Search PubMed⌕ Search

Biomedical subjects

D B Clayson

Publications and source records attributed to D B Clayson.

At least 37 records · Page 2Linked to original sources
PubMed1991

Classification of carcinogens: polemics, pedantics, or progress?

Rodent carcinogens may, for physiological or other reasons, induce cancer by a variety of mechanisms which vary in their ability to affect humans. While the current approach of some regulatory agencies to carcinogen risk assessment and regulation may possibly be justified with most genotoxic carcinogens, this is not true with all nongenotoxic carcinogens. Mechanisms attributable to high dose toxicity occasioned by misuse of the maximum tolerated dose concept, imbalancing of homeostasis, unphysiological conditions, and induced cellular proliferation are reviewed. The greatest present need for meaningful regulation of carcinogens is to obtain public acceptance of the fact that some carcinogens are species specific and probably will not exert their effects in humans.

Animals↗
PubMed1990

Calorie restriction and cellular proliferation in various tissues of the female Swiss Webster mouse.

Two experiments have been conducted to determine the effects of calorie restriction on cellular proliferation in female mouse tissues. In the first experiment, 25% calorie restriction led to a decrease in cellular proliferation, measured by the [3H]thymidine labeling index, in each of the 7 tissues examined. The duct lining cells of the mammary gland were the most affected. This conclusion was confirmed in the second experiment in which levels of 0, 10, 20, 30 and 40% calorie restriction were employed. The difference in response of the duct cells of the mammary gland and the crypt cells of the colo-rectum is discussed in light of the opinion that the formation of cancer of these tissues in humans may be markedly affected by diet.

Analysis of Variance↗
PubMed1990

An overview of current and anticipated methods for cancer prevention.

Cancer prevention techniques include legislative regulation, chemoprevention, adherence to a "healthful" lifestyle, and specialized medical intervention. Attempts at cancer prevention have possibly avoided a dramatic increase in cancer incidence and mortality due to increasing dependence on the products of the chemical industry in many areas of our present civilization, but this is difficult to establish. There is little direct evidence that cancer prevention has led to any major reduction in cancer incidence or mortality.

Carcinogens, Environmental↗
PubMed1990

Role of epidemiology in health risk assessment.

Human health risk assessment has been the object of systematic study in recent years, with formal models of risk assessment and risk management having been proposed by several national and international health agencies. The particular model developed by the Environmental Health Directorate of Health and Welfare Canada was examined in some detail and used to focus on the role of epidemiology in the overall process of risk assessment. In addition to providing information fundamental to the identification of environmental carcinogens and the estimation of carcinogenic risks, epidemiology may also play a role in shaping risk perception and in improving risk communication practices. Taken collectively, epidemiologic data on health risks provide a basis for improved disease surveillance and prioritization of public health concerns. Both descriptive and analytic epidemiologic protocols may be used to gather information on disease etiology. Because of the potential for bias and confounding in observational studies of human populations, epidemiological data should be subjected to careful evaluation in accordance with established criteria before a causal relationship between exposure and disease is inferred. Toxicological studies using nonhuman test systems may be used to avoid these problems, but at the expense of obtaining indirect information on human health risks. Nonetheless, toxicological data provide an important complement to epidemiological data, providing information on potential health risks in advance of human exposure and offering a means of indirectly assessing risks in situations where human studies fail to provide informative results. The complementary roles of epidemiology and toxicology in health risk assessment were examined using four case studies. While the epidemiological evidence linking tobacco consumption to lung cancer is now unequivocal, the corresponding data on involuntary smoking, although strongly suggestive of increasing the relative risk of lung cancer, requires further confirmation before providing the same degree of evidence as now exists for active smoking. At present, the best estimates suggest that overall mortality attributable to active smoking may exceed that due to passive smoking by roughly 100-fold. Despite this large difference in health impact, passive smoking continues to be the focus of much public concern, in part because of the involuntary nature of the risk involved. Because of the abundance of good epidemiological data on tobacco, toxicology has assumed a secondary role in defining the health risks associated with smoking. In contrast, while epidemiological studies with saccharin and formaldehyde have provided unequivocal evidence of carcinogenic effects in animals exposed to high doses, thereby raising concerns over potential human carcinogenicity.(ABSTRACT TRUNCATED AT 400 WORDS)

Canada↗
PubMed1989

Short-term effects of butylated hydroxytoluene on the Wistar rat liver, urinary bladder and thyroid gland.

Long-term feeding of butylated hydroxytoluene (BHT) to rats and mice has been linked to the enhancement of the incidence of liver tumors. It is shown in this paper that in the liver, urinary bladder and thyroid of the male Wistar rat, feeding the highest tolerated doses of BHT for 30 days does not lead to detectable increases in [3H]thymidine labeling. On the other hand, treatment of rats with 0.5% dietary BHT leads to a time-limited increase in liver cell [3H]thymidine labeling that subsided to control values within 8 days. This increase in [3H]thymidine labeling in the liver is accompanied by an unexpectedly large increase in the mitotic index. These results are discussed in the light of the behavior of certain rodent liver tumorigens.

Animals↗
PubMed1989

International Commission for Protection Against Environmental Mutagens and Carcinogens. ICPEMC publication No. 17. Can a mechanistic rationale be provided for non-genotoxic carcinogens identified in rodent bioassays?

In a recent survey of the results of the National Cancer Institute/National Toxicology Program's Carcinogenesis Bioassay Program, Ashby and Tennant (1988) drew attention to the high proportion of carcinogens that were non-genotoxic insofar as their response to the Salmonella-microsome test was concerned. The present review contrasts these findings with what is known mechanistically about non-genotoxic carcinogens that affect the tissues which are considered to be particularly prone to non-genotoxic tumor induction. Excessive and often thresholded increases in cellular proliferation in the affected tissues appear to be one common feature in tumor induction by these agents, which act either through cytotoxicity followed by regeneration or through hormone-mimetic action. It is suggested that a weight of the evidence approach on a chemical by chemical basis is necessary to decide the relevance of these agents to the human situation.

Animals↗
PubMed1989

Absence of effect in stochastic processes: its influence on test validation and test use.

Negativity in stochastic processes presents problems in interpretation because it is never possible to attain an absolutely adequate assurance of safety with such processes. Thus, it is extremely difficult to have complete confidence in the utility of validation studies of new methods in comparison to those that are accepted to be well established, especially when these processes are stochastic in the statistical sense of this term. The regulatory scientist who must make decisions on the basis of available evidence, therefore, has to make a number of assumptions in dealing with negativity. It is important to review the validity and usefulness of these assumptions from time to time to ensure that they cannot be replaced by improved methodology in the light of new scientific knowledge.

Animals↗
PubMed1989

The potential for the use of cell proliferation studies in carcinogen risk assessment.

The use of observations on cellular proliferation in assessing the mechanism of action of certain factors in the genesis of tumors of the urinary bladder, forestomach, and intestine, or on the effects of dietary restriction, is illustrated. It is suggested that, particularly with nongenotoxic carcinogens, such studies may be of great use in risk assessment especially for those cases in which animals are exposed at very much higher levels of the test agent in the carcinogenesis bioassay than are humans as the result of the environmental or other use of the agent.

Animals↗
PubMed1988

A carcinogenesis reversibility study of the effects of butylated hydroxyanisole on the forestomach and urinary bladder in male Fischer 344 rats.

A reversibility study was initiated to determine if the length of feeding with 2% butylated hydroxyanisole (BHA) altered the incidence of forestomach lesions observed after a 24-month observation period. Groups of male Fischer 344 rats were fed 2% BHA for 0, 3, 6, 12, and 24 months and then the basal diet for the completion of the 24-month experimental period. Subgroups were serially sacrificed for histopathological examination and [methyl-3H]thymidine radioautography at the time when each group of animals was transferred to the basal diet and also at 15 months. The results showed that except for carcinomas and some epithelial downgrowths, cellular proliferation, measured by radioautography in the epithelium lining the greater and the lesser curvature of the forestomach, remained dependent on the continuous presence of 2% BHA for, at least, 12 months. Superficial hyperplasias, inflammatory lesions and many of the papillomas regressed after cessation of treatment at 12 months. The epithelial downgrowths did not appear to enlarge after the BHA was withdrawn. The squamous cell carcinomas occurred in almost identical yields whether the rats were fed 2% BHA for 12 months and then returned to the basal diet for 12 months or received 2% BHA continuously for 24 months. It is shown here that at several times, 2% BHA stimulated the [methyl-3H]thymidine labelling index of the transitional epithelium of the urinary bladder and that at 3 months the no observed effect level was greater than 0.5% BHA. The significance of the studies on the forestomach and bladder epithelia are discussed. It is concluded that the lesions induced by BHA are most unlikely to be relevant to humans exposed to much lower levels of BHA.

Administration, Oral↗
PubMed1988

International Commission for Protection against Environmental Mutagens and Carcinogens. ICPEMC working paper No. 5. Genotoxicity tests as predictors of carcinogens: an analysis.

Differences between the results of numerical validation studies comparing in vitro and in vivo genotoxicity tests with the rodent cancer bioassay are leading to the perception that short-term tests predict carcinogenicity only with uncertainty. Consideration of factors such as the pharmacokinetic distribution of chemicals, the systems available for metabolic activation and detoxification, the ability of the active metabolite to move from the site of production to the target DNA, and the potential for expression of the induced lesions, strongly suggests that the disparate sensitivity of the different test systems is a major reason why numerical validation is not more successful. Furthermore, genotoxicity tests should be expected to detect only a subset of carcinogens, namely genotoxic carcinogens, rather than those carcinogens that appear to act by non-genetic mechanisms. Instead of relying primarily on short-term in vitro genotoxicity tests to predict carcinogenic activity, these tests should be used in a manner that emphasizes the accurate determination of mutagenicity or clastogenicity. It must then be determined whether the mutagenic activity is further expressed as carcinogenicity in the appropriate studies using test animals. The prospects for quantitative extrapolation of in vitro or in vivo genotoxicity test results to carcinogenicity requires a much more precise understanding of the critical molecular events in both processes.

Animals↗
PubMed1988

Dietary restriction, cell proliferation and carcinogenesis: a preliminary study.

Four groups of female Swiss Webster mice were given either laboratory chow or a purified (semi-synthetic) diet (AIN-76A) either ad libitum or at 75% of the ad libitum rate for about 30 days. Three tissues, the crypt cells of the jejunum, the dermis and the basal epithelial cells of the esophagus were investigated using [3H]thymidine labelling and by counting mitoses; four other tissues, the alveolar cells of the mammary gland, the crypt cells of the duodenum and colo-rectum, and the transitional cells of the urinary bladder were examined using [3H]thymidine labelling only. In each case dietary restriction led to a reduction of cellular proliferation assessed by these indices. The potential of the approach for the study of the effects of dietary modification on the induction of cancer is discussed.

Animals↗
PubMed1988

Needs for biological risk assessment in interspecies extrapolation.

This paper suggests that not all chemicals shown to be carcinogenic in animals may exert this effect in humans exposed to much lower amounts of the chemical. It is possible that agents which differ in their effects in humans and animals may be identified through the application of Biological Risk Assessment to the experimental results. Chemicals tested in systems in which untreated animals develop high background yields of tumors or in which high-dose toxicity may be a critical factor in the induction of carcinogenesis are suggested as candidates requiring very careful consideration before their carcinogenicity in humans is assumed.

Animals↗
PubMed1987

International Commission for Protection against Environmental Mutagens and Carcinogens. ICPEMC publication No. 13. The need for biological risk assessment in reaching decisions about carcinogens.

The prudent assumption that carcinogen bioassays in rodents predict for human carcinogenicity is examined. It is suggested that in certain cases, as for example the induction of tumors against a high incidence in controls, or in situations in which high dose toxicity may be a critical factor in the induction of cancer, the probability that animal bioassays predict for humans may be low. The term 'biological risk assessment' is introduced to describe that part of risk assessment concerned with the relevance of specific animal results to the induction of human cancer. Biological risk assessment, which is almost entirely dependent on an understanding of carcinogenesis mechanisms, is an important addition to present mathematical modeling used to predict the effects of animal carcinogens that have been demonstrated after high dose exposure, to the effects of the much smaller doses to which humans are perceived to be exposed. Evidence for the conclusions reached by biological risk assessment may sometimes be supported by a careful review of human epidemiological data.

Animals↗
PubMed1986

International Commission for Protection Against Environmental Mutagens and Carcinogens. ICPEMC Working Paper No. 3. The concept of negativity in experimental carcinogenesis.

The problems that arise in the interpretation of experimental data on chemical carcinogenesis are addressed. In particular, the difficulties in demonstrating negative results are shown to present problems in delineating carcinogens from noncarcinogens. The use of the virtually safe dose estimated under the assumption of low dose linearity is shown to lead to potentially anomalous results if used indiscriminately in bioassays in which no statistically significant increase in tumor occurrence is induced. It is suggested that there is a need to establish an operational definition of negativity in carcinogenesis, with the realization that this definition may be revised in light of new information. The establishment of negativity in aligning data from positive and negative experiments and in considering possible thresholds is also discussed.

Animals↗
PubMed1986

Short-term effects of various phenols and acids on the Fischer 344 male rat forestomach epithelium.

A series of phenols and acids was fed to rats for 9 days to determine effects on the [methyl-3H]thymidine labelling index and the histological appearance of the forestomach. A variety of proliferative effects in the rat forestomach were observed which paralleled changes in the [methyl-3H] thymidine labelling index. The 3-tert-butyl isomer of butylated hydroxyanisole (BHA) was as effective as the food grade mixture. In the 4-hydroxybenzoic acid ester series, activity was not found either with the free acid or the methyl ester. With the ethyl, n-propyl and n-butyl esters activity in the perfundic region of the forestomach increased with alkyl chain length, the n-butyl ester being nearly as effective as BHA. In contrast, 4-methoxyyphenol and propionic acid demonstrated their greatest effects in the midregion of the forestomach, the action of propionic acid not being apparent until 21 or 27 days of treatment. It was also found that after a 9-day treatment involving coadministration of BHA and acetylsalicyclic acid, the overall effect of the antioxidant on the forestomach was greatly reduced.

Animals↗
PubMed1986

Effects of deoxynivalenol (vomitoxin) on the humoral and cellular immunity of mice.

Sublethal doses (0.00, 0.25, 0.50 and 1.00 mg/kg b.w./day) of vomitoxin (deoxynivalenol; DON) were studied for their effects on humoral and cellular immunity and serum proteins of inbred, male Swiss Webster mice in a series of 4 separate experiments. Vomitoxin was added to basal diet (less than the detection limit, i.e., less than 0.05 micrograms of vomitoxin per g of feed) and administered to mice for 5 weeks beginning at 21 days of age. Mice in experiment 2 were fed the basal diet for 40 days in addition to the 5-week treatment with vomitoxin. The 1.00 mg/kg dose of vomitoxin resulted in a statistically significant reduction in the serum levels of alpha 1 and alpha 2-globulins, an increase in total serum albumin, and a reduction in feed consumption and body weight gain compared to the control group. The 0.50 mg/kg dose of vomitoxin resulted in significantly reduced serum levels of alpha 2- and beta-globulins while a significant reduction of feed consumption was evident only during Week 4. Similarly, body weight gain in this group of mice was significantly reduced during Week 2 but increased to normal levels during Week 3 and remained parallel to the control for Week 4 and 5. Both levels (0.50 and 1.00 mg/kg) of vomitoxin resulted in a reduced, dose-related, time-to-death interval following a challenge with L. monocytogenes and increased proliferative capacity of splenic lymphocyte cultures stimulated with the phytohemagglutinin P (PHA-P) mitogen compared to the control group of mice. The 0.25 mg/kg dose of vomitoxin did not have any significant effects on the parameters studied. A reasonable estimation of a 'no effect' level for immunologic effects in mice based on these and previous immunological studies would seem to be between 0.25 and 0.50 mg/kg b.w./day.

Administration, Oral↗
PubMed1985

International Commission for Protection Against Environmental Mutagens and Carcinogens. ICPEMC Working Paper No. 2. Diet, mutation and cancer.

Experimental research designed to determine the effects of variations in diet on the carcinogenic and mutagenic processes is difficult to conduct and even more difficult to interpret in terms of the likely response that such variations will have on the expression of human cancer and mutation. Although some of these difficulties may be due to a failure to persuade adequate numbers of highly trained nutritionists to enter into this type of research, a more germaine reason may be that the high level of complexity of both diet and the disease processes is such as to confound present efforts at interpretation. It is suggested that a stepwise analysis of the effects of dietary factors on each critical stage in carcinogenesis or mutagenesis may ultimately lead to results that are more easily interpreted in terms of human response. To this end it is proposed that studies of DNA-carcinogen or DNA-mutagen adduct formation, or other DNA damage, DNA replication and relevant DNA repair at the target site may be a useful guide to the effect of nutritional changes on mutation and/or cancer initiation. DNA replication at various stages of carcinogenesis, modification of hormonal levels, modification of immune response, or other factors as influenced by diet may provide markers for cancer development. The integration of this data to give an overall perception of the effects of nutrition is briefly discussed.

Animals↗