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Background:Type 3 von Willebrand disease (VWD) is an autosomal recessive bleeding disorder, characterized by virtually undetectable plasma von Willebrand factor (VWF) and consequently reduced plasma factor VIII levels. Genetic mutations responsible for type 3 VWD are very heterogeneous, scattered throughout the VWFgene and show high variability among different populations. Methods:Twenty‐five severe VWD patients were studied by direct sequencing of the 51 coding exons of the VWFgene. The total number of VWD type 3 families in Hungary is 24, of which 23 were investigated. Results:Fifteen novel mutations were identified in 31 alleles, five being nonsense mutations (p.Q1238X, p.Q1898X, p.Q1931X, p.S2505X and p.S2568X), four small deletions and insertions resulting in frame shifts (c.1992insC, c.3622delT, c.5315insGA and c.7333delG), one a large partial deletion (delExon1‐3) of the 5′‐region, four candidate missense mutations (p.C35R, p.R81G, p.C295S, p.C623T) and one a candidate splice site mutation (c.1730–10C>A). Six previously described mutations were detected in 17 alleles, including the repeatedly found c.2435delC, p.R1659X and p.R1853X. Only one patient developed alloantibodies to VWF, carrying a homozygous c.3622delT. Conclusion:We report the genetic background of the entire Hungarian type 3 VWD population. A large novel deletion, most probably due to a founder effect, seems to be unique to Hungarian type 3 VWD patients with high allele frequency. In contrast to previous reports, none of the five patients homozygous for the large partial deletion developed inhibitors to VWF. This discrepancy raises the possibility of selection bias in some of the reports.

Background:We studied 24 Hungarian patients from 23 unrelated families to identify the genetic background of the entire type 3 von Willebrand disease (VWD) population in this country. The current report focuses on the molecular characterization of a novel large deletion.Results:A large partial deletion (delExon1–3) of the 5′‐region of the von Willebrand factor gene (VWF) was detected in 12/48 alleles (25% of all type 3 alleles). The 5′‐deletion breakpoint is located in the untranslated region betweenVWFandCD9, whereas the 3′ breakpoint is in intron 3 ofVWF. Analysis of the breakpoints showed Alu Y and Alu SP repetitive sequences at the ends of the deletion, suggesting that a recombination event caused the subsequent loss of the 35‐kb fragment. DelExon1–3 was not found in any of the other screened populations.Conclusion:We report a large novel deletion including exons 1, 2 and 3 ofVWFcommonly causing type 3 VWD in the Hungarian population. This mutation, probably caused by an Alu‐mediated recombination event, and subsequently distributed in Hungary by a founder effect, seems to be unique to Hungarian patients with a high allele frequency. Together, delExon1–3 and 2435delC make up 37.5% of the genetic defects in Hungarian patients with VWD type 3. This offers a rational approach to molecular testing of relevant families in Hungary.

Severe von Willebrand disease (VWD) type 3 is caused by large deletions, insertions, small truncating mutations, splice site mutations and missense mutations of the VWFgene, respectively. Large deletions have been regarded as being a rare cause of VWD type 3. Complete gene deletions have only been identified in Italian and German patients to date. However, their extent and breakpoints have not been determined yet.

The acute and chronic toxicity of chloroform has been studied in laboratory animals. An acute oral LD50 of 2.0 (1.0 - 3.8) g/kg was determined for male rats. When applied to the skin of rabbits, chloroform produced slight to moderate irritation and delayed healing of abraded sking. Absorption of chloroform through the skin of rabbits was apparent but absorption is not expected to present a practical acute hazard. Liquid chloroform produced slight injury to the eyes of rabbits which took over a week to heal. Repeated 1 -hour exposures five days per week for six months to either 85.50 or 25 ppm of the vapor of chloroform resulted in adverse effects in all or some species studied; rats, rabbits, guinea pigs and dogs. The effects at 25 ppm were slight and reversible. Rats exposed to 25 ppm for 4.2 or 1 hour/day for 6 months were not adversely affected. Based on experimental data and published reports on human experience as well as industrial experience with carbon tetrachloride, the authors suggest that when worker's exposures can be expected to be repeated and prolonged, the exposure concentrations be maintained below 25 ppm vapor and that the time weighted average not exceed 10 ppm.

In a preliminary experiment, exposure of rats and guinea pigs to 50 or 11 ppm (v/v) 1,3-dichloropropene vapor for seven hours/day, five days/week for one month had been found to produce liver and kidney injury. In order to determine the effects of more prolonged, repeated exposure to lower concentrations, four species of laboratory animals were exposed repeatedly to nominal concentrations of either 3 or 1 ppm (13.6 or 4.5 mg/m3) 1,3-dichloropropene in air. Rats, guinea pigs, rabbits and dogs received seven-hour daily exposure five days/week to 1 ppm (v/v) (0.9 ppm recovered analytically) for six months with no adverse effect. The only effect in any group exposed to 3 ppm (v/v) (2.6 ppm recovered analytically) was a slight, apparently reversible change seen microscopically in the kidneys of male rats exposed seven or four hours daily. Female rats, male and female rabbits, male and female guinea pigs and female dogs exposed repeatedly to 3 ppm seven hours/day showed no adverse effect. No effects were apparent in either male or female rats killed three months after their last seven-hour exposures to 3 ppm. Based on these data, it is suggested that when repeated, prolonged exposures to the vapors of 1,3-dichloropropene can occur, seven to eight hours daily time-weighted average exposures of workmen not exceed 1 ppm.

Groups of laboratory animals were exposed repeatedly for up to six months to either 500, 200, 100 or 50 ppm vinyl chloride in air. Detectable changes occurred at all but the lowest concentration. The results are discussed and handling precautions suggested.

Experimental animals were exposed to acetylene tetrabromide (1,1,2,2-tetra-bromoethane) by various routes in order to obtain toxicological information necessary to assess the hazards to health associated with the production, handling and use of the material. Results show that the material does not present serious hazards from ingestion, eye contact, skin contact, or from acute inhalation. They do show, however, that the material is quite toxic when given in small repeated doses. An industrial hygiene standard of one ppm is suggested.

Patents, published literature, and commercial usage have established the utility of the propylene glycol ether of methylcellulose (hydroxypropyl methylcellulose) as a food additive and as a formulation aid in drug products. Aqueous solutions of this cellulose gum, like methylcellulose, will gel upon heating. Feeding studies on Methocel, Methocel 60HG, and Methocel 65HG have previously been published. The results of feeding Methocel 70HG and Methocel 90HG in the diet of rats at levels of 0.3, 1.0, 3.0, 10.0, and 20.0 per cent for periods of ninety and eighty-four days, respectively, confirm previous chronic oral toxicity studies that the propylene glycol ether of methylcellulose is extremely low in repeated oral toxicity and that it can be used safely in the drug, food, and pharmaceutical fields where Methocel and Methocel 65 HG have been found suitable.