Regulating and assessing risks of cholinesterase-inhibiting pesticides: divergent approaches and interpretations

This document presents a revised framework for conducting worker and dietary risk assessments for less-than-lifetime exposures to organophosphate or carbamate pesticides based on red blood cell (RBC) or brain acetylcholinesterase (AChE) inhibition or the presence of clinical signs and symptoms. The proposals for appropriate uncertainty factors are based on the biological significance of the cholinesterase (ChE) inhibition noted at the lowest-observed-effect level (LOEL) and the degree of uncertainty in the extrapolation between human and animal data. An extensive evaluation of industry data, not previously summarized, and the available literature indicate that the following risk assessment principles are supportable and protective of human health: Plasma ChE inhibition is not an adverse effect, and therefore should not be utilized in risk assessments. Red blood cell AChE is not associated with the nervous system and inhibition is not per se an adverse (neurotoxic) effect. When available, cholinergic effects or brain AChE inhibition data should take precedence over RBC AChE for determining no-observed-effect levels (NOELs). When available, human RBC AChE inhibition or cholinergic effects data should take precedence over animal data for determining NOELs. Due to the lack of adversity associated with inhibition of RBC AChE, the use of a 10-fold (10x) uncertainty factor from the NOEL is adequate when RBC AChE inhibition data from either animal or human studies are used to assess human risk. Due to greater potential for adversity, NOELs for brain AChE inhibition and cholinergic effects identified in animal studies should receive a default uncertainty factor of 100x; lower uncertainty factors may be used on a case-by-case basis. NOELs based on cholinergic effects noted in human studies should only require a 10x uncertainty factor, since an interspecies extrapolation factor from animals to humans is unnecessary. For RBC and brain AChE activity the threshold for defining a NOEL should be less than or equal to 20% difference from control activity in all species. For risk assessment purposes, duration and route of the study should reflect the expected duration and route of exposure for humans (i.e., a 21-d or 28-d dermal study for subchronic occupational dermal exposure assessment). When dermal data are not available, a subchronic oral toxicity study and an appropriate dermal penetration factor should be used. A general default of 10% absorption should be used, analogous to the United Kingdom and German exposure models that are widely used in Europe. The recommendations in this document are generally consistent with current risk assessment procedures used by Canada, the European Community (EC), and the United Kingdom (UK).     

Socioeconomic variables and rates of diarrhoeal disease in urban Bangladesh

Sociodemographic factors including low maternal education, low economic status, inferior quality of housing, diminished access to water and sanitation facilities, and crowding in the household are associated with increased diarrhoea in the rural setting of many developing countries. To assess the relationship of these variables with diarrhoea rates in children in an urban setting we monitored the episodes of diarrhoea of children less than 6 years of age from 1921 families living in 51 clusters throughout Dhaka city, Bangladesh, for 3 1/2 months. Comparing incidence density ratios, we found that, of the factors listed above, only low family income and living in a one-room house were statistically associated with increased diarrhoea and that none of these variables was associated with a meaningfully increased risk of diarrhoea. We conclude that the risk factors for increased episodes of diarrhoea in the urban setting appear to be different from those of the rural setting.     

Soiled saris: a vector of disease transmission?

We examined the relationship between uses of the sari that are potential health hazards and episodes of diarrhoea in children younger than 6 years in 247 families living in 51 slums in Dhaka, Bangladesh. These misuses appeared to be common (median of three per observation period) and were largely unrecognized by the women as possible sources of disease transmission. There appeared to be a positive correlation between the number of misuses of the sari and episodes of childhood diarrhoea.     

Fire exclusion and the changing landscape of Queensland’s Wet Tropics Bioregion 1. The extent and pattern of transition

The vegetation and geology of the Wet Tropics Bioregion of North Queensland, covering 1?998?150 ha, were mapped at a scale of 1:50?000. The resulting geographic information system (GIS) data base provided an unprecedented opportunity to examine vegetation condition across the entire bioregion. Mapping used colour aerial photography at 1:25?000, informed by ground truthing. Vegetation type, nature of the understory and ground cover, degree and type of disturbance, and the presence of secondary vegetation were described by a coding system, with codes marked directly on the aerial photos.

Analysis of these data has confirmed a picture, which emerged from ground truthing, of large areas of sclerophyll woodland and forest being invaded by a rainforest understory that prevents regeneration of the sclerophyll canopy. Fifty-three per cent of the native vegetation of the bioregion consists of non-rainforest vegetation types, dominated in both area and number by sclerophyll woodlands and forests. Seventeen per cent of the 735?713 ha of sclerophyll woodland and forest types were assessed as having suffered irreversible change. Between 25% and 79% of individual forest vegetation types were judged to have been affected by irreversible change. No climatic changes, or changes in the environment, apart from those related to changing fire regimes, were identified as causative factors. Changed fire regimes, predominantly fire exclusion, are considered to be the most likely cause.     

Combination Use of Angiotensin Converting Enzyme Inhibitors and Angiotensin Receptor Blockers in Diabetic Kidney Disease

Angiotensin converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARB) have played a major role in slowing the progression of diabetic kidney disease, since they lower urine protein levels, lower blood pressure, and slow progression. Studies have suggested that the combination of ACE-I and ARB offered greater benefits for patients with diabetic kidney disease. In 2008, the large ONTARGET study reported no benefit with combination therapy, as compared with monotherapy. This study has changed practice patterns, but few patients in this study had diabetic kidney disease. In this review, the data in favor of the combination use of these agents in patients with diabetic kidney disease and data against the combination are reviewed. At this time, there is little support for using the combination in diabetic patients with no kidney disease or early stage diabetic kidney disease. But there are patients who may benefit from combination use.     

Diagnosis and Treatment of Retrorectal Abscess

Hemodynamic studies have shown that shock following myocardial infarction is caused primarily by sudden reduction in cardiac output to one-half of normal values, with unimportant changes in total blood volume. A high mortality accompanies this condition.

Treatment of heart block and ventricular tachycardia associated with shock can result in dramatic improvement. Morphine, oxygen and digitalis are considered routine treatment, and morphine alone may reverse hypotension without true cardiogenic shock. Although vasopressor agents may produce subjective improvement, in the author's experience they did not decrease the ultimate mortality.

Hypothermia and assisted circulation as therapeutic measures are currently in the experimental stage.     

Neonatal alcohol impairs the context preexposure facilitation effect in juvenile rats: Dose-response and post-training consolidation effects

Alcohol exposure on postnatal days (PND) 4-9 in the rat adversely affects hippocampal anatomy and function and impairs performance on a variety of hippocampus-dependent tasks. Exposure during this developmental window reveals a linear relationship between alcohol dose and spatial learning impairment in the context preexposure facilitation effect (CPFE), a hippocampus-dependent variant of contextual fear conditioning. The purpose of the current report was to examine the effect of a range of alcohol doses administered during a narrower window, PND7-9, than previously reported (Experiment 1) and to begin to determine which memory processes involved in this task are impaired by developmental alcohol exposure (Experiment 2). In Experiment 1, rats pups received a single day binge alcohol dose of either 2.75, 4.00, 5.25 g/kg/day or were sham-intubated (SI) from PND7-9. Conditioned freezing during the test day was evident in all dosing groups, except for Group 5.25 g, indicating no graded dose-related behavioral deficits with alcohol exposure limited to PND7-9. In Experiment 2, rat pups were exposed to the highest effective dose from Experiment 1 (5.25 g/kg/day) or were sham intubated over PND7-9. During training, rats remained in the conditioning context for 5-min following immediate shock delivery. During this test of post-shock freezing, both SI and alcohol-exposed rats given prior exposure to the conditioning context showed comparable freezing levels. Since alcohol-exposed rats showed normal post-shock freezing, deficits by these rats on the test day likely reflect a failure to consolidate or retrieve a context-shock association, rather than a deficit in hippocampal conjunctive processes (consolidation, pattern completion) that occur prior to shock on the training day. These findings illustrate the value of the CPFE for characterizing the separable memory processes that are impaired by neonatal alcohol exposure in this task.     

Evidence of a role for cyclic ADP-ribose in long-term synaptic depression in hippocampus

Ca2+ released from presynaptic and postsynaptic intracellular stores plays important roles in activity-dependent synaptic plasticity, including long-term depression (LTD) of synaptic strength. At Schaffer collateral-CA1 synapses in the hippocampus, presynaptic ryanodine receptor-gated stores appear to mobilize some of the Ca2+ necessary to induce LTD. Cyclic ADP-ribose (cADPR) has recently been proposed as an endogenous activator of ryanodine receptors in sea urchin eggs and several mammalian cell types. Here, we provide evidence that cADPR-mediated signaling pathways play a key role in inducing LTD. We show that biochemical production of cGMP increases cADPR concentration in hippocampal slices in vitro, and that blockade of cGMP-dependent protein kinase, cADPR receptors, or ryanodine-sensitive Ca2+ stores each prevent the induction of LTD at Schaffer collateral-CA1 synapses. A lack of effect of postsynaptic infusion of either cADPR antagonist indicates a probable presynaptic site of action.