The policy chicken and the science egg. Has applied ecology failed the transgenic crops debate?

Ecology has a long history of research relevant to and impacting on real-world issues. Nonetheless problems of communication remain between policy-makers and scientists because they tend to work at different levels of generality (policy deals with broad issues, science prefers specific questions), and complexity (policy-makers want simple answers, ecologists tend to offer multi-factorial solutions) and to different timescales (policy-makers want answers tomorrow, ecologists always seem to want more time). These differences are not unique to the debate about the cultivation of transgenic crops. Research on gene flow is used to illustrate how science and policy are intimately bound together in a value-laden, iterative and messy process unlike that characterised by the 'encounter problem-do science-make policy' model. It also demonstrates how the gap between science and policy is often characterised by value-laden language. Scientists involved in ERA for transgenic crops may find their engagement with policy- and decision-makers clouded by misunderstanding about what one should expect from the other. Not the least of these, that science can define harm, is explored in a discussion of the U.K. Farm Scale Evaluations of herbicide-tolerant GM crops. The varied responses to these extensive trials highlight the problems of linking specific scientific experiments with broad policy objectives. The problems of applied ecology in the transgenic crops debate are not unique but may differ from other areas of environmental policy in the intense politicisation of the debate, the emphasis on assessment of risk and the particularly broad policy objectives.

The Prediction of Risk In Syncope using ECG characteristics (PRISE) pilot study: can heart rate variability be used to predict risk in patients presenting to the emergency department with syncope?

AIM: This study was conducted as a feasibility pilot for the Prediction of Risk In Syncope using ECG characteristics (PRISE) study. The secondary aim was to determine whether heart rate variability (HRV) characteristics may be useful to distinguish low and high-risk syncope patients. METHODS: Adult patients presenting to the emergency department (ED) with syncope over a one-month period underwent a 5-minute 12-lead ECG. Study patients were assigned high, medium or low-risk status according to the ED's existing syncope guidelines as well as one of four likely diagnostic categories. ECG signals from all patients were then analysed and time domain HRV characteristics were derived using WelchAllyn's Cardioperfect interpretation software. A control group of patients was also recruited. RESULTS: Over a 4-week period in July 2007, 32 patients were recruited into the study group and 23 into the control group. ECG tracings of five study group patients were not suitable for analysis. According to the ED's existing syncope guidelines there were nine low-risk, 12 medium-risk and six high-risk patients with diagnostic categories as follows: postural hypotension, five; vasovagal, 16; cardiac, five and other, one. Patients with cardiac syncope had greater mean values for all HRV characteristics except NN number and NN minimum; however, with overlapping confidence intervals. Low-risk patients were more likely to be younger than medium and high-risk patients. No HRV parameters showed any significant differences. CONCLUSIONS: Measuring HRV in the acute ED setting is feasible. If patients with cardiac and neurocardiogenic syncope have different HRV characteristics then it could be useful to determine a patient's underlying cause of syncope in the ED, which would allow earlier decision-making.

Syncope management in the UK and Republic of Ireland.

AIMS: To establish the current practice of emergency department (ED) management of syncope in the UK and Republic of Ireland. METHODS: A survey of "major" or "intermediate" size ED in the UK and Republic of Ireland conducted by postal and telephone questionnaire. RESULTS: 177 (70%) ED responded. 32 (18%) ED have syncope guidelines, which are based on a range of existing guidelines. 97 ED (55%) have an observation ward or clinical decision unit and 48 (49%) of these admit syncope patients to these units. 32 ED (18%) have access to a specialist syncope outpatient clinic. This is most likely to be run by general practitioner specialists (43%) or general physicians (24%). 81% of ED felt that improved research-based guidelines would be useful when managing syncope patients. CONCLUSION: The ED management of syncope patients in the UK and Republic of Ireland is varied. Only 18% of ED have specific guidelines for managing this difficult condition and only 18% have access to a specialist syncope clinic. A robust consensus UK syncope guideline is clearly required.

Validation and application of Caco-2 assays for the in vitro evaluation of development candidate drugs as substrates or inhibitors of P-glycoprotein to support regulatory submissions.

1. An understanding of the role that transporters, in particular P-glycoprotein (P-gp), can play in the absorption, distribution, metabolism and excretion (ADME) of candidate drugs, and an assessment of how these processes might impact on toxicity and the potential for drug-drug interactions in the clinic, is required to support drug development and registration. It is therefore necessary to validate preclinical assays for the in vitro evaluation of candidate drugs as substrates or inhibitors of human P-gp. 2. The present study has characterized a Caco-2 cell monolayer model by determining the bi-directional apparent permeabilities and efflux ratios of the known P-gp substrates ([(3)H]-digoxin, [(3)H]-ketoconazole, [(3)H]-verapamil, [(3)H]-quinidine, dipyridamole and loratidine; 1-100 microM) a non-substrate ([(3)H]-propranolol; 10 microM), or by determining the inhibitory potencies (IC(50)) of inhibitors (verapamil, ketoconazole, quinidine, dipyridamole and probenecid; 0.1-100 microM) on the basolateral-to-apical transport of [(3)H]-digoxin (5 microM), in order to validate methodologies for the identification of substrates or inhibitors of P-gp, respectively. 3. The reproducibility of the [(3)H]-digoxin or verapamil data determined from replicate monolayers across different cell passages indicates that the functional expression of P-gp is consistent across the range of passages (25-40) utilized for transport experiments and that the determination of bi-directional apparent permeability, or IC(50) for inhibition of P-gp, respectively, need only be performed on one occasion for a test compound. [(3)H]-digoxin and [(3)H]-propranolol or verapamil and probenecid were considered to be appropriate positive and negative controls of P-gp-mediated transport, or inhibition of P-gp, respectively, to ensure performance of the assays when assessing candidate drugs. Additionally, the low IC(50) values determined for ketoconazole and quinidine indicated that these inhibitors were suitable to use to confirm the role of P-gp in the efflux of a test compound. 4. These validated Caco-2 assays are robust, reproducible and suitable for routine in vitro evaluation of candidate drugs. They have been successfully applied to development projects resulting in the identification of two candidate drugs as substrates and inhibitors of P-gp, whereas a third was neither a substrate nor an inhibitor of this transporter.

In vivo protein transduction to the CNS.

Proteins and peptides are useful research and therapeutic tools, however applications are limited because delivery to the desired location is not easily achievable. There are two hurdles in protein/peptide delivery to the brain: the blood-brain barrier and intracellular penetration. Penetration to both brain and the intracellular space can be achieved by adjusting hydrophilicity, and small molecule pharmacological agents have been successfully developed using this approach. But with proteins and peptides, it is difficult to modify the hydrophilicity without influencing biological functions. Trans-acting factor protein from the human immunodeficiency virus contains a highly conserved cationic peptide sequence necessary for transduction across the cell membrane. While trans-acting factor peptide has been used for in vitro protein transduction, its in vivo application is very limited because it is rapidly degraded by proteolysis. Polyethylenimine is a chemically synthesized small molecule cationization agent; the charge density is greater than a peptide-based cationic cluster such as trans-acting factor, and it is resistant to proteolysis in vivo. We first tested intracellular protein transduction following direct brain injection in mice using polyethylenimine-conjugated green fluorescence protein and beta-galactosidase (molecular weights 29 and 540 kDa, respectively). Polyethylenimine-conjugates penetrated to the intracellular space immediately surrounding the injection site within one hour. We further tested polyethylenimine-mediated protein transduction following intranasal administration, which bypasses the blood-brain barrier. Polyethylenimine-conjugates in pH 7.5 solution did not reach the brain, probably because the polyethylenimine-conjugates penetrated into the intracellular space where first exposed to the tissue, i.e. at the nasal mucosae. We temporarily reduced the electrostatic interaction between cationized polyethylenimine-conjugates and cellular surfaces by adjusting the pH to 4.5; solution rapidly reached the brain and penetrated to the intracellular space. This study suggests that polyethylenimine is a useful protein transduction agent in the brain in vivo, and adjusting cationic charge interaction can determine the extent of brain penetration.

Monitoring the development of intertidal habitats on former agricultural land after the managed realignment of coastal defences at Tollesbury, Essex, UK.

The managed realignment of coastal defences and subsequent creation of intertidal habitats is one of several 'soft' engineering options that could reduce the costs of maintaining embankments and at the same time deliver environmental benefits. The managed realignment at Tollesbury was one of the first in the UK, undertaken as an experimental test case to improve understanding of the practical techniques and processes involved. Independent studies were undertaken on the development of soils, benthic invertebrates and vegetation within the site in addition to methods of enhancing the process of natural colonisation of saltmarsh plants. Bathymetric and vegetation monitoring were undertaken on the adjacent estuary to determine any breach effect that may be attributed to the realignment. This paper summarises the results from the vegetation, sedimentation and invertebrate monitoring and discusses the implications for other managed realignment schemes in the UK.

Epidemiology, clinical characteristics, and management of adults referred to a teaching hospital first seizure clinic.

BACKGROUND: There are scarce data describing the epidemiology, clinical characteristics, and management of adults who suffer a suspected first seizure. AIM: To describe the epidemiology, clinical characteristics, and management of adults with a suspected first seizure who are referred to a teaching hospital first seizure clinic over a one year period. DESIGN: Prospective descriptive study. METHODS: Data were collected on consecutive adults referred to the Royal Infirmary of Edinburgh between 4 February 2003 and 10 February 2004. RESULTS: 232 patients were referred to the first seizure clinic. Median age was 32 years; 53% of patients were male. Lower socioeconomic groups were more likely to present with a suspected first seizure. Nineteen per cent of patients were admitted to hospital after their suspected seizure episode. Appropriate driving advice was reported in 64% of cases. Seventy two per cent of patients were offered a first seizure clinic appointment within six weeks of referral. Nine per cent of patients had a subsequent seizure while awaiting review. Fifty two per cent of patients were confirmed as having a first seizure at the clinic, of which 56% were provoked by alcohol, recreational drugs, or sleep deprivation. Electroencephalography and computed tomography of the brain were the most common investigations ordered at the first seizure clinic (22% and 22% of patients respectively). CONCLUSION: Adults who suffer a suspected first seizure, and who make a full neurological recovery, can be safely managed as an outpatient. Around half of these patients will have a specialist diagnosis of first seizure and alcohol will be a common precipitating factor.

Early management of adults with an uncomplicated first generalised seizure.

A literature review of first seizures in adults was performed and a management algorithm was constructed. This review highlights the importance of a thorough history and examination, routine biochemistry and haematology, an electrocardiogram, selected neuroimaging, discharge planning with driving and lifestyle advice, and follow-up in a specialist clinic.

Prehospital trauma management: a national study of paramedic activities.

OBJECTIVES: The benefits of prehospital trauma management remain controversial. This study aimed to compare the processes of care and outcomes of trauma patients treated by paramedics, who are trained in advanced prehospital trauma care, with those treated by ambulance technicians. METHODS: A six year prospective study was conducted of adult trauma patients attended to by the Scottish Ambulance Service and subsequently admitted to hospital. Prehospital times, interventions, triage, and outcomes were compared between patients treated by paramedics and those treated by technicians. RESULTS: Paramedics attended more severely injured patients (16.5% versus 13.9%, p<0.001); they attended a higher proportion of patients with penetrating trauma (6.6% versus 5.7%, p = 0.014) and had longer prehospital times. Patients managed by paramedics were more likely to be taken to the intensive care unit, operating theatre or mortuary, (11.2% versus 7.8%, p<0.001) and had higher crude mortality rates (5.3% versus 4.5%, p = 0.07). However, no difference in mortality between the two groups was noted when corrected for age, Glasgow coma score and injury severity score. CONCLUSIONS: This large scale national study shows that paramedics show good triage skills and clinical judgement when managing trauma patients. However, the value of the individual interventions they perform could not be ascertained. Further controlled trials are necessary to determine the true benefits of advanced prehospital trauma life support.

Thrombin stimulates fibroblast chemotaxis and replication.

The serine protease alpha-thrombin, a product of the circulating zymogen prothrombin, plays multiple roles in homeostasis and coagulation. During blood clotting, it is present within fibrin matrices and is likely to be presented to local cell populations. It is known to be a fibroblast mitogen, but its effects on fibroblast recruitment have not been assessed. Here we compared the effect of human alpha-thrombin on chemotaxis and proliferation of human and rat skin fibroblasts and assessed the mechanism of these actions. Fibroblast chemotaxis was assayed using a 48-well Boyden chamber and replication assessed by a spectrophotometric method, based upon the uptake and subsequent elution of methylene blue by fibroblasts. Two fibroblast cell lines were used; fetal rat skin (FR) and newborn human foreskin (HS68). Human alpha-thrombin stimulated FR fibroblast chemotaxis over a wide range of doses (10(-12) M to 10(-7) M). Maximal migration was seen at 10(-10) M; 39 +/- 2.5 cells/high power field (h.p.f.) compared with 19 +/- 3 cells/h.p.f. for media control. In the same assay platelet-derived growth factor, a well characterized fibroblast chemoattractant, caused a maximal stimulation of 44 +/- 5 cells/h.p.f. at a concentration of 3 x 10(-9) M. A similar stimulation was observed with HS68 fibroblasts, although for this cell line maximal chemotaxis (190 +/- 12.5% of control) was seen at 10(-8) M thrombin. Fibroblast replication was optimal at 1.25 x 10(-9) M thrombin (134 +/- 4 and 127 +/- 5% of control for FR and HS68, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Disposition, pharmacokinetics, and metabolism of 14C-fotemustine in cancer patients.

The pharmacokinetics and metabolism of intravenously infused 14C-fotemustine (about 100 mg/m2) were examined in 2 cancer patients. Plasma levels of radioactivity increased to a maximum of 4.1 and 5.5 micrograms equivalents per g when the infusion stopped then declined triexponentially with mean half-lives of about 1/2, 10 and 80 h for the initial, mid and terminal phases, respectively. Plasma levels of intact drug were lower, with maximum levels of 1.1 and 2.8 micrograms/ml, and declined monophasically with a half-life of about 24 min. Plasma clearance was high (1426 and 764 ml/min) with the volume of distribution based on areas of 47.7 and 26.4 l. Most of the radioactivity was eliminated in urine (50.1 and 61.3%) over 7 days with smaller amounts in the feces (6.8 and 0.3%) and only minimal quantities (under 0.1%) as expired carbon dioxide. Metabolites of fotemustine were identified as chloroethanol and N-nitroso-1-imidazolone-ethyl-diethylphosphonate in plasma and as 1-hydantoin-ethyl-diethyl-phosphonate and acetic acid in urine.

Treatment of advanced head and neck cancer with accelerated fractionation.

Forty-eight patients with locally advanced head and neck cancer have been treated with 1.80 Gy 3 times daily, 4 hours between fractions, 3 days per week (Monday, Wednesday and Friday). At 37.80 Gy, fields were reduced and a final tumor dose of 59.40 Gy in 33 fractions given in three and a half weeks. Fifty-six percent of patients had complete resolution of tumor; the overall local control rate was 52% with an average follow-up of 12.5 months. Actuarial survival was 74% at 12 months and 50% at 24 months. Disease-free survival was 48% at 12 months and 32% at 24 months. Acute complications were common, but late complications were rare, two cases of asymptomatic subcutaneous fibrosis. Radiation therapy with accelerated fractionation shows promise of improving the therapeutic ratio.

Treatment results for 149 medulloblastoma patients from one institution.

PURPOSE: Retrospective analysis of patients with medulloblastoma to determine the effectiveness of previous treatments for medulloblastoma and plan for future management strategies. METHODS AND MATERIALS: During the period March 1976 to December 1991, 172 patients with cerebellar medulloblastoma were referred to King Faisal Specialist Hospital and Research Center. One hundred and forty-nine patients were treated with curative intent. There were six postoperative deaths, and 10 patients planned for radiotherapy treatment failed to complete the prescribed course. One hundred and thirty-three patients completed a course of radiotherapy after surgery. Adjuvant chemotherapy was not used routinely (six patients only). Tumors were staged retrospectively according to the Chang staging system. There were no T1 patients, 32 patients had T2 tumors, 76 had T3 tumors, and 29 had T4 tumors. The T stage could not be allocated in 12 patients. Ninety-nine patients required a shunting procedure either pre- or postoperatively. Forty-six patients had complete resection of tumor, 91 had incomplete resection, and 6 patients had biopsy only. The extent of resection could not he determined in six patients. The median radiation dose for the whole brain was 34 Gy, spine 32.5 Gy, and posterior fossa 52.8 Gy. Fraction sizes ranged from 1.7-1.8 Gy for craniospinal fields and 2 Gy for the posterior fossa boost. Seventy percent completed the prescribed course within 7 weeks. RESULTS: Actuarial survival for the whole group of 149 patients was 53% at 5 years and 38% at 10 years. On univariate analysis, patients with T2 tumors did significantly better as compared to patients with T3 and T4 tumors. Survival of patients who had clinical and radiological complete resection of tumor at surgery was significantly better than patients with incomplete tumor removal. The presence of a ventriculoperitoneal (VP) shunt had a significant negative impact on survival. Treatment failure by site was analyzed with respect to the radiation dose. Doses greater than 50 Gy for the posterior fossa, and greater than 30 Gy for craniospinal axis, resulted in significantly better survival. On multivariate analysis, the only significant prognostic factor was the presence of a VP shunt in patients with T2 tumors. CONCLUSION: T stage, VP shunt, radiation doses and extent of surgery were important prognostic factors. In this study, radiation doses of more than 50 Gy to the posterior fossa and 30 Gy to the craniospinal axis resulted in improved survival.

Radiation therapy for retinoblastoma: a retrospective review of 120 patients.

PURPOSE: To characterize the patient population and treatment outcomes in patients with Retinoblastoma (RB) referred for External Beam Orbital Radiotherapy (EBORT) to King Faisal Specialist Hospital & Research Centre (KFSH&RC), Riyadh, Saudi Arabia from 1976 to 1993. METHODS AND MATERIALS: A retrospective study of 120 patients with RB affecting a total of 192 eyes. Patients were divided into three groups. Group A are 60 patients (64 eyes) treated with EBORT to the intact eye to preserve vision. Reese-Ellsworth (RE) Staging was: 1: 12%; 2: 10%; 3: 12%; 4: 23%; and 5: 43%. Twenty-eight patients (47%) also received Vincristine, Adriamycin, and Cyclophosphamide chemotherapy (C/T). Mean follow-up, per patient, was 48.5 months. Standard treatment until 1992 was 45 Gy in 12 fractions of 3.75 Gy, three times weekly over 18 days. Assuming the alpha/beta ratio for early effects and tumor control at 10, Tk = 21 days, Tpot = 5 days, then the Biological Equivalent Dose (BED) was 62 Gy10 for early effects, and 101 Gy3 for late effects. Group B are 28 patients (28 eyes) treated for curative intent with EBORT to the orbit for locally advanced disease, usually after enucleation (24 eyes). Nineteen patients (83%) also had C/T. Mean follow-up was 22.6 months. Group C are 37 patients with advanced disease treated with radiotherapy for palliation. Seventeen (46%) also received C/T. Mean follow-up was 11.7 months. RESULTS: Group A-following EBORT useful vision was retained in RE Stage 1 to 5: 7 of 7, 6 of 6, 4 of 8, 10 of 15, and 7 of 28 eyes, respectively. There was no significant difference between patients who received adjuvant chemotherapy and those who did not. Complications included cataract (27%), retinopathy (25%), vitreous hemorrhage (19%), and orbital deformities (11%). In Group B the local control rate was 71%. In Group C, 10 (27%) of the 37 patients were alive at last contact, and 27 (73%) were either terminal or dead of disease. None of Group A or B patients had positive CSF cytology, bone scan, or bone marrow examination. In Group C 19% had positive CSF cytology, and bone marrow, and 14% had a positive bone scan. CONCLUSIONS: 1) EBORT preserved useful vision in a significant proportion of patients even in eyes with advanced RE Stage RB, but longer follow-up is likely to reveal an even higher complication rate with this regime. 2) High dose per fraction probably contributed to the increased complications. 3) Chemotherapy did not demonstrate any effect on retaining vision in this study. 4) For disease that is confined to within the eye clinically and radiologically, invasive procedures for CSF cytology, bone marrow examination, and bone scan do not seem warranted. 5) The optimum technique, fractionation, and dosage for RB is still not well defined.

Long-term results of accelerated radiation treatment for advanced head and neck cancer.

BACKGROUND AND PURPOSE: This report presents long-term follow-up data from a prospective but unrandomized trial of a continuous 3.5-week course of accelerated radiation treatment (ART) used as primary treatment for patients with loco-regionally advanced head and neck cancer. MATERIALS AND METHODS: Ninety-three patients in three centres in New Zealand and Australia were treated with ART (59.40 Gy in 33 fractions over 24-25 days). Their disease originated from three anatomical regions (oral cavity, 35 patients; pharynx, 31 patients; larynx, 27 patients). Seventy-nine of these patients had stage III or IV cancers. RESULTS: Follow-up ranged from 68 to 203 months (median 139 months). Loco-regional (LR) failure occurred in 52 patients leading to a 10-year actuarial expectation of LR control of 38%. The actuarial expectation of LR control at 10 years was highly dependent on stage and for stage III, IVA and IVB patients it was 57+/-8.1%, 32+/-1.7% and 7+/-0.5%, respectively. Multivariate analysis could not confirm an independent impact of primary site or histological differentiation on LR failure. Two patients died of acute toxicity of treatment and six patients developed grade 3/4 late complications affecting soft tissues only, yielding an actuarial expectation of complications of this severity at 5 years of 9%. No cases of osteoradionecrosis or myelitis were observed. CONCLUSION: This ART, which has proved easy to use at a number of large and small centres, has produced encouraging long-term LR control at a cost of limited soft tissue morbidity.

Accelerated fractionation radiotherapy for advanced head and neck cancer.

Between 1981 and 1986, 89 patients with advanced head and neck squamous cancer were treated with a continuous accelerated fractionation radiotherapy (AFRT) regimen. Three fractions of 1.80 Gy, 4 h apart, were given on three treatment days per week (Monday, Wednesday, Friday), and the tumour dose was taken to 59.40 Gy in 33 fractions in 24-25 days. Acute mucosal reactions were generally quite severe, but a split was avoided by providing the patient with intensive support, often as an in-patient, until the reactions settled. Late radiation effects have been comparable to those obtained with conventional fractionation. The probability of local-regional control was 47% at 3 years for 69 previously untreated patients, whereas it was only 12% at one year for 20 patients treated for recurrence after radical surgery. Fifty-eight previously untreated patients with tumours arising in the upper aero-digestive tract were analysed in greater detail. The probability of local-regional control at 3 years was 78% for 17 Stage III patients and 15% for 31 Stage IV patients. This schedule of continuous AFRT is feasible and merits further investigation.

The prevalence and spatial distribution of viruses in natural populations of Brassica oleracea.

We report a survey of four viruses (beet western yellows luteovirus (BWYV), cauliflower mosaic caulimovirus (CaMV), turnip mosaic potyvirus (TuMV), turnip yellow mosaic tymovirus (TYMV)) in five natural populations of Brassica oleracea in Dorset (UK). All four viruses were common; 43% of plants were infected with BWYV, 60% with CaMV, 43% with TuMV and 18% with TYMV. For each virus there were significant differences in the proportion of infected plants among populations, which were not completely explained by differences in the age of plants. Multiple virus infections were prevalent, with 54% of plants having two or more virus types. There were statistically significant associations between pairs of viruses. The CaMV was positively associated with the other three viruses, and BWYV was also positively associated with TuMV. There was no detectable association between BWYV and TYMV, whereas TuMV and TYMV were negatively associated. We suggest these associations result from BWYV, CaMV and TuMV having aphid vectors in common, as aphids are attracted to plants that already have a virus infection. Infected plants were distributed randomly or were very weakly aggregated within populations. The implications of widespread multiple virus infections in natural plant populations are discussed with respect to the release of transgenic plants expressing virus-derived genes.

The comparative disposition of [14C]-fotemustine in non-tumourous and tumourous mice.

The distribution and excretion of radioactivity from [14C]-fotemustine was examined in mice with melanomas at different stages of development to determine whether the disease state substantially alters the disposition of the drug and its metabolites. Normal BDF1 mice and mice that had been subcutaneously grafted with B16 melanoma either 1, 3, 7, 14 or 21 days previously were used. The animals were killed at either 5 min, or at 3, 24 or 96 h after receiving an intravenous dose of [14C]-fotemustine (20 mg/kg) and were examined either by whole-body autoradiography or by liquid scintillation counting of excreta and tissues of interest. The majority of the [14C]-fotemustine dose was excreted in the urine, with similar amounts being measured in both non-tumourous animals (61.6% +/- 13.1%) and tumourous mice grafted 14 days previously (67.2% +/- 5.7%). Small amounts of radioactivity, again similar in both non-tumourous and tumourous mice, were recovered in the faeces (5.4% +/- 5.6% and 3.6% +/- 1.8%, respectively) and as carbon dioxide (7% +/- 3.5% and 6.4% +/- 1%, respectively), with minimal amounts being expired as chloroethanol (less than 1%). When mice were examined 5 min after dosing, there was extensive tissue distribution accounting for 75% +/- 10% of the dose. The highest concentrations determined by both whole-body autoradiography and liquid scintillation counting were measured in the excretory organs, with 33 and 28 micrograms Eq/g being found in the liver and kidney, respectively. High levels were also seen in the lung and plasma (19.8 and 19.5 micrograms Eq/g, respectively). Analysis of variance indicated that groups of tissues, such as the excretory organs, blood and plasma or the pigmented tissues, showed distinct but inconsistent patterns. Only tumours at 14 and 21 days of development were suitable for examination, and these showed levels of 12.1 micrograms Eq/g; however, the tumour-to-plasma ratio increased from between approx. 0.5 and 0.6 at 5 min to approx. 2 at 96 h after dosing, suggesting retention within the melanoma, whereas the ratio for the femur remained at approx. 1. Whole-body autoradiography showed that the distribution in the tumour was not uniform, but rather was concentrated in the peripheral area (presumably viable cells) as opposed to the central necrotic region. Thus, the high and sustained concentration of radioactivity found in the active cells of the melanoma may provide an explanation for the high efficacy of the drug.

Toxicity of pyrethroids to rats after direct injection into the central nervous system.

The administration of very small doses of two synthetic pyrethroids, cismethrin and deltamethrin, into the lateral ventricles of the brain or the subarachnoid space around the spinal cord, produced signs of toxicity in rats that were similar to those observed after iv injection of much larger doses. Intraventricular injection of the radiolabeled pyrethroids demonstrated that the onset of toxicity corresponded to the radiolabel reaching a threshold level in the brain stem, cerebellum or upper spinal cord. The injection of similarly labeled pyrethroid solutions into the lumbar region of the spine indicated that there was very little movement of the pyrethroid up the spinal cord to the brain. This corresponded to the signs of toxicity occurring only caudal to the site of injection. It was concluded that both pyrethroids produce their different syndromes of toxicity predominantly by their action on the spinal cord.

Preliminary investigations into the involvement of the intestinal microflora in CNS toxicity induced by 1,3-dinitrobenzene in male F-344 rats.

Administration of a single oral dose of 20 mg/kg of 1,3-dinitrobenzene caused ataxia in germ-free male F-344 rats but not in conventional rats. Repeated oral dosing of 20 mg/kg, 1,3-DNB was required to cause ataxia in conventional rats. Considerable differences were observed between the uptake, tissue distribution and excretion of DNB in germ-free and conventional rats.