Human & Experimental Toxicology

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 spatial parameters and electronic structures of 100 exogenous and endogenous chemicals have been determined by computer graphics, from which their oxidative metabolism by the cytochromes P-448 (activation) or the other families of cytochromes P-450 (generally detoxication) have been predicted.

2 The spatial parameters of these chemicals primarily determine the family of cytochrome P-450 by which the chemicals are metabolized and the electronic structures primarily determine their ease of oxidative metabolism.

3 The role of oxidative metabolism of xenobiotics by the cytochromes P-448, and their binding to the cytosolic Ah receptor, are considered in relationship to the mechanisms of chemical toxicity, mutagenicity, carcinogenicity, and co-carcinogenicity.

4 The mechanisms of chemical toxicity and carcinogenesis are considered in respect of activation through cytochrome P-448-mediated, conformationally-hindered oxygenation to reactive intermediates which, unlike most cytochrome P-450-oxygenated metabolites, are not acceptable substrates for conjugation and detoxication and therefore react with essential intracellular macromolecules.

5 The computer graphic method of determining the molecular conformations and electronic structures of molecules is a rapid, scientifically-based procedure for evaluation of the potential toxicity, mutagenicity and carcinogenicity of chemicals.

. The aims of toxicity tests vary according to the use or proposed use of the substance to be tested. More knowledge about physiological and homeostatic control mechanisms will be needed before one can reliably distinguish between adaptive responses and toxic effects.

More attention needs to be paid to quantifying the intrinsic sensitivity of certain methods used by toxicologists, particularly those with histopathological end-points.

Much more attention should be paid than at present to seemingly beneficial effects of exposure o test materials since an understanding of these may throw useful light on mechanisms underlying oxic effects.

Overfeeding gives rise to a wide variety of effects which impact in a major way on both general oxicity and oncogenicity end-points.

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 Lged two years are presented.

' Complacency with regard to the relevance of rodent models for predicting toxicity for man is inwarranted.

. The evidence discussed here is derived from epidemiology, long-term bioassays in laboratory animals, and predictive short-term tests.

Epidemiological data are obtained directly from human studies and are most compelling when hey demonstrate a large relative risk and a clear dose-response in association with a distinctive umour type. Exposure to a suspected carcinogen and the doses involved are, however, often difficult to determine, and the most sophisticated epidemiological methods are relatively insensitive. There are no epidemiological data for most occupational/environmental chemicals.

Long-term bioassays can present major problems in design, interpretation and extrapolation. 'articular difficulties are associated with the planning of appropriate dose levels and the occurrence of certain tumours at high incidence in both control and test groups. Results from animal bioassays et priorities for concern and action but they cannot be reliably used for quantitative assessment of human risk.

Evidence of potential carcinogenicity derived from short-term predictive tests, involving a wide variety of systems with diverse end-points, is increasingly important. Emphasis is placed on the teed for more in vivo procedures with a broadening of the scope of somatic cell targets.

1 The discoveries that pre-treatment with certain compounds could increase the amounts of drug metabolizing enzymes present in the liver and that metabolism could enhance as well as reduce the toxicity of exogenous molecules were important milestones in toxicology.

2 Some clinically important adverse effects (vitamin D deficiency, reduced efficacy of oral contraceptives, interactions with anticoagulants) were found to be due to enzyme induction by, for example, anticonvulsants.

3 Intestinal enzymes are also inducible and can respond rapidly to individual compounds while the liver enzymes respond more slowly to the diet as a whole. Although promoting hepatic tumours in rats and mice, phenobarbitone does not have this effect in man because there seems to be a threshold for promotion which human use does not exceed. In neither case is there evidence that reduction is harmful rather than adaptive in man.

4 As to the future, post-marketing surveillance will continue to be important in assessing the safety of new products, and knowledge of the metabolism and pharmacokinetics of new compounds in experimental animals and in man will assume greater importance. Finally, greater understanding of intracellular processes will pave the way to the study of toxicology at the macromolecular level and thus to critically assess the validity of the animal models currently used in toxicity testing.

1 The design of the classical three segment reproductive test for new drugs is described and the relative merits of the USA/EEC and the Japanese guidelines are discussed.

2 The importance of pharmacokinetic studies in the interpretation of teratology studies and extrapolation to humans is mentioned in relation to caffeine, sodium valproate and cyclophosphamide.

3 Changing ideas on the design of multi-generation studies are reviewed.

4 Recent developments in the fields of behavioural teratology, chemicals in breast milk and transplacental carcinogenesis are described.

1 Toxicology plays an important part in the prevention of work related disease.

2 The toxic effects of substances used at work are similar to those of other types of chemical, hence similar methods of investigation are used.

3 A very wide range of substances is used at work. The conditions of use determine the degree of exposure and the likelihood of adverse effects.

4 The scope for control of risks depends on a knowledge of likely adverse effects and the availability of technical and managerial means for reducing exposure.

5 The relationships between the employee, his employer, suppliers, expert advisers and the regulatory authorities determine the effectiveness with which toxic risks are identified and control measures implemented.

1 Chemical treatment of crops is essential not only to reduce losses but also to prevent certain food related diseases.

2 Pesticides, unlike many other compounds, are designed to kill higher organisms and thus pose special toxicological problems.

3 It is important to understand the mechanism of action of the pesticide in the target organism in order to assess risk/benefit as accurately as possible.

4 In future the need for pharmacokinetic/dynamic and comparative metabolic data will increase and it will become important to gather human exposure data for certain commonly used compounds, data which are sadly lacking at present.

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 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.

The human diet may act as a carrier for substances which have a deleterious effect on human health either acutely or after chronic intake.

These substances can be divided into nutrients, contaminants, food additives and natural toxicants.

Recent research has mainly focused upon the contaminants and additives. This has led to regulatory measures which aim to prevent disease from exposure to such chemicals.

The natural toxicants have not been as widely studied as the other classes of dietary toxins. Their possible impact on human health, however, justifies stimulation of research into this important branch of toxicology.

Manufacturers of cosmetics and toiletries have a clear responsibility under Article 2 of the EEC Cosmetics Directive to ensure that their products are safe for use.

They have shown that they are able to discharge this responsibility, as illustrated by the type of safety assessment programme described in this paper and by market-place experience.

Considerable resources are invested by industry in safety assurance. As might be expected, this is particularly true of larger companies which have been responsible for many recent technological advances.

Industry will continue to regard the safety of its products as paramount, and contends that existing legislation is more than adequate to ensure continued safety-in-use.

The safe limits of alcohol intake are difficult to define because of individual variations in susceptibility to damage. The present recommendations are based largely on epidemiological studies of liver damage.

Recent investigations indicate that alcoholic brain damage is much more common than previously suspected. More information is required about its natural history and the characteristics of individuals most likely to suffer damage.

Thiamin (vitamin B ₁) deficiency has long been associated with brain damage and may result from a number of additive causes in the alcoholic patient. New information indicating damage to the protein moeity of some of the thiamin-using enzymes has been reviewed, as have possible mechanisms of brain cell necrosis.

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 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 p-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 (> 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 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.

Major advances in analytical toxicology followed the introduction of spectroscopic and chromatographic techniques in the 1940s and early 1950s and thin layer chromatography remains important together with some spectrophotometric and other tests. However, gas- and high performance-liquid chromatography together with a variety of immunoassay techniques are now videly used.

The scope and complexity of forensic and clinical toxicology continues to increase, although the compounds for which emergency analyses are needed to guide therapy are few. Exclusion of the presence of hypnotic drugs can be important in suspected 'brain death' cases.

Screening for drugs of abuse has assumed greater importance not only for the management of the habituated patient, but also in 'pre-employment' and 'employment' screening. The detection of licit drug administration in sport is also an area of increasing importance.

In industrial toxicology, the range of compounds for which blood or urine measurements (so called 'biological monitoring') can indicate the degree of exposure is increasing. The monitoring of environmental contaminants (lead, chlorinated pesticides) in biological samples has also proved aluable.

In the near future a consensus as to the units of measurement to be used is urgently required and more emphasis will be placed on interpretation, especially as regards possible behavioural effects of drugs or other poisons. Despite many advances in analytical techniques there remains a need for reliable, simple tests to detect poisons for use in smaller hospital and other laboratories.

1 The background, scope and limitations of laboratory methods for the diagnosis of inorganic dead 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.