Review of risk factors for osteoporosis with particular reference to a possible aetiological role of dietary salt.

Laboratory animal, clinical and epidemiological studies in the published literature have been reviewed in order to establish whether excessive salt intake is an important risk factor for the development of osteoporosis and whether an intervention strategy based on salt restriction would be beneficial in the prevention of osteoporosis. Genetic factors appear to be far more important than the combination of nutritional, hormonal, environmental and lifestyle factors in the pathogenesis of osteoporosis. The most important single non-genetic factor is oestrogen deficiency in postmenopausal women. Preventive measures should be aimed at maximizing peak bone mass at skeletal maturity and retarding bone loss thereafter. Apart from postmenopausal oestrogen deficiency, various factors have been incriminated as risk factors for osteoporosis, and these include age at menarche, age at and years since menopause, insufficient physical exercise, alcohol, smoking, low calcium intake, low or high protein intake and high intake of phosphorus, sodium or caffeine. Many of the risk factors are considered to be weak, although when combined they could impact significantly on bone health. Increased intakes of various nutritional factors (potassium, magnesium, zinc, vitamin C), fibre and alkaline-producing fruit and vegetables favour adult bone health. Calcium homeostasis is normally well regulated such that increased calcium loss via the urine leads to increased calcium absorption from the gut. However, the duration of this adaptive process may be greater than that of many of the studies demonstrating that increased salt intake leads to both increased sodium and calcium in the urine. In any case, higher urinary calcium output appears to be seen only in a minority of humans in response to increased salt intake. As numerous factors-genetic, nutritional, hormonal and lifestyle-are involved in the maintenance of calcium homeostasis, it is difficult to devise human studies which adequately take into account all the important factors. Another difficulty is that many past studies have relied on imprecise methods for the measurement of bone resorption. Nor have studies based on the use of the laboratory rat produced clear answers to the problem because the rat, as a species, is uniquely deficient in its ability to handle the relevant minerals. Limited studies to date indicate that increased sodium intake neither exerts a consistent effect on various biomarkers of bone health nor leads to irreversible changes in the bone modelling process in men or in pre- or postmenopausal women. We conclude from the available evidence that increased sodium (or salt) intake is not an important risk factor for osteoporosis and that a reduction of salt intake from 9 to 6g/day in the diet would not be beneficial as an intervention measure in the prevention of osteoporosis. More research is needed to (i) assess the effects (especially long-term) of various nutrients including sodium on bone health, (ii) assess the long-term value of any intervention strategy involving reduced intake of a particular nutrient such as sodium; and (iii) determine whether subpopulations exist particularly in the elderly (e.g. sodium-responsive subjects) in which adaptation to sodium-induced hypercalciuria may be compromised. General prudence dictates that excessively high levels of dietary salt should be eschewed by those persons with raised blood pressure or a limited range of genetic disorders. However, for the generally healthy person there is no sound evidence that the consumption of salt at the present average level of 9g/day constitutes a risk factor for osteoporosis.

Accuracy of clinical diagnosis of lung cancer in Budapest in an institute specializing in chest diseases.

Among 250 consecutive autopsies (170 males and 80 females) performed at the Institute of Pulmonology in Budapest in 1996/7, there were 132 deaths in which cancer of the lung/bronchus was deemed to be the underlying cause of death. At autopsy, six cases previously thought to be dying from lung cancer were found to have died from other diseases (false positive rate = 5%). Twelve lung cancer deaths were also found to have been missed, a false negative rate of 9%, which was similar for adenocarcinoma, squamous carcinoma, and small cell carcinoma cases. Our findings confirmed the expectation expressed earlier that death certification of lung cancer would be more accurate in an institute specializing in chest diseases, to which patients had to be fit enough to be transferred, than in two general hospitals in Budapest. Nevertheless, since most cases certified as dying from lung cancer die without the benefits available in the specialized institute, the estimated false negative and positive rates for lung cancer death certification in Hungary remain high, at an estimated 56% and 30%, respectively. The much lower autopsy rates in most other countries than in Hungary points to there being considerable inaccuracy in lung cancer mortality rates internationally.

The safety-in-use of 10% carbamide peroxide (Opalescence) for bleaching teeth under the supervision of a dentist.

Fears that the dentist-supervised use of a product that contains carbamide peroxide and that emits hydrogen peroxide may not be safe from the viewpoints of toxicity and cancer risk were engendered by unrealistic animal tests. These fears prompted the UK Government Departments of Trade and Industry (DTI) and of Health (DOH) to try to prohibit the marketing of Opalescence (manufactured by Ultradent Inc.). Faced with the fact that Opalescence had already been awarded a CE mark under the EC Medical Devices Directive, the DTI and DOH attempted to bring about its prohibition by reclassifying Opalescence as falling under the EC Cosmetics Directive, according to which the marketing of products containing more than 0.1% hydrogen peroxide is not permitted.

A brief history of the use of laboratory animals for the prediction of carcinogenic risk for man with a note on needs for the future.

This review discusses developments during the last 60 years in the field of carcinogenicity testing based on the use of laboratory animals. Improvements that have occurred in the quality of animals and in the way in which tests are conducted are considered, along with the importance of distinguishing between fatal and incidental tumours. Still to be faced is a need to control calorie intake in the course of carcinogenicity testing. A necessity for a better understanding of how disturbances of physiological and/or hormonal status can predispose to tumour development and for more comparative metabolism studies is stressed. Recognition of the fact that thresholds exist for carcinogenesis by non-genotoxic compounds poses a need for avoiding unrealistically high levels of exposure and for more and better information on how different species metabolise test agents.

Evaluation of the aetiological role of dietary salt exposure in gastric and other cancers in humans.

The findings in laboratory and epidemiological studies relevant to the assessment of salt for carcinogenic potential are reviewed. Associations between the high consumption of certain highly salted foodstuffs, particularly in some oriental countries, and increased risk of cancer of the stomach do not incriminate salt per se. Some highly spiced foods contain potent genotoxic carcinogens, irrespective of whether they also contain salt. There is evidence in laboratory animals that high concentrations of salt may increase the incidence of gastric cancer caused by such carcinogens. This may well be attributable to a marked and sustained regenerative response in the gastric mucosa of laboratory animals chronically exposed to the cytotoxicity of hyperosmolar concentrations of salt, such a mitogenic response favouring the progression towards neoplasia. However, there is no laboratory evidence whatsoever to indicate that salt per se is a carcinogen for any site in the body; neither is there any reliable epidemiological evidence to indicate that dietary salt affects the incidence of gastric or other cancers. A particular problem in the interpretation of epidemiological studies is that the consumption of diets containing highly salted, spicy foods is often associated with low intakes of fruit and green vegetables, which contain cancer-protective antioxidants. In Western countries the incidence of cancer of the stomach has been falling for some 50 years. The consensus view is that this fall is attributable to improved food hygiene and increasingly available facilities for refrigeration. There are no grounds for supposing that the fall is attributable to a decreasing intake of salt. A high dietary salt intake does not necessarily entail exposure to salt in concentrations high enough to damage the gastric mucosa. The typical Western diet would not be expected to provide such high salt concentrations. It is concluded that there are no grounds for believing that a reduction in the average daily salt intake in the Western diet would have any effect on the risk of developing any form of cancer.

Long-term inhalation toxicity of N-vinylpyrrolidone-2 vapours. Studies in rats.

In previous subchronic studies inhaled N-vinylpyrrolidone-2 (NVP) was haemotoxic, hepatotoxic and irritant to the nose. In the first of two long-term studies, study A, Sprague-Dawley rats were exposed by inhalation to 0, 5, 10 or 20 ppm NVP (6 hr/day, 5 days/wk) for 24 months. Satellite groups were killed after 3, 12 or 24 months. In study B, female Sprague-Dawley rats were exposed to 0 or 45 ppm NVP for 3 months and killed at 3 or 12 and 24 months post-exposure. In study A, survival was unaffected, but reduced body weight gain, haemotoxicity, effects on clinical chemistry parameters indicative of hepatotoxicity, increased liver weight, hepatocellular carcinomas, necrosis, reparative hyperplasia, adenomas and adenocarcinomas of the nasal cavity, and squamous cell carcinomas of the larynx were seen. Increased tumour incidence was seen only in the liver and upper respiratory tract. In study B, the effect of NVP on body weight evident at 3 months disappeared before 1 yr, but effects on liver pathology persisted throughout the subsequent 21-month exposure-free period, and a few liver tumours were seen at 2 yr. As NVP gave negative results in a battery of in vitro and in vivo genotoxicity tests, it appears that the tumours that arose were manifestations of a non-genotoxic mechanism.

Subchronic inhalation and oral toxicity of N-vinylpyrrolidone-2. Studies in rodents.

N-Vinylpyrrolidone-2 (NVP) is a monomeric compound used as an industrial intermediate. Nine of 11 studies previously reported involved exposure of rats (two different strains), mice or hamsters to NVP by the inhalation route at concentrations of up to 120 ppm (6 hr/day, 5 days/wk) over a period of 1 wk to 12 months. The remaining two studies involved exposure of rats to NVP through the drinking water or by gavage at dose levels of up to 100 mg/kg body weight/day. Reduced body weight gain was seen in rats exposed by inhalation to 5 ppm or more for 3 months and in mice and hamsters exposed to 45 ppm for only 1 day. Effects were seen on haematological (reduced haemoglobin, erythrocyte count, haematocrit) and clinical chemistry parameters (specially raised gamma-glutamyltransferase activity and decreases in plasma protein), liver weight increase and liver lesions (centrilobular single-cell necrosis and foci of hepatocellular alteration) in rats and mice but not hamsters. Rats exposed to 40 mg/kg body weight/day NVP or more for 3 months by gavage developed similar liver changes. Atrophy of olfactory epithelium and hyperplasia of nasal respiratory epithelium was seen in rats exposed by inhalation to 5 ppm NVP for 7 wk but not in response to 1 ppm for 13 wk (no observed-adverse-effect level, NOAEL). These studies indicated that the upper respiratory tract and the liver are the main targets for NVP toxicity.

Accuracy of admission and clinical diagnosis of tumours as revealed by 2000 autopsies.

Admission, clinical and autopsy diagnoses of tumour were computed in 2000 consecutive cases, aged 30-80 years, using data collected in two university pathology departments in Budapest, Hungary. Based on diagnosis of tumour, regardless of site, as the underlying cause of death false-negative rates were 37.4% at admission and 8.8% clinically. Corresponding false-positive rates were 8.4 and 9.1%. General practitioners who correctly diagnosed a tumour as the cause of the terminal illness identified the primary site wrongly in 20.6% (90/436) of cases. Hospital clinicians did so in 20.4% (130/636) of cases. Overall, of site-specific tumours considered as the underlying cause of death at autopsy, 27.4% were incorrectly diagnosed clinically and 50.4% at admission. Diagnostic errors were particularly common for tumours of the lung, liver, ovary and gall bladder. Graduate and postgraduate education, planning of the health care system and quality of cancer care may benefit from statistical data derived from autopsy diagnoses.

Misdiagnosis of lung cancer in a 2000 consecutive autopsy study in Budapest.

OBJECTIVE: To determine the accuracy of lung cancer mortality data based on clinical observations in the absence of autopsy and to identify factors affecting the accuracy of diagnosis. METHODS: Admission, pre-autopsy and post-autopsy diagnoses were recorded for 1000 consecutive autopsies in each of two University departments in Budapest with high autopsy rates for persons dying in hospital. In those 87 cases where one or more diagnosis included primary lung cancer, additional data were collected concerning clinical investigations relevant to the diagnosis and the histological type lung cancer, and on smoking habits. RESULTS: 59% (36/61) of lung cancers seen at autopsy were not detected pre-autopsy, while 50% (25/50) of those diagnosed pre-autopsy were not confirmed at autopsy. Many misdiagnoses arose because patients were too ill to be properly investigated and/or died before investigations could be completed. Accuracy of diagnosis increased with the number of diagnostic techniques applied, but was still far from perfect in the absence of necropsy. Underdiagnosis was commoner in non-smokers and overdiagnosis commoner in smokers. CONCLUSIONS: Without necropsy, lung cancer misdiagnosis is common, especially when modern diagnostic procedures cannot be fully employed. Knowledge of smoking habits may affect diagnostic accuracy.

The Biosure Study: influence of composition of diet and food consumption on longevity, degenerative diseases and neoplasia in Wistar rats studied for up to 30 months post weaning.

The 1200-rat Biosure Study had six interrelated aims: (1) To see whether dietary restriction (80% ad lib.) reduces the age-standardized incidence of fatal or potentially fatal neoplasia before the age of 30 months. (2) To see whether the beneficial effects of diet restriction can be achieved by (a) limiting the daily period of access to food to 6 hr, or by (b) limiting the energy value of the diet. (3) To see whether reduced calorie intake between weaning and age 4 months influences survival and/or incidence of non-neoplastic and neoplastic diseases. (4) To compare effects of food consumption, energy intake and protein intake on survival and disease. (5) To study the relationships between body weight at different ages with eventual survival and disease incidence. (6) To provide a database for studying relationships between various in-life measurements and eventual survival and disease incidence in individual animals. Twelve groups of SKF Wistar rats consisting of 50 animals of each sex were fed according to different dietary regimens from when they were weaned at the age of 3 wk until they died, or had to be killed because they were sick, or until the experiment was terminated at 30 months. For five of the 12 dietary regimens, satellite groups consisting of 30 animals per sex were maintained in parallel and used to supply information on the effect of diet on circulating hormone levels during the course of the study. During the 13 wk post weaning a Standard Breeder diet (SB) was provided either ad lib. (four groups), 80% ad lib. (three groups), or with access to food limited to 6 hr per day (one group). During this same period two other groups were fed a Low Nutrient Breeder diet (LB) ad lib. A further group was fed a Low Nutrient Maintenance (high fibre) diet (LM) ad lib. Finally, one group was fed the high protein Porton Rat diet (PR) ad lib.(ABSTRACT TRUNCATED AT 400 WORDS)

Accuracy of admission and pre-autopsy clinical diagnoses in the light of autopsy findings: a study conducted in Budapest.

Pre- and post-autopsy diagnoses of underlying cause of death were compared in consecutive autopsies on persons aged 30 to 80 years; 1000 from each of two pathology departments in Budapest. Data on admission diagnoses and on contributory causes of death were also analysed. At autopsy, the percentages of deaths by underlying cause were neoplasms (any site) 34.9%, diseases of the circulatory system 40.2%, digestive system 13.8%, endocrine, nutritional, metabolic or immune systems 2.7%, and respiratory system 2.2%. For these five disease groupings, the percentages of cases diagnosed clinically as the underlying cause of death which were confirmed at autopsy were, respectively, 90.9%, 84.0%, 82.9%, 55.2% and 32.5%. Although, out of 697 cases with an autopsy diagnosis of neoplasia as the underlying cause, there were only 61 (8.8%) where neoplasms were not diagnosed clinically as the underlying cause, this conceals the fact that in 130 (18.7%) the two diagnoses differed as to the site of the primary neoplasm (ICD 3 digit code). The fact that 43% of post-mortem diagnoses (ICD major category) of underlying cause are missed on admission, and that 19% are missed clinically, indicates that improved clinical diagnostic procedures have not diminished the need for high autopsy rates. Morbid anatomy needs to be better resourced.

Historical histopathological control data for laboratory rodents: valuable treasure or worthless trash?

The reasons for variation in longevity and disease incidence in untreated control animals in chronic toxicity and carcinogenicity tests in laboratory rodents are reviewed and discussed. Genetic drift, dietary composition, caloric intake, age of animals at the termination of studies, the skill, experience and diligence of the pathologist, the diagnostic criteria used and the appropriateness of statistical procedures are considered to be the most important sources of variation. It is suggested that more attention needs to be paid to the sources of nutrients in animal diets and that 'closed formula' diets should be eschewed. The reliability of historical data depends critically on the extent to which 'like' can be compared with 'like'. The most important variables in relation to histopathological data are considered in this context.

Styrene: toxicity studies--what do they show?

Styrene is efficiently metabolized to styrene oxide, which is itself readily detoxified by the same enzymes as those involved in the metabolism of various foodstuffs. Styrene oxide, like many intermediate metabolites of foodstuffs, is genotoxic and, if introduced directly into the stomachs of rodents in high doses/concentrations, gives rise to cancers of the forestomach. Exposing mice to doses of styrene high enough to overwhelm the capacity of the body to detoxify styrene oxide has been reported to increase lung tumor incidence in mice. The findings in eight epidemiological studies provide reassurance that occupational exposure to styrene is not associated with increased cancer risk. Tests for reproductive toxicity have given negative results, but effects on blood dopamine and hypothalamic and pituitary function and menstrual cycling under conditions of very high exposure have been reported. In light of all the available information, it is concluded that migration of styrene from food-wrapping materials is not a matter for toxicological concern.

Review of lead toxicology relevant to the safety assessment of lead acetate as a hair colouring.

The literature on lead toxicology has been critically reviewed to provide a safety assessment of lead acetate as a hair colouring. The main objectives were: (i) to determine the additional lead contribution from hair-colouring use to the total daily environmental lead intake; and (ii) to assess the toxicological significance of this additional contribution. The review also focuses attention on newer issues of concern over the effects of environmental lead on human health. Data available in animals and humans (including occupational exposure), mainly on lead acetate and other inorganic lead salts, have been presented and evaluated in respect of the following: absorption, distribution and excretion following ingestion; percutaneous absorption; carcinogenicity; genotoxicity; reproductive toxicity; neurological/behavioural status with particular reference to neuropsychological effects in children; and effects on other systems (e.g. cardiovascular). It is concluded that the absorption of lead from hair-colouring use represents about 0.5% of the lead absorption from the current average daily environmental lead intake. No convincing evidence could be found of any deleterious effect of current environmental lead levels on human health and thus the tiny contribution of lead acetate exposure from hair-colouring use can be regarded unequivocally as being toxicologically insignificant.

Risks of premature death and cancer predicted by body weight in early adult life.

In a study of 30 months duration, involving 600 male and 600 female Wistar rats fed on 12 different diets/dietary regimes, none of which involved deliberate exposure to any known genotoxic carcinogen, highly significant between-group differences were observed in survival and incidence of various neoplastic and non-neoplastic diseases. A full report of the findings is being prepared. Here we report that, irrespective of diet or dietary regime, there were highly significant correlations of body weight at 29 weeks of age with premature death (P less than 0.0001 in both males and females), with development of benign or malignant neoplasm of any site (P less than 0.0001 in males and P less than 0.01 in females) and with development of malignant neoplasm at any site (P less than 0.0001 for sexes combined). Numerous kinds of neoplasm contributed to these overall correlations. The most significant were pituitary tumour (P less than 0.0001), mammary gland tumour (P less than 0.0001), squamous or anaplastic carcinoma of the jaw (P less than 0.001), and subcutaneous mesodermal tumours (P less than 0.05). The 20% of rats that were heaviest at 29 weeks were more than twice as likely to die prematurely than the lightest 20% (2.56 times--males, and 2.11 times--females), and almost twice as likely to develop a malignant tumour (1.87 times for the sexes combined). These findings have important implications for the design and interpretation of carcinogenicity tests in rodents and of laboratory and human studies of relationships between diet, ageing-related degenerative diseases, and cancer.