycidol (100μM), benzo[a]pyrene (100μM) and tamoxifen (50μM) were not.3 The stable epoxides 1,1,1 trichloropropene-2,3-oxide (100μM) and trans stilbene oxide (100μM) but not glycidol (100μM) were toxic to dividing lymphocytes only after a 72-h exposure. Tamoxifen (30μM), aflatoxin B1(30μM) and their metabolites were also toxic to dividing lymphocytes. Benzo[a]pyrene (100μM) and naphthalene (100/μM) were not toxic either in the absence or presence of the extracel lular metabolising system.4 Benzo[a]pyrene (100/μM) and aflatoxin B1(30μM) were directly genotoxic to lymphocytes, this genotoxicity was significantly enhanced by the presence of the extracellular metabolising system. This indicates that both intracellular and extracellular bioactivation of these two compounds can produce genotoxicity. In contrast, naphthalene and tamoxifen were non-genotoxic.
Glucocorticoid amelioration of nephrotoxicity: a study of cephaloridine- methylprednisolone interaction in the rat
Authors: Harvey PW , Healing G. , Major IR , McFarlane M. , Purdy KA , Olatunde O. , Garcia Conesa MT , Everett DJ , Cockburn A. 
Published: December 2008

Groups of ten male rats were treated with a high challenge dose of cephaloridine (CPH, 3750 mg kg -1), with methyl prednisolone (MP, 100 mg kg-1) or with cephaloridine and methylprednisolone (CPH + MP) by single subcutaneous injection. A control group received the injection vehicles only. Urine was collected from all animals daily over 18-h collection periods, up to 96 h after treatment. Blood was collected at 24, 48, 72 and 96 h after treatment. At necrop sy, kidneys were weighed, processed and examined histopathologically. Results show that methylprednisolone significantly ameliorated the nephrotoxicity of the challenge dose of cephaloridine. CPH-only treated rats had severe toxic nephrosis characterised by acute tubular necrosis, and elevated blood urea and creatinine. By contrast, the major ity of CPH + MP treated rats had only a slight or moderate toxic nephrosis, and had lower blood urea and creatinine levels compared with rats treated with CPH only, indicat ing preservation of kidney function. Interestingly, rats treated with CPH + MP had higher urinary enzymes (alka line phosphatase, lactate dehydrogenase, gamma glu tamyltransferase and N-acetyl-B-glucosaminidase) as well as protein and glucose, compared with rats treated with CPH only. This is taken to indicate that rats treated with CPH only had such marked kidney damage and necrosis that the population of cells able to produce these marker enzymes was significantly and rapidly depleted, but the protection afforded by methylprednisolone allowed CPH + MP treated rats to sustain urinary enzyme output. Effects on urinary glucose and other parameters such as body weight and kidney weight demonstrate interactions between glucocorticoid pharmacology and cephaloridine nephrotoxicity. Finally, the significance of these findings is discussed in terms of a generic mechanism of protection conferred by glucocorticoids in certain types of nephrotox icity and related to similar findings in rats treated intra venously with cisplatin, an anti-neoplastic agent for which the clinical utility in man is often limited by adverse effects on the kidney.
A review of drug-induced Leydig cell hyperplasia and neoplasia in the rat and some comparisons with man
Authors: Prentice DE , Meikle AW 
Published: December 2008

This paper describes control of normal Leydig cell func tion and testosterone production. The macroscopic and histopathological appearances of spontaneous Leydig cell hyperplasias and tumors (LCT) in the rat are reviewed together with their incidence and hormonal status. Drugs which induce LCTs in chronic studies are discussed and include busereline, carbamazepine, cimetidine, finas teride, flutamide, gemfibrozil, histrelin, hydralazine, indomethacin, isradipine, lactitol, leuprolide, metronida zole, mesulergine, nafarelin, norprolac and vidarabine. The known mechanisms of LCT induction in the rat are reviewed together with other possible etiological factors. The incidence, clinical picture and etiological factors of LCTs in man are also surveyed. Hormone production in Leydig cells and LCTs in rats and man are compared. Differences between the two species are considered, par ticularly with regard to Leydig cell control mechanisms. The paper concludes that drug-induced LCTs in rats are most probably not predictive for man and their occurrence has little relevance in human safety assessment.
The generation of a human dermal equivalent to assess the potential contribution of human dermal fibroblasts to the sulphur mustard-induced vesication response
Authors: Lindsay CD , Upshall DG 
Published: December 2008

1 A human dermal equivalent (HDE) gel was constructed from rat tail tendon collagen (type 1) and human dermal fibroblasts (HFs). Histological studies revealed that the HFs within the HDE gel matrix assumed the shape of differentiated dermal fibroblasts and were metabolically viable as determined by the MTT assay. 2 The HDE system was developed to determine if viable, differentiated HFs have the potential to contribute to tis sue damage by releasing the proteolytic enzyme elastase following exposure to sulphur mustard (HD). Elastase was measured, using the substrate suc-ala-ala-val-p- nitroanilide (SAAVNA), because of its association with various human pathological bullous skin diseases. An additional elastase substrate (suc-ala-ala-ala-p- nitroanilide ; SAAANA) was also used. A miniaturised assay was employed to measure lactate dehydrogenase (LDH), a cytosolic enzyme released following damage to the cell membrane. 3 Elastase levels (measured with SAAVNA) increased to over 740% of those in control culture medium at 24 h after exposure of the HDE to HD (2 mM) and may there fore be part of the mechanism associated with dermo- epidermal separation and blistering in humans follow ing exposure of skin to HD. LDH was released from the HDE after exposure to HD in a time dependent fashion, suggesting a steady leakage of cytosolic constituents after the initial exposure. 4 The results suggest that differentiated human dermal fibroblasts have the potential to contribute to the devel opment of the vesication response by releasing proteases such as elastase extracellularly after HD exposure. These types of studies cannot be conducted in humans on ethical grounds because of the mutagenic properties of HD. The HDE model therefore has an important advantage in studies on the mechanism of action of HD.