摘要:

AbstractAlmost from its discovery in 1879, the use of saccharin as an artificial, non-nutritive sweetener has been the center of several controversies regarding potential toxic effects, most recently focusing on the urinary bladder carcinogenicity of sodium saccharin in rats when fed at high doses in two-generation studies. No carcinogenic effect has been observed in mice, hamsters, or monkeys, and numerous epidemiological studies provide no clear or consistent evidence to support the assertion that sodium saccharin increases the risk of bladder cancer in the human population. Mechanism of action studies in the one susceptible species, the rat, continue to provide information useful in assessing potential risk to the human from saccharin consumption. Unlike typical carcinogens which interact with DNA, sodium saccharin is not genotoxic, but leads to an increase in cell proliferation of the urothelium, the only target tissue. It also appears that the effect of saccharin is modified by the salt form in which it is administered, despite equivalent concentrations of saccharin in the urine. The chemical form of saccharin in the urine is unaffected, and there is no evidence for a specific cell receptor for the saccharin molecule. Changes in several urinary parameters, such as pH, sodium, protein, silicates, volume, and others, appear to influence the reaction of the urothelium to sodium saccharin administration. Silicon-containing precipitate and/or crystals appear to be generated in the urine under specific circumstances, acting as microbrasive, cytotoxic material. Using a mathematical model of carcinogenesis, which encompasses the temporal dynamics and complexity of the process at a cellular level, including spontaneous genetic transitions, it has been shown that the effects of sodium saccharin can be explained entirely in terms of its non-genotoxic influence on cell proliferation. In interpreting these analytical studies in the human context, particularly as they pertain to the urinary milieu which appears to be pivotal in the effect of sodium saccharin, we are led to the conclusion that there is a threshold effect in male rats and that an effect on the human urothelium is unlikely at even the highest levels of human consumption.

ISSN:1040-8444    

DOI:10.3109/10408449009089867

出版商:Taylor&Francis    

年代:1990

数据来源: Taylor

摘要:

AbstractThe high reactivity of heavy metals with biological systems is well documented, although some disagreement remains on the precise dose-effect relationships involved. This represents a question of considerable importance, especially in attempts to assess the risks of exposure. The implicit assumption is usually made that a threshold concentration of specific metals exists in the most sensitive target organ, so that an increased frequency of functional lesions will be expected if this threshold is exceeded. The threshold for the metal defines its so-called critical level, and this review was written in order to examine the theoretical and practical difficulties in establishing such a level. Among these may be cited, for instance, the dependence of what constitutes the target tissue on the speciation of the metal, the changes in apparent critical level with rate and route of metal administration, the short half-life of some of the metals as well as their compartmentation in the tissues, and the considerable initiation delay frequently preceding the appearance of lesions. For these and other reasons a useful approximate value for a critical concentration has only been proposed so far for the total Cd concentration in the renal cortex of chronically exposed human adults.

ISSN:1040-8444    

DOI:10.3109/10408449009089868

出版商:Taylor&Francis    

年代:1990

数据来源: Taylor

摘要:

Abstract“Risk Assessment”is a general term used with increasing frequency by both scientists and regulators. Scientifically based risk assessments consider available toxicologic data when judging which agents pose a significant risk to the human population. The science of toxicology focuses on identifying potential hazards to human health using surrogate animal studies. Margins of Safety and establishment of ADIs (Acceptable Daily Intakes) are methods applied to animal test data to set“safe”levels of potential exposure. While the use of Safety Factors in development of the ADI can support a pragmatic conclusion of safety, this approach cannot provide estimates of the probability of harm or the degree of safety. Therefore, Quantitative Risk Assessment (QRA) methods using mathematical models have been advanced to extrapolate from animal exposures which are usually high to much lower human exposure levels where experimental response is absent. Such methodology has been applied primarily by U.S. regulatory agencies to experimental oncogenic responses to estimate the risks of chemical exposure. The present manuscript considers both methods for evaluation of chemical safety and focuses on the scientific merits and limitations of each.

ISSN:1040-8444    

DOI:10.3109/10408449009089869

出版商:Taylor&Francis    

年代:1990

数据来源: Taylor

摘要:

AbstractThis review evaluates the available information on the effects of mainstream and environmental tobacco smoke on the immune system in animals and humans. The primary emphasis is on mainstream smoke since little information is available on the effects of environmental smoke. The effects of mainstream tobacco smoke on the immune system in humans and animals are similar. Animals exposed to mainstream tobacco smoke for periods of a few weeks generally exhibit a slight immu-nostimulation. However, subchronic and chronic exposure studies indicate that immunosuppressive changes develop. Lymphocyte proliferation in response to the mitogens PHA and LPS is decreased, suggesting compromise of cell function. Antibody production can be suppressed. Smoke-exposed animals that are challenged with metastasizing tumors or viruses have been shown to exhibit a higher incidence of tumorigenic and infectious diseases, respectively. Localized immunological changes in the lung can include reduction of bronchus-associated lymphoid tissue and immunoglobulin levels. Smoking-related changes in the peripheral immune system of humans have included elevated WBC counts, increased cytotoxic/suppressor and decreased inducer/helper T-cell numbers, slightly suppressed T-lymphocyte activity, significantly decreased natural killer cell activity, lowered circulating immunoglobin titers, except for IgE which is elevated, and increased susceptibility to infection. The effects of environmental tobacco smoke on the immune system, in contrast to mainstream tobacco smoke, have just begun to be investigated and information available in the literature, to date, is limited. Immunoreactive substances are known to be present in environmental tobacco smoke, but to date, environmental tobacco smoke has been more closely associated with irritation than sensitization. A few studies have indicated a potential for environmental smoke-induced hypersensitivity and suppression of immunoregulatory substances. In contrast, other investigators have failed to detect immunological or other biological changes associated with environmental smoke. Clearly, more research is needed to resolve these differences.

ISSN:1040-8444    

DOI:10.3109/10408449009089870

出版商:Taylor&Francis    

年代:1990

数据来源: Taylor