Shortcomings of current strategy for toxicity testing of food chemicals: polyols.
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Animals↗
Biomedical subjects
F J Roe
Publications and source records attributed to F J Roe.
Influence of food intake and sexual segregation on longevity, organ weights and the incidence of non-neoplastic and neoplastic diseases in rats.
In a small-scale experiment the effects of four variables were investigated in male and female Wistar rats fed on a standard laboratory chow and not deliberately exposed to any carcinogen. The variables investigated were (i) diet restriction by limiting access to food to 6.5 hr/day instead of 24 hr/day; (ii) housing males in a single-sex room as distinct from a mixed-sex room; (iii) life-long segregation of males from females, as distinct from access to one virgin female for 5 days during each alternate week; and (iv) uniparity in females versus life-long virginity. The endpoints compared were body-weight gain, longevity, visible and palpable swellings, absolute and relative organ weights, microscopically confirmed malignant neoplasms that contributed to death before the end of the study at 2 yr, incidence of other neoplasms in decedents and rats killed at the end of the study, and the incidence of various non-neoplastic conditions including myocardial inflammation and fibrosis, chronic progressive nephropathy, liver glycogen storage and fatty degeneration, mammary gland hyperplasia and secretory activity, pancreatic polyarteritis, radiculoneuropathy and certain testicular changes. The results indicated major beneficial effects of dietary restriction on most of the endpoints. By comparison the other variables had only marginal effects. Leydig-cell hyperplasia and neoplasia occurred at significantly higher incidences in males housed intermittently with females than in permanently segregated males. No convincing differences were seen between females that littered once and those that remained virgins. The relevance of these findings to the prediction of cancer mortality risk in man and to the design of rodent carcinogenicity studies is discussed.
Animals↗
Occupational cancer: interaction with life style factors.
It is argued that as the major occupational cancer risks become matters of historical interest, research epidemiologists working in the field should broaden their approaches to encompass life style factors. In the investigation of possible low-cancer risks, it no longer makes any sense to confine their data-collecting activities solely to exposure to dusts and chemicals at work and to regard exposure to chemicals at home, in the garden or during leisure activities simply as possible confounding variables. Furthermore it is becoming more and more meaningless to undertake any epidemiological investigation aimed at detecting or defining a low level of cancer risk without taking into account what and how much, for example, people eat, drink and smoke. Possible exposure to chemicals at work is increasingly becoming a source for confounding variables in relation to life-style-associated cancer risks, as distinct from life-style being a source of confounding variables in epidemiological studies of occupation-associated cancer risks.
Female↗
Non-genotoxic carcinogenesis: implications for testing and extrapolation to man.
It is argued that non-genotoxic mechanisms may be more important than genotoxic mechanisms in the genesis of cancer and that the use of tests for genotoxicity to screen chemicals for carcinogenicity in the hope of being able to prevent human cancer is ill-based. The general applicability of the two-stage model for carcinogenesis is also questioned. It is argued that tumour promotion as a second step in a two-stage process is only one of many possible non-genotoxic mechanisms involved in carcinogenesis and not a very important one at that. Many cancers arise against a background of prolonged disturbance of hormonal status leading to hypertrophy and/or hyperplasia of the tissues in which cancers eventually arise. This sequence of events does not fit the two-stage paradigm according to which genetic-damage (initiation) is followed by the stimulation of cell proliferation (promotion). In hormonal carcinogenesis cellular proliferation precedes genetic damage. It is suggested that the genetic damage that occurs as a secondary event in hormonal carcinogenesis may be due, not to exposure to environmental (exogenous) mutagens, but to endogenous mutagens generated during normal metabolic processes in hyperplastic and hypermetabolic cells. Perhaps the rate of damage to DNA in such cells overwhelms the capacity for DNA repair. Cancer is an ageing-related disease. The incidence and severity of both non-neoplastic and neoplastic lesions are greatly enhanced by over-nutrition in laboratory rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Relevance for man of the effects of lactose, polyols and other carbohydrates on calcium metabolism seen in rats: a review.
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Animals↗
Toxicity testing: some principles and some pitfalls in histopathological evaluation.
1. The aims of toxicity tests vary according to the use or proposed use of the substance to be tested. 2. More knowledge about physiological and homeostatic control mechanisms will be needed before one can reliably distinguish between adaptive responses and toxic effects. 3. More attention needs to be paid to quantifying the intrinsic sensitivity of certain methods used by toxicologists, particularly those with histopathological end-points. 4. Much more attention should be paid than at present to seemingly beneficial effects of exposure to test materials since an understanding of these may throw useful light on mechanisms underlying toxic effects. 5. Overfeeding gives rise to a wide variety of effects which impact in a major way on both general toxicity and oncogenicity end-points. 6. Extrapolation to man usually involves the use of tumour incidence data to predict cancer mortality in humans. Important new data on the effect of overfeeding on cancer incidence in rats aged two years are presented. 7. Complacency with regard to the relevance of rodent models for predicting toxicity for man is unwarranted.
Animals↗
Let us forget "tumour promotion" and start thinking about mechanisms of non-genotoxic carcinogenicity.
Both genotoxic and non-genotoxic mechanisms may contribute to carcinogenesis. Each may be effective by itself, or the two may act in any combination to boost the risk of neoplasia. Non-genotoxic carcinogens may act in a wide variety of ways and not simply as second stage carcinogens (i.e. promoters) on previously initiated cells. There is no justification for assuming that cancers have to be "initiated" by genotoxic carcinogens. Prior exposure to a genotoxin is obviously not necessary for hormonal carcinogenesis in which evidence of DNA damage occurs as a late, and not an early, event. Perhaps hormone-induced hyperplasia renders cells more sensitive to environmental or endogenous genotoxins? New data indicating that overnutrition predisposes to increased mortality from malignant neoplasms of a wide variety of kinds in rats is briefly presented. It is suggested that the use of the terms "initiator" and "promoter" should now be phased out in favour of "genotoxic carcinogens" and "non-genotoxic carcinogens", respectively.
Animals↗
Liver tumors in rodents: extrapolation to man.
Man is a poor model for the prediction of agents that are hepatocarcinogenic for laboratory rodents. Relatively few agents are known to cause any form of primary liver cancer in man. The most important is hepatitis B virus, for which there is possibly a model in the woodchuck but not one in rats or mice. The only other agents known to cause primary liver cancer in man are certain steroid hormones, vinyl chloride, and thorium dioxide. There are animal models for the first two of these and a reasonable expectation that thorium dioxide would produce liver tumors in animals if the appropriate experiments were done. Aflatoxin, a potent hepatocarcinogen in rats and other species but not mice, is strongly suspected of being an important human hepatocarcinogen in certain geographical areas of the world, but the evidence is circumstantial. There is no more than a weak association between the nutritional type of cirrhosis secondary to excessive intake of alcohol and increased primary liver cancer in man, and no evidence at all that ethanol per se causes liver tumors in mice, rats, hamsters, or mastomys. By contrast, a very large number of chemicals to which people in the West have been exposed for many decades have been found to be hepatocarcinogens in laboratory rodents. In most cases the levels of exposure required to produce liver tumors in rodents far exceed those to which man is normally exposed. The problem is to guess whether low-level exposure to such rodent hepatocarcinogens poses any real liver cancer threat to man?The mortality from primary liver cancer is very low in countries such as England and Wales where there is widespread exposure to low doses of both natural and synthetic agents which, in high dosage, cause liver tumors in rodents. This suggests that, if there is any risk, it can only be very small. Death rate data collected in England and Wales by the Registrar General are consistent with there having been a small increase in the incidence of primary liver cancer in England and Wales during the past 20 years, but the apparent increase might well be a consequence of revisions in the International Classification of Diseases system and not real. During the first half of the present century the age-standardized incidence of primary liver cancer in England and Wales was falling.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Effect of monochlorobenzene on rat liver.
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Animals↗
Safety evaluation of cimetidine: report at the termination of a seven-year study in dogs.
Cimetidine in tablet form was administered orally daily to eight male and four female beagle dogs at a dose level of 144 mg kg-1 for 385 weeks. Four male and two female control dogs received placebo tablets. Treatment with cimetidine did not affect the clinical condition of the dogs, but was associated with a slightly less rapid weight gain. Five dogs (two cimetidine-treated and three controls) were killed during the course of the study for reasons not related to treatment. Treatment with cimetidine did not affect haematological, clinical chemical, urinalysis or electrocardiographic parameters. Multiple biopsies of gastric mucosa taken at intervals of approximately six months from Week 177 to Week 363 showed no change which could be attributed to treatment with cimetidine. There were no toxic effects on the gastric mucosa of any dog. At necropsy no treatment-related findings were reported except for reduction in prostate size in 6/8 males receiving cimetidine. This was expected in view of previous experience with cimetidine.
Animals↗
Three-generation reproduction study of rats ingesting up to 10% sorbitol in the diet--and a brief review of the toxicological status of sorbitol.
Groups of 12 male and 24 female 5-wk-old Charles River CD (SD) BR rats (F0) were fed a sucrose-containing ground cereal-based diet in which 0, 2.5, 5.0 and 10.0% (w/w) sorbitol was included at the expense of sucrose. The rats were first mated after 14 wk on the diet. F1a litters were born 19 wk after the start of the study and F1b litters at wk 30. Groups of 12 male and 24 female F1b rats were first mated when 18 wk old. They gave rise to F2a litters after 3 wk and to F2b litters 10 wk later. Likewise, groups of 12 male and 24 female F2b rats were first mated when 18 wk old, producing F3a and F3b litters 3 wk and 10 wk later, respectively. F0 rats were killed 33 wk after the start of the study, F1a in wk 22, F1b in wk 68, F2a in wk 57, F2b in wk 92 and F3a in wk 96. Apart from slight reductions in food consumption in sorbitol-fed F1b males and in body-weight gain in sorbitol-fed F0, F1b and F2b rats of both sexes, treatment was associated with no clinically observed effects. There were no deaths attributable to treatment and no adverse effects on mating performance or pregnancy rates in the parent animals of any generation. Treatment was associated with no consistent adverse effect on any measure of reproductive performance or behaviour during gestation or lactation. No abnormal pups were observed in any generation. Not unexpectedly, caecal enlargement was consistently observed at necropsy of sorbitol-treated rats of all generations and significant rises in serum calcium were observed in F0 males and females exposed to 10% sorbitol and in F1b males exposed to either 5 or 10% sorbitol. Differences between treated and control F3a rats in respect of T3 and TSH levels were probably spurious as they followed no consistent pattern. Similarly, between-group variations in gonadal weight were considered to have no toxicological significance because they lacked consistency and were not accompanied by any histologically-evident changes. Microscopic examination of lesions from F1a and F2a animals, of gonads from F1b and F2b and of selected tissues from the F3a generation revealed no changes of toxicological significance.(ABSTRACT TRUNCATED AT 400 WORDS)
Adrenal Medulla↗
How long should toxicity tests in rodents last?
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Animals↗
Chloromethylation: three lung cancer deaths in young men.
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Adult↗
Relationship of body-weight gain to longevity and to risk of development of nephropathy and neoplasia in Sprague-Dawley rats.
The relationship of weight gain to survival, risk of development of chronic progressive nephropathy and risk of development of various neoplasms has been studied in the control groups from two routine chronic toxicity studies in Sprague-Dawley rats. The groups comprised 100 CFY strain rats of each sex observed up to the age of 109 wk and 120 CD strain rats of each sex observed up to 111 wk of age (females) or 121 wk (males). The eventual incidence of tumours was found to be related to body weight at several ages. There was also a statistically significant association between high body weight at various ages and increased mortality, particularly in the CD strain and particularly in females. The 'heavy' rats proved to have an increased risk of developing both progressive nephropathy and certain tumours. This relationship was particularly marked for pituitary tumours in both sexes and for benign and malignant mammary tumours in females, and was significant irrespective of whether tumours coexisting with marked or severe progressive nephropathy were classified as fatal or incidental. There was also some evidence that increased body weight was positively associated with risk of islet-cell tumours and lipomatous tumours in males and fibromatous tumours in females. The observations illustrate how non-specific factors, such as those that affect body weight, may profoundly influence mortality and tumour incidence in chronic toxicity studies. The findings also highlight the difficulty of classifying particular neoplasms as incidental or fatal where other potentially life-threatening pathology (e.g. progressive nephropathy) is present.
Adenocarcinoma↗
Enzootic and epizootic adrenal medullary proliferative disease of rats: influence of dietary factors which affect calcium absorption.
Adrenal medullary hyperplasia and neoplasia occur both enzootically and epizootically in untreated laboratory rats. The lesions are typically chromaffin-negative and are found incidentally in animals that have died from unrelated causes or have been killed at the end of long-term toxicity/carcinogenicity tests. Urinary excretion of catecholamines is not usually increased. Environmental, particularly dietary, factors are seemingly much more important than genetic ones as determinants of the incidence of proliferative lesions. Recent observations of enhancement of adrenal medullary proliferative disease in rats by the feeding, in high dietary concentration, of certain polyols (sorbitol, mannitol, xylitol, lactitol), or of lactose, suggested that increased absorption of calcium from the gastrointestinal tract may be a risk factor. This evidence is reported and discussed in the light of other evidence linking disturbed calcium homeostasis with adrenal medullary function in the rat. In man, adrenal medullary proliferative disease is relatively rare and there is no evidence of any relation between the hypercalcaemia associated with hyperparathyroidism and increased risk of phaeochromocytoma. Adrenal medullary proliferative disease in rats is usually seen against a background of multiple endocrine neoplasia, with the pituitary gland, the pancreatic islets and the thyroid C-cells being most commonly affected in addition to the adrenal medulla. A parallel between this situation and Sipple's disease in humans has previously been suggested. We now stress the possible importance of three factors as determinants of enzootic and epizootic adrenal medullary proliferative disease in rats: excessive food intake, excessive dietary levels of calcium and phosphate and excessive intake of other food components, such as vitamin D and poorly absorbable carbohydrates, which predispose to increased calcium absorption.
Adrenal Gland Diseases↗
Occupational cancer. Where now and where next?
For each kind of occupationally associated cancer, there are three distinct stages in the development of the problem: recognition of a possible problem, confirmation, and the introduction of preventive measures. In the past, recognition of a possible problem depended heavily on chance and on the powers and observation of dedicated physicians and surgeons. Confirmation consisted of the collection of further anecdotal evidence and the conduct of case-referent (case-control) or other studies. The introduction of preventive measures often lagged woefully behind confirmation that a problem existed. Recently, the power of epidemiology as a primary investigative tool has grown to the point where unsuspected associations between occupation and cancer risk may be the first hint that a problem exists. However, it is important to recognize that investigative epidemiology is capable of constructing misleading pictures. In the future there is bound to be continuing pressure to reduce maximal permissible exposure to proven carcinogens. For chemicals for which there is no more than suspicion based on laboratory tests, one must ensure that regulatory action is based on good science, sound judgement, and common sense, rather than on the machinations of those with vested interests, of ambitious lawyers, or of the lunatic fringe. Less than 10% of all cancers are likely to be due to occupational factors. Therefore, even turning the world upside down with safety precautions against actual and suspected carcinogens would only marginally affect the present human cancer burden.
Adult↗
Certain aspects of the responses of laboratory rats to exposure to (a) nitrogen dioxide and (b) tobacco smoke.
Exposure of rats to 150 ppm NO2 for 2 hours causes death from pulmonary oedema. Continuous exposure to 25 ppm for 150 days causes gross enlargement with loss of elastic recoil and proliferative and metaplastic epithelial changes in the vicinity of the terminal bronchioles. Continuous exposure to 2 ppm results in an initial loss of cilia and focal hyperplasia of the terminal bronchiolar epithelium, but these changes, for the most part, quickly subside. Chronic daily exposure of rats to tobacco smoke results in proliferative and metaplastic epithelial changes in the vicinity of the terminal and respiratory bronchioles. Also, both at this site and elsewhere, aggregates of golden-brown pigment-laden macrophages accumulate in the lungs. The proliferative/metaplastic changes are similar to those seen in response to NO2, asbestos and other irritant gases and particles. The aggregates of golden-brown macrophages are seemingly a special feature of the response to tobacco smoke. Some rats exposed for over two years to tobacco smoke, develop foci of squamous metaplasia, firstly in the region of terminal bronchioles, but later at points scattered throughout the lung parenchyma. Comparable changes have not been reported in rats exposed to NO2. Although no strictly comparable data for NO2 and tobacco smoke exposure are available, it is reasonable to conclude that, whereas the NO2 in tobacco smoke may contribute to the production of cuboidal/columnar metaplasia in the vicinity of terminal bronchioles, it otherwise plays little part in the aetiology of lesions in the lungs of smoke-exposed rats.
Animals↗