Human toxicology最新文献

1. The background, scope and limitations of laboratory methods for the diagnosis of inorganic lead poisoning are outlined in the context of the work of a specialist clinical laboratory for trace element analysis. 2. Data for blood lead, haemoglobin and erythrocyte zinc protoporphyrin concentrations are presented in cases of clinical and sub-clinical poisoning due to accidental or occupational exposure. 3. Data from population surveys of children and adults subject to either environmental or occupational exposure are also shown. 4. In general, analysis for lead in an appropriate specimen of blood offers the single most useful index of exposure. 5. The importance of good accuracy control in such measurements is emphasized.

1. Ecotoxicology is concerned ultimately with the effects of pollutants on populations not individuals. Sub-lethal effects, and changes to the environment, can have a greater impact on population size than does acute toxicity. 2. Effective concern about effects of pollutants on wildlife developed after the Second World War with the advent of synthetic pesticides, and the difficulties encountered then in the evaluation of the effects of insecticides are still with us. 3. Effects on wildlife are probably often unnoticed and to demonstrate causes of observed effects is usually difficult. 4. Two underlying problems are that ecology is still a relatively young science and that we lack a consensus on the value of wildlife. 5. We need to improve our predictive abilities for effects of pollutants and we also need long-term monitoring schemes that have clear objectives.

1. The use of pharmacokinetics in toxicology, clinical pharmacology and in the individualization of dosage has been critically examined. 2. In toxicity studies, doses are given to animals with the aim of achieving substantially higher plasma levels than the therapeutic level in man. However, small animals have faster metabolic rates, shorter life spans and drug clearance is many fold faster than in man, and this difference may not be compensated for by simply mg per kg dosing. Since toxicity still occurs at these lower levels, it begs the question whether small animals require such high doses to produce toxic effects. 3. A literature survey revealed that only 5 to 31% of the papers studied attempt to relate activity with plasma levels. Examples are given of how such relationships can be used, as with D-fenfluramine, where by investigating individual responses using drug plasma levels as a probe, a greater understanding of eating disorders may be obtained. Also, with tertatolol its prolonged pharmacological activity (greater than 24 h) can be explained mathematically despite a plasma half-life of only 3 h. 4. The advantages and disadvantages of population kinetics are discussed in relation to its use in individualizing dosage, particularly in disease, its appreciation by pharmaceutical companies and regulatory authorities and the information which has been obtained so far. 5. It is of interest that one of the youngest of drug development disciplines, pharmacokinetics, is now one of the most important.

1. The ultimate objective of toxicology is the reduction of morbidity and mortality that occurs in man as a result of exposure to toxic substances. 2. The present emphasis on 'strategic' research could divert funding to answer specific but largely irrelevant questions to the detriment of 'basic' research. 3. True advances can only be made if 'basic' research is supported to the same extent as 'strategic' research and if the regulation of environmental chemicals is based on good evidence from clinicians, epidemiologists and scientists.

1. The alarming increase in the incidence of self-poisoning in Western countries in the 1950s prompted the establishment of the National Poisons Information Service in the UK and the designation of certain Regional Poisoning Treatment Centres. 2. The substances taken in acute poisoning episodes largely reflect the poisons available in the community and, in the UK at least, have changed with fashions in prescribing although psychotropic drugs and analgesics always predominate. 3. Intensive supportive care with repeat-dose oral activated charcoal and even haemoperfusion has been proved effective in acute poisoning with central nervous depressant drugs such as barbiturates even though these latter drugs are now rarely encountered in overdose. 4. Other advances in clinical toxicology include the introduction of the opiate antagonist naloxone, Fab antibody fragments for life-threatening digoxin overdosage and proven treatment for paracetamol poisoning. Analytical toxicology has also made a major contribution. 5. On the debit side, formal psychiatric assessment of patients after acute poisoning remains contentious, tricyclic antidepressants are still a major problem and there is no effective treatment for poisoning with paraquat or for paracetamol when presentation is delayed. 6. As to the future, although the 'epidemic' of serious acute poisoning of the 1960s and 70s appears to be past its peak, there will always be unusual and serious problems and the UK poisons information services must develop to make the best use of computer-based technology.

1. Present attitudes to drug safety have been shaped largely by a series of disasters. 2. In 1937 about 107 people in the USA died of poisoning by diethylene glycol used as a vehicle for sulphanilamide which led to the requirement that all formulations must be licensed by the FDA before marketing. 3. Up to 1960 the rate of production of new drugs outstripped the ability to introduce them safely. In Germany, thalidomide, an effective sedative, had been introduced in 1956 but it was not until 1961, when an estimated 10,000 babies worldwide had been born with birth deformities, that the teratogenicity of this compound was recognized. 4. Further legislation soon followed, both reducing the number and lengthening the time required to introduce a new drug onto the market. However, problems were encountered with practolol in the 1970s and with benoxaprofen in the 1980s, the latter highlighting the need to make special provision for drug use in the elderly. 5. As to the future, more attention will be paid to the special needs of children and to the possible effects of genetic differences in metabolism.

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.

1. Aflatoxins are toxic, carcinogenic secondary fungal metabolites produced by certain moulds that commonly infest foods. Measurement of aflatoxins in human serum would give a direct measurement of exposure. 2. Twenty-seven serum samples from UK blood donors were found to contain aflatoxin levels not greater than 64 pmol/l (20 pg/ml) by an enzyme-linked immunosorbent assay. 3. These findings may indicate that present UK guideline tolerances for aflatoxin in imported food are effective in limiting human exposure to toxic aflatoxins in the UK diet, though further work would be needed to confirm this. In particular, sub-populations suspected of being at higher risk may need special considerations.

In bacteria, there is evidence that a damage inducible repair response system known as the adaptive response exists since pretreatment with low doses of a simple monofunctional alkylating agent leads to a decrease in both the lethal and mutagenic effects of a subsequent challenge dose of the agent. The evidence for an analogous system in mammalian cells has proved to be inconsistent to date. The induction of chromosome repair mechanisms in human cells by low-dose radiation from tritiated thymidine has been shown to make the cells refractory to the induction of chromosome aberrations by X-rays. The present communication investigates the induction of an adaptive response in human lymphocytes from four donors and V79 cells using SCE and mutation as endpoints and MNNG and MNU for the adapting and challenging treatment. It is clear that a reproducible model of the adaptive response in human lymphocytes is difficult to establish because of the variability between different donors and different culture times. In V79 cells, assays with much larger cell numbers are required to detect a reproducible response with such small changes in mutant frequency. To demonstrate an adaptive response conclusively in mammalian cells will probably require the use of more sensitive experimental protocols and alternative methods of administration of adaptive doses of mutagen.

The effects on vision of ingestion of the anticholinesterase pyridostigmine bromide (60 mg), assessed from pharmacokinetic data to provide at least 20% inhibition of blood cholinesterase over the 1 1/2-4 1/2 h experimental period, was compared with 60 mg lactose in a double-blind crossover protocol. Contrast sensitivity to stationary oscilloscope-generated gratings of 3-40 c/deg showed a small but significant increase of 7% which was consistent with a small reduction in pupil diameter, surmised to cause a small improvement in optical quality. This reduction in pupil diameter was, however, overshadowed by a larger though still non-significant reduction on the second visit to the laboratory compared with the first. Contrast sensitivities to laser interference fringes observed in the Maxwellian view, by which the effects of the optical media are essentially bypassed, thus providing an entirely neural assessment, were unchanged after pyridostigmine. It is concluded that pyridostigmine may be given as a prophylactic in anticipation of exposure to an organophosphorus anticholinesterase without a deleterious effect on stationary visual function.