bluuebunny/crossref_metadata_2025 huggingface dataset:
Therapeutic efficacy of sodium nitrite and 4-dimethylaminophenol or hydroxylamine co-administration against cyanide poisoning in rats
Authors: Bhattacharya R.
Published: December 2008

1 The therapeutic efficacy of combined treatment of sodium nitrite (NaNO2) and 4-dimethylaminophenol (DMAP) or hydroxylamine (H2NOH) was investigated in potassium cyanide (KCN) intoxication in male rats.

2 Therapy with NaNO2(0.27 mmol kg-1) + DMAP (0.09 mmol kg-1) or NaNO2+ H2NOH (0.09 mmol kg-1, produced a protection index (ratio of LD50of KCN in rats receiving therapy to an LD50of KCN in rats given only 0.9% saline) of 2.5 and 2.0 respectively.

3 Both the regimens exhibited a beneficial effect in terms of improving the survival time and postural defects in rats exposed to 2 LD50KCN.

4 NaNO2+ DMAP showed a significant protective effect in the disposition of the plasma cyanide level at different time intervals.

5 The NaNO2+ DMAP regimen was superior to NaNO2+ H2NOH in terms of reactivating the inhibited brain cytochrome oxidase enzyme.

6 The addition of sodium thiosulphate (Na2S2O3) in both the regimens increased the degree of protection.

7 The results suggest that combined therapy with NaNO2+ DMAP could significantly reduce the toxic effects of cyanide, compared with NaNO2+H2NOH treatment.
High performance liquid chromatography with ultraviolet detection used for laboratory routine determination of fluvoxamine in human plasma
Authors: Belmadani A. , Combourieu I. , Bonini M. , Creppy E.E.
Published: December 2008

Fluvoxamine is an antidepressant drug introduced into the clinic in 1986. It acts by selectively inhibiting neuronal serotonin recapture. It can be quantified by several meth ods, including high performance liquid chromatography. The HPLC method used so far needs special equipment and has poor sensitivity. The technique is difficult and time consuming. An easier, quicker and more sensitive HPLC assay for the routine determination of fluvoxamine in human plasma has therefore been developed.

After alkalinisation and direct extraction by a mixture of n-hexane-isoamylic alcohol 985: 15 (v/v) of plasma samples, the organic phases were further extracted by HCl 0.1 N.

Thirty μL of the final extract (with loxapine as internal standard) were injected directly into a C-8 column with a mobile phase consisting of 370 mL acetonitrile, 0.4 mL diethylamine, 630 mL of distilled water, 25 mL pic B5. UV detection at 254 nm was used.

The whole process was completed in 40 min. The detec tion limit was 10 ng mL-1. No interference was found either with several benzodiazepines or with antidepres sant drugs commonly associated during treatments.
Preliminary in vitro investigation into the use of alkaline elution assay for the biomonitoring of humans exposed to genotoxic agents
Authors: Leroy Therese , Lison Dominique , Lauwerys Robert
Published: December 2008

1 This in vitro study was undertaken as a preliminary approach before assessing whether the alkaline elution assay can be applied to peripheral blood lymphocytes (PBL) for the monitoring of humans exposed to genotoxic agents such as polycyclic aromatic hydrocarbons (PAH). We have compared in vitro, with the aid of the alkaline elution assay, the formation and the repair of DNA single- strand breaks (ssb) induced by different genotoxic agents [gamma-irradiation, ethyl methanesulfonate (EMS), benzopyrene diol epoxide (BPDE)] on quiescent and PHA-stimulated human lymphocytes and on a fibroblast cell line.

2 Gamma-irradiation (4 Gy) induced an equivalent amount of DNA ssb in the three cell types. On the other hand, after treatment with EMS (10mM) and BPDE (50μM), a higher production of DNA ssb was observed in replicat ing cells (PHA-stimulated lymphocytes and fibroblasts) when compared with quiescent lymphocytes.

3 After gamma-irradiation, all cell types repaired more than 65% of ssb within 1 h. After treatment with EMS, we noted a deficient DNA repair capacity in quiescent lym phocytes in comparison with replicating cells. In all cell types treated with BPDE, more breaks were observed after a 2 h repair period than immediately after treatment, demonstrating the involvement of a slow repair mecha nism after BPDE treatment.

4 Several conclusions can be drawn from this pilot study, (i) when assessing in vitro the induction and the repair of DNA lesions induced by chemicals, it seems rea sonable to test both non-replicating and replicating cells since their response may be different; (ii) in view of the relative persistence of DNA damage induced in vitro by BPDE in resting lymphocytes, chronic exposure to PAH could give rise to a certain accumulation of DNA damage in coke oven workers lymphocytes. Further studies will be necessary to determine whether these damages could be detected by alkaline elution.
Decorporation of thorium-228 from the rat by 3,4,3-LIHOPO and DTPA after simulated wound contamination
Authors: Stradling G.N. , Gray S.A. , Pearce M.J. , Wilson I. , Moody J.C. , Burgada R. , Durbin P.W. , Raymond K.N.
Published: December 2008

1 With DTPA as a comparison, the siderophore analogue 3,4,3-LIHOPO has been examined for its ability to remove 228Th nitrate from the rat after subcutaneous (sc) and intramuscular (im) injection to simulate wound contamination. The commencement of treat ment was delayed 30 min, 6 h or 1 d and the animals killed at 7 d.

2 In all cases 3,4,3-LIHOPO was appreciably more effec tive than DTPA although the efficacy of treatment and the relative effectiveness of the ligands decreased rapidly with their delay in administration.

3 Optimum removal with both ligands occurred when initial local administration at 30 min after exposure was followed by repeated intraperitoneal injection at 6 h, 1, 2 and 3 d. Under these conditions the body con tent of 228Th was reduced to 20% of controls after sc injection and 15% after im injection. The correspond ing values using repeated DTPA administration were 80% and 54%.

4 It is concluded that 3,4,3-LIHOPO represents, poten tially, a considerable advance on DTPA, the current agent of choice for the treatment of wounds contami nated by 228Th.
Setting air quality standards for carcinogens: an alternative to mathematical quantitative risk assessment — discussion paper
Authors: Maynard R.L. , Cameron K.M. , Fielder R. , McDonald A. , Wadge A.
Published: December 2008

1 It has been accepted in many countries that the regula tion of ambient air quality should involve the use of health-based air quality standards.

2 Setting standards for air pollutants which are genotox ic carcinogens presents difficult problems to the regu lator, in that the prediction of the effects on health of low levels of exposure is suspected to be inaccurate, and is not presently amenable to either experimental or epidemiological verification.

3 In some countries, techniques of Mathematical Quantitative Risk Assessment (MQRA) have been adopted to calculate acceptable levels of exposure to, or the unit risk factors for, genotoxic carcinogens. We regard these approaches as unsatisfactory.

4 An alternative approach, based upon a number of argued premises, a strategy which identifies decision points and the cautious application of uncertainty fac tors, is described.
Effects of variation in detoxification rate on dose monitoring through adducts
Authors: Föst U. , Törnqvist M. , Leutbecher M. , Granath F. , Hallier E. , Ehrenberg L.
Published: December 2008

1 Föst et al. ( Human & Experimental Toxicology 1991; 10: 25) have shown that ethylene oxide (EO) added to human blood gave rise to a higher level of adducts to haemoglobin (Hb) when the donors were deficient in an erythrocytic glutathione S-transferase (GST, later found to be GST-theta) than in blood from persons pos sessing this enzyme, and drew the conclusion that this polymorphism in detoxification rendered Hb adducts less suitable for biological monitoring.

2 By fitting a kinetic model to the data, the present study shows that the Hb adduct level gives a correct measure of the dose (concentration integrated over time) rele vant to risk estimation.

3 It does illustrate, however, the importance of knowing an individual's detoxification efficiency, when Hb adduct measurements are used to assess environmen tal exposure, for example in occupational surveillance.
A stepwise procedure for evaluating irritant materials in normal volunteer subjects
Authors: Dykes P.J. , Black D.R. , York M. , Dickens A.D. , Marks R.
Published: December 2008

1 The cutaneous response to a known irritant has been assessed in human volunteer subjects using both clini cal scoring and two non-invasive instrumental meth ods ; erythema measurement using an erythema meter and capillary blood flow using a laser Doppler device.

2 Aqueous solutions (0.5% and 1%) of sodium hydroxide were applied to back skin for 3, 15 and 60 min with assessments immediately after removal and at 1, 24 and 48 hours.

3 Increased erythema was seen with increasing duration of exposure and an increase was also seen at 1 h, 24 h and 48 h after removal of the patch. The results obtained with the erythema meter paralleled the clini cal erythema scores. However, the laser Doppler device showed the greatest changes immediately after removal of the patch with subsequent readings show ing a gradual decrease.

4 Statistical analysis of the data has been carried out to determine the accuracy and precision of the assess ment procedures and to determine the minimum test panel size for detecting irritant reactions.

5 Comparison between back and forearm skin indicated a greater sensitivity to sodium hydroxide on the back.

6 The results of this study define an ethical approach to testing irritant materials in human subjects and pro vide the basis for the development of a classification system for cutaneous irritants.
Persistence of sodium monofluoroacetate in rabbits and risk to non-target species
Authors: Gooneratne S.R. , Eason C.T. , Dickson C.J. , Fitzgerald H. , Wright G.
Published: December 2008

1 Sodium monofluoroacetate (1080), a vertebrate pesti cide used in New Zealand, was administered orally to rabbits at two dose levels (sub-lethal and lethal) to determine how long 1080 would persist in plasma, liver, kidney, and muscle so that the risk of consump tion of meat from lethally or sub-lethally poisoned rab bits by non-target species could be assessed.

2 The plasma elimination half-life in rabbits receiving a sub-lethal dose was 1.1 h. Retention of 1080 in tissue was greater in rabbits dosed with a lethal dose than in those that received a sub-lethal dose. Irrespective of the dose level, concentration of 1080 in muscle, kidney, and liver was substantially lower than in the plasma.

3 Poisoning of dogs is possible because of their extreme susceptibility to 1080. Poisoning of birds is less likely. The risk of secondary poisoning is reduced as the con centration of 1080 declines in putrefying carcasses.
A comparison of the acute pathology induced by 3-phenylamino-1,2-propanediol (PAP) and its mono-oleoyl ester in rodents with the toxic oil syndrome in man
Authors: Carthew P. , Edwards R.E. , Dorman B.M. , Verschoyle R.D.
Published: December 2008

Phenylamino-1,2 propanediol (PAP) and its mono-oleoyl ester have been identified in samples of the cooking oil thought to be responsible for the Toxic Oil Syndrome (TOS) which occurred in Spain in 1981. The acute toxicity of PAP and its mono-oleoyl ester have been examined in rats and mice, after daily administration for periods of up to 14 days to determine whether these compounds could produce any of the pathologies of TOS. Even at the highest dose, the 1-mono-oleoyl ester of 3-phenylamino-1,2 propanediol did not cause any toxicity in rats or mice when given intraperitoneally. 3-Phenylamino-1,2 propane diol, however, was toxic when administered to rats by this route. After 6-10 consecutive daily doses of PAP, at the highest dose administered (350 mg kg-1), all of the rats became unwell. Postmortem examination showed that the major pathology present was massive pulmonary throm boembolism. Further investigations of the toxicity of PAP after intravenous administration showed that it was not directly vasotoxic. The pulmonary thromboembolism seen with intraperitoneally administered PAP was due to the toxic effect of PAP on the mesenteric tissue and blood ves sels, causing thrombosis which subsequently embolised the blood vessels in the lung. Intra-gastric administration of PAP caused no toxicity in rats. Comparatively, the pathology seen after intraperitoneal administration of PAP was not thought to be representative of the pathology of the toxic oil syndrome in man.
Superoxide radical and toxicity of environmental nickel exposure
Authors: Novelli Elb , Rodrigues NL , Ribas BO
Published: December 2008

Three nickel compounds were tested for pancreatic, hepatic and osteogenic damage in rats by a single i.m. injection Ni++ (7 mg kg-1). The nickel induced biochemical alterations included significantly increased levels of serum alkaline phosphatase in rats with NiS (75%) and NiO (50%). Amylase and aspartate transaminase were also increased, and lipoperoxide was increased in rats with NiO (5.6-fold) and NiS (3.4-fold). No serum changes were observed with NiCl 2. Daily injection of Cu-Zn superoxide dismutase (SOD) conjugated with polyethylene glycol pre vented the serum level changes, indicating that superoxide radical is an important intermediate in toxicity of nickel insoluble compounds.
In vitro and in vivo percutaneous absorption of 14C-chloroform in humans
Authors: Dick D. , Ng Kme , Sauder DN , Chu I.
Published: December 2008

Chloroform has been found in potable water and there is concern that significant dermal absorption may arise from daily bathing and other activities. The present study examines percutaneous absorption of 14C-chloroform in vivo using human volunteers and in vitro using fresh, excised human skin in a flow-through diffusion cell sys tem. Fifty microlitre doses of either 1000 μg ml-1 chloro form in distilled water, (16.1 μg cm-2) or 5000 μg ml-1 of chloroform in ethanol, (80.6 μg cm-1) were applied to the forearm of volunteers with exhaled air and urine being collected for analysis. Single doses of either 0.4 μg ml-1 chloroform in distilled water (low dose, 0.62 μg cm-2, 1.0 ml dosed) or 900 μg ml-1 chloroform in distilled water (high dose, 70.3 μg cm -2, 50 μl dosed) were applied to discs of the excised abdominal skin placed in flow-through dif fusion cells and perfused with Hepes buffered Hank's bal anced salt solution, with a wash at 4 h. In vivo absorption was 7.8 ± 1.4% (water as vehicle) and 1.6 ± 0.3% (ethanol as vehicle). Of the dose absorbed in vivo, more than 95% was excreted via the lungs (over 88% of which was CO2), and the maximum pulmonary excretion occurred between 15 min and 2 h after dosing. The percentage of dose absorbed in vitro (skin + perfusate) was 5.6 ± 2.7% (low dose) and 7.1 ± 1.4% (high dose). The above data demon strate that a significant amount of the dissolved chloro form penetrates through the human skin, and that a higher percentage of the applied dose was absorbed using water as vehicle. In addition, the in vitro method offers a good estimate for in vivo data.
Effects of a protein kinase C inhibitor, Ro 31-7549, on the activation of human leuko cytes by particulate stimuli
Authors: Ruotsalainen Marjo , Savolainen Kai M
Published: December 2008

1 A new specific protein kinase C (PKC) inhibitor, Ro 31- 7549, was used to explore the mechanisms by which particulate stimuli, quartz and chrysotile, stimulate human polymorphonuclear leukocytes (PMNL) to pro duce reactive oxygen metabolites (ROM). Also soluble stimuli, formyl-Methionyl-Leucyl-Phenylalanine (fMLP) and phorbol myristate acetate (PMA) were used.

2 Ro 31-7549 inhibited chrysotile-induced free intracellu lar calcium ([Ca2+]i) elevations but did not have an effect on quartz-induced elevations of [Ca2+] i. Both quartz and chrysotile induced production of ROM were partially inhibited by Ro 31-7549. fMLP-induced elevation of [Ca2+]i was inhibited by Ro 31-7549 whereas PMA did not affect [Ca2+]i. Ro 31-7549 strongly inhibited fMLP- induced ROM production, and completely abolished that induced by PMA.

3 These results suggest that PKC may have an important role in the activation of PMNL to produce ROM by par ticulate and soluble stimuli. However, the inhibition of chrysotile-, but not of quartz-induced [Ca2+]i elevations by Ro 31-7549 provides evidence that both PKC-depen dent and -independent mechanisms may play a role in the activation of human leukocytes to produce ROM.
A biologically-based algorithm for predicting human tissue: blood partition coefficients of organic chemicals
Authors: Poulin Patrick , Krishnan Kannan
Published: December 2008

A biologically-based algorithm for predicting the tissue: blood partition coefficients (PCs) of organic chemicals has been developed. The approach consisted of (i) describing tissues and blood in terms of their neutral lipid, phospho lipid, and water contents, (ii) obtaining data on the solu bility of chemicals in n-octanol and water, and (iii) calcu lating the tissue: blood PCs by assuming that the solubility of a chemical in n-octanol corresponds to its solubility in neutral lipids, the solubility in water corresponds to the solubility in tissue/blood water fraction, and the solubility in phospholipids is a function of solubility in water and n- octanol.

The adequacy of this approach was verified by compar ing the predicted values with previously published experi mental data on human tissue (liver, lung, muscle, kidney, brain, adipose tissue): blood PCs for 23 organic chemicals. In the case of liver, lung, and muscle, the predicted PC val ues were in close agreement with the higher-end of the range of experimental PC values found in the literature. The predicted brain: and kidney: blood PCs were greater than the experimental PCs in most cases by approximately a factor of two. Whereas the adipose tissue: blood PCs of relatively less hydrophilic chemicals were adequately pre dicted, the predicted PCs for relatively more hydrophilic chemicals were much greater than the experimentally- determined values.

There was a good agreement between the predicted and experimentally-determined blood solubility of the 23 chemicals chosen for this study, indicating that the over- estimation of tissue:blood PCs by the present method is not due to under-estimation of blood solubility of chemicals. Rather, it might be due to the lower tissue solubility of chemicals observed experimentally due to the complexity of the tissue matrices.

This novel approach of describing tissues in terms of the type of lipid and water content should enable the predic tion of the tissue:blood PCs of organic chemicals with information on their solubility in water and n-octanol, for developing physiologically-based toxicokinetic models.
Amisulpride poisoning: a report on two cases
Authors: Tracqui A. , Mutter-Schmidt C. , Kintz P. , Berton C. , Mangin P.
Published: December 2008

The first two observations of human poisoning involving the recently developed neuroleptic amisulpride are described. In both cases drug determination was per formed using reversed-phase HPLC coupled with diode- array detection. Case 1 was a nonfatal overdosage in which the ingestion of 3.0 g amisulpride induced an attack of seizures, then light coma with agitation, hyperthermia, mydriasis, minimal extrapyramidal features, tachycardia and slight prolongation of the QT interval; the blood con centration of amisulpride was 9.63 μg ml-1. Case 2 was a fatality attributed to amisulpride in which the measured blood concentration was 41.70 μg ml-1. Our results are discussed in the light of data previously reported on the toxicity of substituted benzamides.
Reducing animal numbers in the fixed-dose procedure
Authors: Stallard N. , Whitehead A.
Published: December 2008

The fixed-dose procedure (FDP) was proposed by the British Toxicology Society (1984) 1as an alternative to assessment of acute oral toxicity via estimation of the LD50. The procedure is incorporated in OECD guidelines on acute oral toxicity testing.2

Whitehead and Curnow (1992)3used a mathematical model to describe the statistical properties of the FDP. This paper uses a simplified model to investigate further the procedure. In particular the effects of altering the number of animals included at each stage in the procedure are evaluated. It is shown that a reduction in the number of animals tested makes little difference to the toxic classifi cation of a substance with a steep dose-response curve, but has increasing effect as the dose-response curve becomes shallower. The simplified model also shows that in the proposed procedure the most likely classification depends on the LD 7 of the substance tested. Changing the number of animals tested results in the most likely classification depending on other LD values.

The effect of additional variation is also considered. Such variation might arise from within-laboratory differ ences. Although this increases the range of substances for which misclassification is likely, the increase is not much affected by the number of animals tested.
Bismuth salts and neurotoxicity. A randomised, single-blind and controlled study
Authors: Noach LA , Eekhof Jla , Bour LJ , Posthumus Meyjes FE , Tytgat Gnj , Ongerboer de Visser BW
Published: December 2008

The aim of this work was to investigate whether the nor mal use of colloidal bismuth subcitrate (CBS) and bismuth subnitrate (BSN) exhibits neurotoxic side-effects. A ran domised, single-blind controlled study was carried out in 66 patients with H. pylori associated gastritis. Patients were randomised to receive either amoxicillin (control group) for 4 weeks or BSN for 8 weeks or CBS for 8 weeks. Clinical and neurophysiological tests including elec troneurography (ENG) and spectral electroencephalogra phy (EEG) were performed before and after therapy. No clinically relevant changes were observed with clinical tests as well as with ENG and spectral EEG recordings within each group and between the groups. It was con cluded that the normal use of CBS and BSN does not exhibit clinical neurotoxicity.
Therapeutic efficacy of combined meso 2,3-dimercaptosuccinic acid and calcium disodium edetate treatment during acute lead intoxication in rats
Authors: Flora Gjs , Seth PK , Prakash AO , Mathur R.
Published: December 2008

1 The therapeutic ability of Ca disodium EDTA and meso 2,3-dimercaptosuccinic acid (DMSA) was studied, both individually and when given in combination, in reducing lead concentration in blood and other soft tissues, and in restoring lead induced altered biochemical variables in acute lead intoxicated rats.

2 Combined treatment with the above two chelating agents was more beneficial in reducing blood and hepatic lead compared to treatment with these drugs alone. Kidney lead concentration however, remained high fol lowing combined treatment, indicating the possibility of extra renal burden following treatment.

3 Lead sensitive biochemical variables also responded more favourably to combined treatment than treatment with these drugs alone. However, clinical biochemical indices indicate caution regarding the use of this new treatment regimen, and further investigation is required.
Development of brain free radical scavenging system and lipid peroxidation under the influence of gestational and lactational cadmium exposure
Authors: Gupta Amita , Gupta Alka , Shukla Girja S
Published: December 2008

1 Rat pups were exposed to cadmium (Cd) gestationally and lactationally through mothers receiving 20 ppm Cd in drinking water, ad libitum, from zero day of pregnancy.

2 The sequential measurement of brain lipid peroxidation showed an increase in thiobarbituric acid reactive sub stances at 1 (73%), 7 (30%), 14 (22%) and 21 (354%) days of age compared to respective controls.

3 A marked variation in reduced glutathione levels was observed at different postnatal ages of both control and Cd-treated groups. The levels of brain total sulphydryls were increased significantly in experimental animals at 1 (30%) and 7 (12%) days of age.

4 Cd exposure increased the activities of superoxide dis mutase and glutathione peroxidase by 45% and 104%, respectively, at day one. However, the continuous expo sure inhibited them at 7, 14 and 21 postnatal days.

5 Cadmium treatment elevated the levels of brain catalase and glutathione reductase at all the studied ages with a maximum alteration of 66% and 50%, respectively, at 21 days of age.

6 The data indicate that the exposure of pregnant mothers to low doses of Cd produced changes in the brain antioxi dant defence mechanisms at critical periods of develop ment which may have serious implications in later life.
Deaths from pesticide poisoning in England and Wales 1990-1991
Authors: Thompson JP , Casey PB , Vale JA
Published: December 2008

1 Data on deaths from pesticide poisoning occurring in England and Wales in 1990 and 1991 have been collated. Pesticides were responsible for 44 of 3978 deaths from poi soning (excluding carbon monoxide and other gases) over this period.

2 At least 66% of all pesticide fatalities were due to sui cide and overall there was a predominance of males (male:female ratio 2.4:1). Eighty per cent of deaths occurred in those more than 44 years old and no child under 10 years old died, although almost 50% of suspected pesticide poisoning incidents involve this age group.

3 Herbicides were responsible for 35 of the 44 deaths; seven were caused by insecticides, one by a molluscicide and one by an unspecified agent. The herbicide, paraquat, was responsible for 33 of 44 deaths (75%) and, although fewer fatalities have occurred from this cause in recent years, paraquat remains the most common cause of fatal pesticide poisoning in England and Wales.
Chronic copper intoxication due to ingestion of coins: a report of an unusual case
Authors: Hasan N. , Emery D. , Baithun SI , Dodd S.
Published: December 2008

We report an unusual case of acute copper intoxication in a patient who died after swallowing more than 700 coins mainly of 1p and 2p denomination. At autopsy the liver showed fibrosis and extensive copper deposition was demonstrated in the histological sections. Electron probe microanalysis also confirmed the presence of copper in the hepatic tissue.
Inter-subject variability in the metabolism of aluminium following intravenous injection as citrate
Authors: Talbot R.J. , Newton D. , Priest N.D. , Austin J.G. , Day J.P.
Published: December 2008

1 Six healthy male volunteers received intravenous injec tions of 26Al as citrate. Accelerator mass spectrometry and γ-ray spectrometry were used to determine levels of the tracer in blood and excreta at times up to 5-6 d.

2 There was a rapid clearance from blood (mean 2% of injection remaining after 1 d) and major loss in urine (59% up to 1 d), but 27 ± 7 (s.d.)% was retained in the body at 5 d. Faecal excretion was negligible (1% up to 5 d).

3 The mean results accord with the early metabolic pat tern in the single subject of a previous, more extensive study, who had retained 4% of the injection after 3 y. Together, the two studies point to the likelihood of large inter-subject differences in the long-term accumulation of dietary aluminium by populations receiving a given level of daily intake.
Differences in amiodarone, digoxin, flecainide and sotalol concentrations between antemortem serum and femoral postmortem blood
Authors: O'Sullivan JJ , McCarthy PT , Wren C.
Published: December 2008

1 The concentrations of amiodarone/desethylamiodarone, digoxin, flecainide and sotalol were measured in serum collected immediately prior to death and in postmortem blood collected from the femoral vein and artery of an 18-year-old male with congenital heart disease who developed a fatal arrhythmia.

2 The concentrations of all four drugs in the sample col lected during life were consistent with the dosage given and in the range accepted for normal therapy.

3 There were no differences in amiodarone/desethylamio darone, flecainide and sotalol concentrations in arterial or venous postmortem blood.

4 The concentrations of desethylamiodarone, digoxin, fle cainide and sotalol but not amiodarone, were higher in postmortem blood than in antemortem serum. The flecainide concentration was significantly greater than the upper limit associated with toxicity in life. Without knowledge of the true concentration measured in life, this apparently high, toxic concentration would have suggested that death could have resulted from arrhyth mogenic/proarrhythmic effects of the drug in excess.

5 These results further demonstrate the hazards in inter preting postmortem blood concentrations following suspected drug intoxication.
Pesticide incidents reported to the Health and Safety Executive 1989/90- 1991/92
Authors: Thompson JP , Casey PB , Vale JA
Published: December 2008

1 Data concerning pesticide incidents investigated by the Field Operations Division (FOD) of the Health and Safety Executive (HSE) in Great Britain have been collated for the three year period April 1989 to March 1992. Over this period the HSE investigated 613 incidents concerning pes ticides : 338 related to general or environmental com plaints not involving human poisoning and 275 were sus pected poisoning incidents.

2 The two hundred and seventy-five suspected poisoning incidents were assessed by the Pesticide Incidents Appraisal Panel (PIAP) as 'confirmed', 'likely', 'unlikely', 'not confirmed', or that there were 'insufficient data' to make an assessment. Assessed data are unavailable for eight incidents reported in 1989.

3 Four hundred and eighteen members of the public were involved in 202 assessed incidents and 79 workers were exposed in 65 assessed incidents. Overall, 129 (48%) inci dents were assessed as 'confirmed' or 'likely', 121 (45%) as 'unlikely' or 'not confirmed' and in 17 (6%) there were 'insufficient data' to form a judgement. Incidents occur ring in an occupational setting were assessed as 'con firmed' or 'likely' more frequently (62%) than those involving members of the public (44%).

5 Thirty-six per cent of those involved in a 'confirmed' poisoning incident were working with a pesticide or were in close proximity to the operator; 41% were on private property adjacent to a field being sprayed and a further 23% involved those walking, cycling or jogging past a sprayed field.

6 These data underestimate the number of occupational pesticide poisoning incidents in Great Britain as incidents involving sheep dips are not considered by PIAP but are dealt with by a parallel scheme run by the Veterinary Medicines Directorate. In addition, few of the non-occupa tional incidents, for example those referred to one of the UK National Poisons Information Service Centres, are included in these data.

7 Sixty deaths from pesticide poisoning were recorded in England and Wales between 1989-1991, though the major ity of cases followed the deliberate ingestion of a pesticide rather than occupational exposure. Only one of these was reported to the HSE and that concerned the deliberate ingestion of mevinphos. A second death reported to the HSE involved a farmer who died some 11 months after he became unwell following fumigation of his glasshouse soil with methyl bromide by a contractor. It is unlikely that this death was related to exposure to methyl bromide.

8 Over the 3 year period of the study there was an increase in the number of prosecutions laid before the courts (Under the Control of Pesticides Regulations 1986 made under the Food and Environment Protection Act 1985), though the number of Enforcement Notices served decreased. In addition, the average total fine decreased for the incidents prosecuted successfully.
Estimating the magnitude of carcinogenic effects in long-term animal studies
Authors: Stallard N. , Whitehead A.
Published: December 2008

Carcinogenicity studies seek to compare the incidence of tumours in animals exposed to the substance under inves tigation and animals used as controls. The conventional method of analysis is the Peto test, which assumes that tumours are either instantly fatal or have no effect on mor tality and requires a judgement to be made regarding the lethality of each tumour. Such an assumption seems unre alistic and the judgement is often difficult to make and unreliable. The need for such a judgement and the assumption of extreme lethality can be removed by using parametric multi-state models. In this modelling approach the transition of animals between the states 'alive without a tumour', 'alive with a tumour' and 'dead' is modelled mathematically.

This paper compares the Peto test with tests based on two parametric multi-state models in terms of the sensitiv ity of the tests to detect carcinogenicity. The sensitivity, or power, is shown to be low for commonly used numbers of animals, depending chiefly on the expected total number of animals with tumours. The Omar and Whitehead multi state model is found to be slightly more powerful than the Dewanji et al. model and at least as powerful as the Peto test. Provided the parametric assumptions are appropri ate, this method thus gives a test that is more sensitive than the Peto test and enables estimation of tumour onset and mortality rates without the requirement of tumour lethality judgements.
Central neurotoxicity induced by subchronic exposure to 2,4-pentanedione vapour
Authors: Garman RH , Dodd DE , Ballantyne B.
Published: December 2008

1 Male and female Fischer 344 rats were exposed to 2,4- pentanedione (2,4-PD) vapour acutely (4 h) at 1265 or 1811 ppm, or for 6 h day-1 , 5 days a week for 14 weeks to 0, 101, 307 or 650 ppm.

2 Mortality occurred during or within a few hours of the acute exposures (10% at 1265 ppm; 70% at 1811 ppm). No animal had gross or microscopic brain lesions.

3 All female rats (20) and 10 of 30 male rats exposed to 650 ppm 2,4-PD vapour died by the 38th study day (29 exposures); there were no subsequent male deaths. Twenty-five of the 30 animals that died, and seven of the 15 males that survived, had light microscopical evidence of degenerative lesions, principally within the caudate/putamen nuclei, nuclei of the cerebellar medulla, and vestibular nuclei. Less frequently involved, in animals that died, were various regions of the cerebral cortex. The early histopathological lesions, seen from the 16th study day (12 exposures) to the 38th study day (28 exposures) were characterised by malacia. When present, lesions in male rats surviving the 14-weeks of 650 ppm 2, 4-PD expo sure were characterised by malacia and gliosis. No peripheral nerve lesions were seen by light or transmis sion electron microscopy.

4 Neither mortality nor neuropathology were seen in rats subchronically exposed to 101 or 307 ppm, 2,4-PD vapour.
Cell proliferation in lung fibrosis-associated hyperplastic lesions
Authors: Nishikawa A. , Furukawa F. , Imazawa T. , Ikezaki S. , Otoshi T. , Fukushima S. , Takahashi M.
Published: December 2008

1 Cell proliferative activity of atypical bronchioloalveolar epithelia in lung fibrosis cases treated with bleomycin (BLM) or radiation was investigated by studying the his tochemistry of the argyrophil nucleolar organiser regions (AgNORs) and proliferating cell nuclear antigen (PCNA).

2 Five and 14 autopsy cases of individuals who died of pulmonary fibrosis, caused by BLM treatment and irra diation respectively, were compared with (i) six control subjects who proved to have no apparent fibrosis of the lung at autopsy and (ii) four lung squamous cell carci noma cases.

3 Histopathologically, both the BLM-treated and irradiat ed cases showed extensive collapse of the lung caused by severe fibrosis, although proliferative epithelial lesions such as atypical bronchioloalveolar hyperplasia and squamous metaplasia were more prominent in the former.

4 The mean AgNOR numbers in both atypical hyper plasias and metaplasias, of either BLM or irradiation cases, were significantly higher than in control bronchi oloalveolar epithelial areas, whereas they were lower than in the lung cancers. Data for PCNA-labelling indices were in line with those for AgNORs.

5 The results indicate that atypical hyperplastic lesions in the bronchioloalveoli arising during the fibrosing process as induced by BLM, and by irradiation, are highly proliferative.
An overview of the toxicology of HFA-134a (1,1,1,2-tetrafluoroethane)
Authors: Alexander DJ , Libretto SE
Published: December 2008

1 This paper reviews the results of preclinical toxicology studies on HFA-134a carried out by Glaxo Research and Development Ltd.

2 A comprehensive range of studies was conducted in ani mal models suitable for the type of investigation.

3 The inhalation route of administration was used in all in vivo studies (with the exception of local tolerance and sensitisation studies) as patients will be exposed only to vapour during actuation of metered-dose inhalers. Cell cultures used for in vitro studies were also exposed to the vapour.

4 There was no mortality of rodents or dogs at extremely high vapour concentrations (81%v/v).

5 HFA-134a was considered not to be toxic or oncogenic and to provide a safe alternative to chlorofluorocarbons for use in pharmaceutical metered-dose inhalers.
Neurotoxicity following the ingestion of a Chinese medicinal plant, Alocasia macrorrhiza
Authors: Chan Tyk , Chan LY , Tam LS , Critchley Jajh
Published: December 2008

1 A case of poisoning due to the raw root tuber of a Chinese medicinal plant, Alocasia macrorrhiza is pre sented.

2 The patient developed neurological (severe pain and numbness in the perioral area and throat) and gastro intestinal (nausea, vomiting, abdominal pain) symptoms immediately after eating the root tuber.

3 A. macrorrhiza has properties and morphology very similar to another medical plant, A. odora. The root tuber of the latter is known to contain a neurotoxin, sapotoxin.
Skin irritation testing in man for hazard assessment — evaluation of four patch systems
Authors: York M. , Basketter DA , Cuthbert JA , Neilson L.
Published: December 2008

1 The limitations of the Draize rabbit skin irritation test for hazard evaluation for man are widely documented. Nevertheless it remains the prescribed method for deter mining acute skin irritation hazard.

2 While the use of human testing for risk assessment of irritants is well established, the use of predictive testing in man for hazard identification has not been explored widely, and this is the object of the research programme.

3 The experiment described in this report evaluates the sensitivity of four patch testing systems (Finn chamber, Hill Top patch, Van der Bend chamber, and Webril patch) using a total of six irritant substances.

4 Following preliminary range-finding experiments, test materials were applied to the upper outer arm for up to 4 h. Assessments were performed immediately after patch removal and at 1, 24, 48 and 72 h.

5 Webril and Hill Top patches generated the greatest lev els of response, although responses with Finn and Van der Bend were observed. Hill Top patches are recom mended for future development work.

6 The use of very small preliminary panels to predict the effects in larger panels using different volunteers was only of limited value as each volunteer was found to have different irritant thresholds.
Reproductive toxicity of chronic lead exposure in male and female mice
Authors: Pinon-Lataillade G. , Thoreux-Manlay A. , Coffigny H. , Masse R. , Soufir J-C.
Published: December 2008

The reproductive toxicity of lead was investigated in NMRI mice exposed to 0.5% lead acetate in drinking water from day 1 of intra-uterine life until 60 days after birth. Compared with control mice, the weights of lead- exposed fetuses and subsequently of the lead-exposed weaned pups, male and female, diminished by 11 and 13% respectively. The lead-exposed male and female offspring of lead-exposed dams were mated with unexposed females and males, to examine the effect of lead exposure on reproductive function. Male fertility was not affected but reduced female fertility was observed: litters were smaller and a smaller number of implantation sites was found in lead-exposed females. In lead-exposed males, the weights of the body, testes and epididymes diminished by about 13%, and seminal vesicle and ventral prostate weights, by about 29%. Testicular histology and the number and mor phology of epididymal spermatozoa were normal. The lev els of plasma FSH, LH and testosterone, and of testicular testosterone, were not modified. These results suggest that the hypothalamic-pituitary-testicular axis is not adverse ly affected by the above lead exposure, and that therefore the decreased seminal vesicle and ventral prostate weights might not be the consequence of reduced testosterone lev els. The hypothesis that lead has a direct effect on these organs as well as a secondary effect resulting from possi bly reduced food consumption by lead-exposed mice can not be excluded. Consequently, in male NMRI mice, expo sure to lead might affect reproductive function by acting directly and/or indirectly on accessory sex organs.
Pharmacokinetic, pharmacodynamic, and pharmacotoxic profiles of recombinant- methionyl human interleukin-2 [alanine- 125] (r-metHuIL-2[ala-125]) following intravenous and subcutaneous administration in rats
Authors: LeBel CP , Langlois L. , Bell DP , Young JD , Kenney WC , Payne BJ , Sendelbach LE , Wong Lck
Published: December 2008

Comparative pharmacotoxicity studies in rats were per formed to evaluate the response to r-metHuIL-2[ala-125] following 2 or 4 weeks of daily intravenous or sub cutaneous administration, as well as to evaluate pharmacokinetic and pharmacodynamic responses. Pharmacokinetic analysis indicated that r-metHuIL-2[ala- 125] showed high bioavailability and nonlinear concentra tion profiles. Pharmacodynamic responses to intravenous or subcutaneous dosing with r-metHuIL-2[ala-125], as measured by white blood cell counts, were comparable. Preclinical safety studies (6, 30, and 150 μg kg-1 day -1) indi cated that r-metHuIL-2[ala-125], whether given intra venously or subcutaneously, was associated with increased circulating and infiltrating levels of lympho cytes and eosinophils. Bone marrow lymphoid hyperpla sia and splenic extramedullary hematopoiesis were simi larly observed in each study. This pattern of effects was considered an exaggerated pharmacodynamic response to r-metHuIL-2[ala-125]. Of further note was a histopatholog ic finding described as hepatocyte single cell necrosis which was observed following both intravenous and sub cutaneous administration and was considered to be a toxic response to high doses of r-metHuIL-2[ala-125]. The no observable adverse effect level (NOAEL) for r-metHuIL- 2[ala-125] via intravenous administration was 6 μg kg -1 day-1, while that for subcutaneous administration was 30 μg kg-1 day-1. Data herein present a form of rHuIL-2 with pharmacokinetic and pharmacodynamic profiles that are similar when given by these two systemic routes. Pharmacotoxic data, based on NOAELs, suggest that sub cutaneous administration may be a preferred clinical route of administration.
Isolation and characterisation of human proximal tubular cells derived from kidney cortical segments
Authors: McLaren J. , Whiting P. , Simpson J. , Hawksworth G.
Published: December 2008

1 Human renal proximal tubular cells (HPTC) were isolat ed by collagenase digestion and purified following fil tration and isopycnic Percoll density centrifugation. This method used cortical tissue obtained from surgical nephrectomies and was both rapid and simple, provid ing a preparation of cells with high viability (> 93 ± 3%) and recovery (16 ± 7 x 106 cells g-1of cortical tissue).

2 Characterisation of the isolated cells showed that, in terms of morphology, enzyme profile, transport systems and hormonal responsiveness, they were > 95% proxi mal tubular. The transport systems obeyed Michaelis- Menten kinetics, with the kinetic parameters of the glu cose transport system (Km= 2.5mM, Vmax= 7.7 nmol min-1mg-1protein) suggesting a higher proportion of PT cells originating from the S1-S2segment of the nephron. Isolated HPTC also maintained levels of reduced glu tathione (GSH) (11.9 ± 3.2 nmol mg-1protein) and exhib ited cytochrome P450-dependent activity, levels of spectrally determined P450 being 0.22 ± 0.07 nmol mg-1protein.

3 These results demonstrate the isolation of a viable and functioning homogeneous preparation of HPTC from cortical tissue, with potential for use in short term phar macological, physiological and toxicological studies.
The preclinical toxicological evaluation of sumatriptan
Authors: Owen K. , Hartley K. , Tucker ML , Parkinson MM , Tweats DJ , Jackson MR
Published: December 2008

1 Sumatriptan is a potent and selective 5-HT1receptor agonist marketed for the treatment of migraine by both oral and subcutaneous routes. An extensive toxicologi cal programme employing high doses of sumatriptan was carried out in a range of animal species. The stud ies evaluated both the local and systemic tolerance to single and repeated dosing, effects on all stages of repro duction, as well as the genotoxic and oncogenic poten tial of sumatriptan.

2 The administration of relatively high single and repeat ed doses of sumatriptan was well tolerated by both rodents and dogs by the oral, subcutaneous and intra venous routes. Behavioural effects, suggestive of involvement of the central nervous system, were the most obvious result of such doses and were generally more pronounced in dogs than rodents. The reason for this may be related to the higher plasma concentrations of the drug achievable in dogs. Additional observations restricted to dogs, were transient, and included tachy cardia, facial oedema and breaks in the continuity of secretion films on the corneal surface. A tendency for an increase in weight gain was seen for rats, while a slight decrease was usually seen for dogs. The only pathologi cal changes related to treatment with high concentra tions of sumatriptan consisted of local reactions at the site of subcutaneous administration.

3 Sumatriptan is an indole; the structures of this chemical class show varying propensities for nitrosation. However, appropriate testing with sumatriptan failed to identify any mutagenic nitroso compounds.

4 Sumatriptan was neither genotoxic nor oncogenic.

5 Reproductive studies demonstrated that sumatriptan was not teratogenic and had no effect on peri- and post natal development. Some embryotoxicity was observed, but only at maternally toxic doses. A slight decrease in the success of insemination was also noted at high oral doses in rats.

6 Results of the toxicological programme performed in support of migraine therapy with sumatriptan provide good assurance of safety for subcutaneous and oral use.
The fixed-dose procedure and the acute-toxic-class method: a mathematical comparison
Authors: Stallard N. , Whitehead A.
Published: December 2008

The fixed-dose procedure (FDP), proposed by the British Toxicology Society, and the acute-toxic-class (ATC) method, proposed by the German Federal Health Authority, provide alternatives to the LD50 test for classify ing substances by their acute oral toxicity. This paper pre sents a mathematical model that is used to compare the two procedures in terms of their classification properties and the required numbers of animals.

It is found that the classification properties of the proce dures depend on the dose levels used, the number of ani mals tested per dose and the criteria that are used to decide whether testing should continue at a higher or lower dose. For substances with steep dose-response curves, the most likely classification is determined chiefly by the choice of the dose levels whilst the number of ani mals and continuation criteria used are increasingly important for substances with dose-response curves with a smaller slope.

The use of toxicity as a possible endpoint as in the FDP and the use of a two-stage testing procedure at each dose as in the ATC method are both found to reduce the expect ed numbers of animals required with little effect on the classification properties. On the strength of these findings it is indicated that a new procedure combining the dose levels and testing approach of the ATC method with the inclusion of toxicity as an endpoint as in the FDP would be more efficient than either the FDP or the ATC method.