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).

Elemental diet for refractory atopic eczema.

A total of 37 children with refractory wide-spread atopic eczema were treated with an antigen avoidance regimen comprising hospitalisation, exclusive feeding with an elemental formula for a median duration of 30 days, and measures to reduce exposure to pet and dust mite antigens at home. After the initial period of food exclusion, food challenges were performed at intervals of seven days, and the patients followed up for at least 12 months. Ten of the children (27%) either failed to respond to the regimen or relapsed within 12 months. Improvement in the eczema was seen in 27/37 (73%) patients, by discharge from hospital their disease severity score had fallen to a median of 27% of the pretreatment figure, and only 3/27 required topical corticosteroids. There were no clinical or laboratory findings which could be used to predict the outcome. Drawbacks to the regimen were prolonged hospitalisation (median 70 days), a fall in body weight and serum albumin concentration, and a risk of anaphylactic shock (4/37 cases). A strict antigen avoidance regimen may be associated with improvement of atopic eczema where conventional treatments have failed.

Six food diet for childhood atopic dermatitis.

Sixty-three children with severe atopic dermatitis aged 0.4 to 14.8 years, were treated with a diet eliminating all but six foods for a 6-week period. Nine (14%) abandoned the diet before 6 weeks had elapsed. Twenty-one (33%) completed the diet but did not benefit. Thirty-three (52%) patients obtained greater than or equal to 20% improvement in the disease severity score at 6 weeks, and for these patients, foods were reintroduced singly at weekly intervals. The outcome at 12 months was the same for the group who responded to the diet, the group who failed to respond, and the group who failed to comply, because of the tendency for dermatitis to improve markedly in all three groups. Although dietary elimination of this type may be associated with immediate improvement, the long term outcome appears to be unaffected by dietary success or failure.

Calcium intake and cows' milk free diets.

In children with atopic eczema on elimination diets, the calcium intake was below the estimated requirement in 15 out of 20 who avoided cows' milk and received no milk substitute, and in three out of 26 who avoided cows' milk but were provided with a soya or casein hydrolysate formula.

Nutritional hazards of elimination diets in children with atopic eczema.

The intake of nutrients over a five day period was studied in 23 children whose atopic eczema was being treated by the avoidance of multiple foods. The results were compared with those from 23 healthy control children not on a diet. Significantly low intakes of calcium were discovered in 13 patients but not in controls. Avoidance of multiple foods is potentially hazardous and requires continued paediatric and dietetic supervision.

Induction of multiple cytochrome P-450 species in housefly microsomes--SDS-gel electrophoresis studies.

1. Microsomal fractions isolated from various housefly strains have been characterized with respect to multiple forms of cytochrome P-450 by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. 2. Susceptible NAIDM houseflies were pretreated with known inducers of cytochrome P-450, and their microsomal electrophoretic profiles were compared to control NAIDM microsomes, using as standards partially purified cytochrome P-450s from noninduced NAIDM houseflies. 3. Tentatively, at least five different species of cytochrome P-450 may exist in the NAIDM housefly strain. 4. A comparison of the microsomal electrophoretic profile of different housefly strains also indicates the presence of at least two additional cytochrome P-450 species. 5. Induction with alpha-pinene and phenobarbital was expressed by a shift of the maximum absorbance at 452 nm in the CO-difference spectrum to lower wavelengths in the NAIDM strain; whereas, beta-naphthoflavone, although increasing the amount of cytochrome P-450, did not change the wavelength of maximum absorbance. 6. Cytochromes of the P-452 type appear to predominate in the susceptible NAIDM strain, while cytochromes of the P-450 and P-448 types predominate in resistant strains.

Obstructive jaundice and renal masses.

An 82-year-old patient with obstructive jaundice secondary to simple renal cyst also suffered pain and vomiting from partial duodenal obstruction. The symptoms were relieved by aspiration of 1,750 ml of fluid. This reaccumulated over a five-year period when aspiration again relieved his symptoms, which then only consisted of epigastric fullness. Review of the literature shows jaundice to be an extremely rare symptom of renal cyst.