The association between treatment and systemic inflammation in acromegaly.

OBJECTIVE: Acromegaly is characterized by an excess of growth hormone (GH) and insulin like growth-factor 1 (IGF1), and it is strongly associated with cardiovascular diseases (CVD). Both acute and long-lasting pro-inflammatory effects have been attributed to IGF1. Previous results suggest the presence of systemic inflammation in treated patients. Here we assessed the association between treatment of acromegaly, systemic inflammation and vascular function. DESIGN: Ex vivo cytokine production and circulating inflammatory markers were assessed in peripheral blood from treated and untreated acromegaly patients (N = 120), and compared them with healthy controls. A more comprehensive prospective inflammatory and vascular assessment was conducted in a subgroup of six treatment-naive patients with follow-up during treatment. RESULTS: Circulating concentrations of VCAM1, E-selectin and MMP2 were higher in patients with uncontrolled disease, whereas the concentrations of IL18 were lower. In stimulated whole blood, cytokine production was skewed towards a more pro-inflammatory profile in patients, especially those with untreated disease. Prospective vascular measurements in untreated patients showed improvement of endothelial function during treatment. CONCLUSIONS: Acromegaly patients are characterized by a pro-inflammatory phenotype, most pronounced in those with uncontrolled disease. Treatment only partially reverses this pro-inflammatory bias. These findings suggest that systemic inflammation could contribute to the increased risk of CVD in acromegaly patients.

[E-health in long-stay psychiatric care: blended care psycho-education on psychosis]. / E-health in langdurige klinische zorg: psycho-educatie over psychose in de vorm van blended care.

We investigated the extent to which patients in long-stay psychiatric care can benefit from e-health applications. In our psychiatric hospital, we introduced a blended care course for psycho-education on psychotic disorders, in which we combined an internet module with face-to-face group sessions. We report on our findings, illustrated with a few vignettes.

The effects of water supply on infant and childhood mortality: a review of historical evidence.

The provision of clean water is mentioned as an important factor in many studies dealing with the decline of mortality in Europe during the late nineteenth and early twentieth centuries. In developing countries too, improved water supply is assumed to have a strong impact on mortality. When studying the effect of water supply on public health, researchers are confronted with many methodological problems. Most of these also apply to historical studies of the subject. We review the evidence from this historical research, taking into account the methodological problems observed in contemporary impact evaluation studies, and we use more refined data from the Dutch city of Tilburg, enabling us to overcome many of these shortcomings. Finally, we discuss some factors which may explain why we failed to discover an effect of the availability of piped water on the level of childhood mortality.

PIP: The UN designation of the 1980s as the International Drinking Water Supply and Sanitation Decade has stimulated research into the effect of water supply on public health. This paper opens with a review of studies that have attempted to quantify the impact of improved water supply (improved quality and/or increased quantity) on infant and child mortality in 19th- and early 20th-century France, the Netherlands, Germany, Sweden, and the US. The next section reviews studies on the health effects of water supply on contemporary populations in the developing world. The paper continues by discussing some of the methodological problems contained in such research including the difficulty of predicting the sign of the correlation between waterworks and morality rates, the difficulty in choosing which dependent variable to use, data limitations, problems finding appropriate control groups, unequal conditions prevailing before adoption of a specific public health improvement, failure to analyze mortality by age, and failure to determine seasonal differences. Next, a study of the effect of water supply on the population in the Dutch city of Tilburg in the early 20th century is presented. This study answers some of these methodological problems because it uses available individual-level data on health indicators and water supply. Analysis of the data, including use of a hazard rate model with the independent variables of water supply, socioeconomic status, father's income level, age of mother at birth, birth order of child, interval to next child, season of birth, number of rooms in the house, and district of birth, was performed for three age groups from birth to five elapsed years. This study revealed no discernable effect of the availability of piped water on the level of childhood mortality. The paper ends by proposing various explanations for these findings.

Role of genotoxicity assays in the regulation of chemicals in The Netherlands: considerations and experiences.

This paper discusses genotoxicity testing and data interpretation as applied in The Netherlands in the context of the regulation of chemicals. Guidelines were first formulated in 1981 and their use evolved in practice, on the basis of increasing experience at the national and international levels. The distinction between in vitro assays to detect intrinsic genotoxic properties and in vivo assays as a subsequent phase to show the realization of this potential in an intact organism has always been a cornerstone of the Dutch approach. Several critical aspects of the use of short-term genotoxicity tests in sequential schemes are discussed, such as their predictivity for carcinogenicity, the limited database concerning the performance of short-term in vivo assays, the relevance of devising separate strategies to test for possible carcinogenicity and germ cell mutagenicity, and the use of short-term tests to discriminate between genotoxic and non-genotoxic carcinogens. Examples are given of how short-term tests contributed to the toxicological evaluation of chemicals in The Netherlands.

Chronic inhalation toxicity and carcinogenicity study of methyl bromide in Wistar rats.

The toxicity and carcinogenicity of methyl bromide (MeBr) were studied in male and female Wistar rats exposed by inhalation to 0, 3, 30 or 90 ppm MeBr 6hr/day, 5 days/wk for 29 months. After 13, 52 and 104 wk ten rats/sex/group were killed to provide interim information. Body weights, clinical signs, haematology, biochemistry and gross and microscopic pathology were studied. Mortality was increased by wk 114 in the 90-ppm group. Body weights in males and females of the 90-ppm group were lower than those of the controls throughout the study. Increased incidences of degenerative and hyperplastic changes of the nasal olfactory epithelium were observed in all exposed groups, the incidences being positively correlated with the MeBr concentration; the nasal lesions did not progress appreciably with time. Exposure to 90 ppm MeBr was associated with an increased incidence of lesions in the heart (thrombi, myocardial degeneration), and with hyperkeratosis in the oesophagus and forestomach. Data on site, type and incidence of tumours in the various groups did not indicate carcinogenic activity of MeBr.

Chronic toxicity and carcinogenicity of bis(tri-n-butyltin)oxide (TBTO) in the rat.

In a 106-wk toxicity and carcinogenicity study, groups of 60 male and 60 female weanling Wistar rats were fed 0, 0.5, or 50 mg bis(tri-n-butyltin)oxide (TBTO)/kg diet. In males, feed consumption was increased in all treated groups and increased water consumption occurred at 5 and 50 mg/kg. During the second year, body weight decreased in the 50-mg/kg males, while the females in that group showed no weight gain. Excess mortality was confined to the 50-mg/kg group towards the end of the study. Haematological changes, comprising anaemia, lymphocytopenia and thrombocytosis were noted mainly at the high-dose level. Also, signs of decreased kidney function and increased plasma enzyme activities (alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase) were noted. No effects on serum hormone concentrations (thyrotropin, follicle stimulating hormone, luteinizing hormone or insulin) were observed, except for a decrease in the free thyroxin:thyroxin ratio in both sexes at the high-dose level. Higher serum IgM and IgA levels were present at 50 mg/kg, while, in females, IgG was decreased. At 50 mg/kg, the ovaries, adrenals, spleen (females), heart (males), pituitary, liver and kidneys were increased in weight, but the thyroid weight was decreased in females. The total tin concentrations in liver and kidneys showed a dose relationship and, in general, the concentrations were similar after 1 and 2 yr. Non-neoplastic histological alterations after 1 yr consisted of a decrease in the cell height of the thyroid follicles in all dose groups, with a reduced number of psammoma bodies at 50 mg/kg, a decrease in splenic iron content at 5 (females only) and 50 mg/kg, and a slight bile-duct activation. After 2 yr, only the thyroid changes were still present. In addition, at 2 yr, vacuolation and pigmentation of the proximal tubular epithelium and nephrosis were enhanced at 50 mg/kg. The incidence of benign tumours of the pituitary was significantly elevated and enhanced at 0.5 and 50 mg/kg. At 50 mg/kg increases in pheochromocytomas in the adrenal medulla and in parathyroid adenomas (males) were noted, while adrenal cortical tumours were decreased (males). There was a low, non-dose-related incidence of pancreatic carcinoma. Other tumour rates were in line with control data. It is concluded that lifetime feeding of 50 mg TBTO/kg diet induces toxicity in various organ systems. An increase in some common tumours was found at the high dose, probably due to hormonal or immunological changes.(ABSTRACT TRUNCATED AT 400 WORDS)

Asbestos: toxicology and risk assessment for the general population in The Netherlands.

Within the scope of the preparation of Integrated Criteria Documents for priority compounds in The Netherlands, the possible health effects of oral and inhalatory exposure to asbestos for the general population were evaluated. It was concluded from the results of experiments in animals that exposure to asbestos by the oral route is not carcinogenic and is not expected to present a health risk to the general population. Inhaled asbestos, however, is distinctly carcinogenic to man, giving rise to lung tumours, and mesotheliomas of the pleura and peritoneum. Chrysotile asbestos appears to be less potent in inducing mesotheliomas than the amphiboles, but all types of asbestos appear to have a similar potency for inducing lung cancer. The risk of mesothelioma is not expected to be influenced by smoking, whereas the risk of lung cancer is expected to be ten times higher in smokers than in non-smokers exposed to the same asbestos concentrations. Risk-assessment models for the inhalatory route, for the general population, are based on linear non-threshold extrapolation of occupational exposure to much lower environmental concentrations. These models give only a rough approximation of the risk of environmental exposure to asbestos. In accordance with the Air Quality Guidelines of the World Health Organization (World Health Organization, 1987), it was estimated that an extra risk of lung cancer of one in 10(6) (in the general population, with 30% smokers) may be presented by lifetime exposure to asbestos fibres longer than 5 microns, measured by electron microscopy, at concentrations of 100-1000/m3. It was further estimated that an extra risk of mesothelioma of one in 10(6) may be presented by lifetime exposure to 10-100 amphibole fibres/m3 or to a range of 100-10000 chrysotile fibres/m3 (fibres longer than 5 microns). From the current asbestos concentrations, the risk of mesothelioma for the general population in The Netherlands appears to be negligible; the extra risk of lung cancer is expected to be higher than 1 in 10(6) near asbestos sources, whereas it appears to be negligible in background areas and in most large cities and industrial areas. However, it must be borne in mind that the validity of the risk figures given is difficult to judge.

Aspartame: review of recent experimental and observational data.

In this report the neurotoxicity of aspartame and its constituent amino acids aspartic acid and phenylalanine is reviewed. The adverse reactions ascribed to the consumption of aspartame-containing products, as reported in the U.S.A., are discussed and placed in perspective with the results of recent behavioural studies in humans and animals. The issue of common intake levels associated with proposed uses of aspartame is addressed. In brief, the following conclusions can be drawn: When aspartame is consumed at levels within the ADI-limit of 40 mg/kg body wt, there is no significant risk for an aspartate-induced neurotoxic effect in the brain. When aspartame is consumed at levels within the ADI-limit by normal subjects or persons heterozygous for phenylketonuria (PKU) the resultant plasma phenylalanine concentrations are practically always within the normal postprandial range; elevation to plasma concentrations commonly associated with adverse effects has not been observed. Persons suffering from phenylketonuria (PKU-homozygotes) on a phenylalanine-restricted diet should avoid consumption of aspartame. PKU-homozygotes on the (less strict) phenylalanine-liberalized diet should be made aware of the phenylalanine content of aspartame. In the available behavioural studies in humans with acute dosing, no adverse effects were observed. Long-term studies on behaviour and cognitive function in (sensitive) humans are lacking. Analyses of adverse reaction reports made by consumers in the U.S.A. have not yielded a specific constellation of symptoms clearly related to aspartame that would suggest a widespread public health hazard associated with aspartame use. Focussed clinical studies are now being carried out in the U.S.A.; the results should provide additional evidence concerning the interpretation of the reports on adverse reactions ascribed to aspartame. In the regulation of admitted uses for aspartame the possibility of intake levels exceeding the ADI-limit in some groups of consumers should be a point of attention.

Evaluation of the genetic and embryotoxic effects of bis(tri-n-butyltin)oxide (TBTO), a broad-spectrum pesticide, in multiple in vivo and in vitro short-term tests.

The genetic and embryotoxic effects of bis(tri-n-butyltin)oxide (TBTO) were evaluated in multiple in vivo and in vitro short-term tests preparatory to its potential wide use as a molluscicide in control of schistosomiasis. When tested in the rec assay in Bacillus subtilis, TBTO was not mutagenic and it did not induce reverse mutations in Klebsiella pneumoniae. Neither in the presence nor in the absecne of rat liver activation system did TBTO produce point mutations in Salmonella typhimurium strains TA1530, TA1535, TA1538, TA97, TA98 or TA100. TBTO was matagenic in strain TA100 in a fluctuation test, but only in the presence of rat liver S9 (Aroclor-induced). TBTO did not induce gene mutations in the yeast Schizosaccharomyces pombe, mitotic gene conversions in the yeast Saccharomyces cerevisiae, nor sister-chromatid exchange in Chinese hamster ovary cells in the presence or absence of rat or mouse liver S9. In the latter cells, structural chromosomal aberrations, endoreduplicated and polyploid cells were induced. TBTO did not induce gene mutations in V79 Chinese hamster cells (to 8-azaguanine-, ouabain- or 6-thioguanine-resistance) in the presence of a rat liver postmitochondrial fraction or in cell (hamster embryo cells and human and mouse epidermal keratinocyte)-mediated assays. In mouse lymphoma cells, TBTO did not induce 6-thioguanine- or BUdR-resistant mutations. As many tumour promoters inhibit metabolic cooperation between V79 Chinese hamster 6-thioguanine-resistant/-sensitive cells, TBTO was tested but showed no such activity. TBTO was examined for the induction of recessive lethal mutations in adult Berlin K male Drosophila melanogaster, either by feeding or by injection. Doses of 0.37 or 0.74 mM did not increase the number of X-linked recessive lethal mutations. An increased number of micronuclei was observed in the polychromatic erythrocytes of male BALB/c mice 48 h after a single oral dose of TBTO (60 mg/kg bw), while a lower dose (30 mg/kg bw) was ineffective. Neither of the two doses had induced micronuclei 30 h after treatment. The reproductive toxicity of TBTO was studied in NMRI mice. In a 10-day toxicity study, the LD50 and LD10 were 74 and 34 mg/kg bw, respectively. An increased frequency of cleft palates was seen in the fetuses of mice (compared with controls, 0.7%) treated orally during pregnancy with 11.7 mg/kg TBTO (7%), 23.4 mg/kg (24%) or 35 mg/kg (48%).(ABSTRACT TRUNCATED AT 400 WORDS)

Toxicology of gallates: a review and evaluation.

The propyl, octyl and dodecyl esters of gallic acid have been studied extensively in a large number of animal experiments involving oral dosing. Experimental data on general toxicity and studies on reproduction, teratogenicity and mutagenicity are also available. Most of the key toxicity studies, however, date back to the 1950s, do not meet current standards of toxicity testing and do not provide evidence for carcinogenic or mutagenic action of the gallates. Mutagenicity studies with octyl gallate and dodecyl gallate are lacking. The biokinetics of propyl gallate apparently differ from those of octyl and dodecyl gallate, the octyl and dodecyl esters being absorbed and hydrolysed to a lesser degree than the propyl ester. In toxicity studies with propyl gallate, growth retardation, anaemia, kidney and liver changes and hyperplasia of the forestomach were the most prominent effects at dose levels above 10,000 mg/kg feed. At 5000 mg/kg feed, liver enzyme induction was seen. In the available studies with octyl gallate or dodecyl gallate as the test compound, effects were found at 3000 mg/kg feed or higher levels. In studies performed with the various gallates, no effects were observed at a dose level of 1000 mg/kg feed, a level that was adopted as the no-effect level by the FAO/WHO Joint Expert Committee on Food Additives (JECFA) in 1976. This committee established an acceptable daily intake (ADI) for man of 0.2 mg/kg body weight (as a sum of propyl, octyl and dodecyl gallates). A re-evaluation of the toxicity of gallates indicates that a 'classic' long-term toxicity study of propyl gallate meeting current standards is required. As yet, the available toxicological evidence indicates that gallates may be used safely as antioxidants.

Carcinogenicity study in rats with a mixture of eleven volatile halogenated hydrocarbon drinking water contaminants.

A lifetime carcinogenicity study was carried out in Wistar rats, with a mixture of the following halogenated hydrocarbons: trichloromethane, tetrachloromethane, monobromodichloromethane, trichloroethylene, tetrachloroethylene, 1,2-dichlorobenzene, 1,3,-dichlorobenzene, 1,4,-dichlorobenzene, 1,2,3,-trichlorobenzene, 1,2,4,-trichlorobenzene, 1,3,5-trichlorobenzene. From this mixture 0.22, 2.2, or 22 mg was added per liter drinking water representing concentrations being three orders of magnitude higher than found in several water wells. Most of the changes found in body weight, hematology and pathology correlated with intercurrent diseases or were in accordance with background pathology. With respect to incidence and time of occurrence of tumors, no significant differences were found between the control and the high dose group when lifespan correction was applied. Thus it is concluded that in the present study no significant toxic or carcinogenic effects are induced by lifetime exposure of rats to a mixture of volatile halogenated hydrocarbons in the drinking water.

Critical considerations on the significance of carcinogenic and mutagenic compounds in drinking water.

Public and scientific concern has been expressed on the possible hazards of trace amounts of organic compounds with carcinogenic and mutagenic properties, identified in drinking water. For a number of these compounds, the carcinogenicity is well established according to IARC criteria, but the extremely low concentrations (less than 1 microgram/l) indicate a neglectable risk to humans. Some compounds, mainly volatile halogenated alkylated hydrocarbons, may be present at higher concentrations, but for these the weight of evidence for carcinogenicity often is very poor, being demonstrated in mouse liver only. The relevance of mouse liver tumours may be seriously questioned, especially after exposure to hepatotoxic doses and in the absence of sufficient evidence for genotoxicity. It is therefore not justified, to use a non-threshold approach in the toxicological evaluation of these compounds. More or less similar conclusions can be derived for the organic "mutagens" identified in water, that is either their concentration is extremely low or sufficient evidence for genotoxicity is lacking. It is concluded therefore, that, at the present time, drinking water in the Western world can be regarded in general as "chemically safe".

Carcinogenicity study with epichlorohydrin (CEP) by gavage in rats.

Weanling Wistar rats of both sexes were given epichlorohydrin by gastric intubation for 2 years, 5 times a week at dosages of 0, 2, and 10 mg/kg body weight. Mortality and body weight gain were recorded and histopathological examination for tumours was carried out; after 1 year also haematology was performed. Towards the end of the study a slight dose-related increase in mortality was observed in males, along with a decrease in mean body weight in the survivors. At pathological examination a high incidence (100% for females, 81% for males) of squamous cell carcinomas of low-grade malignancy was observed in the forestomach of animals at risk (greater than 18 months) from the 10 mg/kg group. In the 2 mg/kg group forestomach tumours were found at a lower incidence (7% for females, 14% for males), whereas this tumour was not found in control animals. Other tumours diagnosed in this study occurred at background level and were not influenced by treatment.

Induction of early lesions in the forestomach of rats by 3-tert-butyl-4-hydroxyanisole (BHA).

BHA was administered to Wistar rats at a dose level of 2% in a powdered diet for periods of 1, 2 and 4 wk. After 1 wk epithelial damage, mild hyperplasia and hyperkeratosis of the forestomach mucosa was observed. The hyperplasia and hyperkeratosis showed progression at wk 2 and 4 whereas other epithelial defects regressed. The lesions were most pronounced in the vicinity of the limiting ridge. A further 4 wk of feeding without BHA resulted in a complete regression of epithelial defects, although the hyperplastic changes were still apparent. Other rats were given 1 g BHA/kg body weight/day by gastric intubation in arachis oil for 1, 2, 4, 8, 16 or 32 days. Increased mitotic activity was observed after 1 day and mild hyperplasia after the second intubation, but inflammatory response and superficial defects were not prominent and the hyperplasia of the squamous epithelium did not appear to result from initial damage and subsequent hyper-regenerative activity. A gradual regression of the hyperplastic changes occurred after eight daily intubations. The lesions were found in the apex of the forestomach remote from the limiting ridge. It is concluded that BHA incorporated in powdered diet or given in arachis oil by oral intubation causes lesions in the rat forestomach similar to that reported for BHA given in a pelleted diet (Ito et al. J. natn. Cancer Inst. 1983, 70, 343; idem, Gann 1983, 74, 459). The hyperplastic changes in the mucosa occur rapidly and their localization is dependent on the mode of application. Following withdrawal of the BHA there was almost complete regression of the lesion, only a residual mild hyperplasia remaining after 4 wk.

Mutagenicity of methyl bromide in a series of short-term tests.

Methyl bromide is commonly used as a soil fumigant in greenhouses. In the framework of a toxicological evaluation, it was tested for possible genotoxic properties in two bacterial test systems (the fluctuation test using Klebsiella pneumoniae and the plate test using Salmonella typhimurium TA100 and TA98), two systems using mammalian cells in vitro (forward mutations at the TK and HPRT loci in L5178Y mouse lymphoma cells and unscheduled DNA synthesis in primary rat-liver cells) and in the sex-linked recessive lethal test using Drosophila melanogaster. Methyl bromide was active in all tests except the DNA-repair assay. The results indicate a relatively low mutagenic efficiency of the compound, as expected from its alkylating properties.