Careers in Toxicology Industrial

Transcription

1 Careers in Toxicology Eco-toxicologist

2 For an up-to-date guide to courses and related subjects in the UK, please visit the British Toxicology Society web-site at

3 Careers in Toxicology What is Toxicology? In today s world, many thousands of chemicals that are used within our environment have been developed for our benefit. Unfortunately, some may have harmful effects on living systems. Toxicology is the study of how these harmful effects may occur - in humans, other animals, plants and the environment - and how they can be avoided or minimised. It combines a wide variety of scientific disciplines which include general subjects such as biology and chemistry, and more specific areas such as pharmacology, physiology, molecular biology, immunology, pathology, epidemiology - and, of course, statistics. Toxicology plays a vital part in many aspects of our lives. It can help to ensure that the food we eat and the water we drink are clean and free from contaminants, that the air we breathe is pollutant-free, and that the drugs we take to treat disease are as safe as possible. Toxicology also has a central role in protecting the environment from the harmful effects of chemicals and other noxious agents - for example, the damage to vegetation caused by acid rain, or the problems of increased exposure to ultra-violet radiation caused by changes in the earth s atmosphere. Toxicology is the study of how harmful effects may occur - in humans, other animals, plants and the environment - and how they can be avoided or minimised Toxicology is a dynamic subject which is expanding and adapting as society changes and new demands have to be met. It offers tremendous mental stimulation and is becoming increasingly important in determining our quality of life and that of future generations. As with most sciences, pure or applied, toxicology can be viewed as an attempt to solve a detective puzzle set by nature. In addition to offering a satisfying intellectual challenge, toxicology also has the advantage of making a very tangible social contribution in terms of increased public safety by either identifying toxic chemicals, or enabling safer ones to be developed. Toxicologists monitor the impact of a toxic material on human health and are concerned with the impact of such materials on the health and status of the environment

4 How do I become a toxicologist? Toxicology may be studied at both undergraduate and postgraduate level. For example, those students who have passed A or A/S levels in science subjects, or have passed their BTEC or an appropriate HNC, can enter directly into several degree courses in which toxicology is taught in combination with other subjects such as biochemistry or pharmacology. For those students with a relevant degree, such as chemistry, biochemistry, pharmacology, pharmacy, medicine, veterinary medicine or environmental sciences, there are a number of full or part-time postgraduate courses in which toxicology is taught as a single subject, or combined with a second discipline such as forensic science or analytical chemistry. This type of course often leads to the qualification of MSc. Toxicology also forms a large component of degree courses in occupational hygiene, at both undergraduate and postgraduate level, and in the postgraduate training of occupational health workers. Once qualified, these graduates may study for a higher degree (PhD or MPhil) by performing research in toxicology in a suitable university science department (e.g. pharmacology, biochemistry or molecular toxicology). Alternatively, they can gain experience in toxicology by working in a research laboratory, or perhaps in regulatory services at industrial or government research establishments. After several years relevant experience, they can gain an advanced qualification in toxicology, such as the Diploma of the Institute of Biology in Toxicology, Diploma of the American Board of Toxicology or the Diploma in Toxicology from the Royal College of Pathologists. Those students seeking qualifications in environmental toxicology or ecotoxicology will receive a general training in subjects such as biology, ecology, environmental science or atmospheric science, which will contain elements of toxicology, often disguised as pollution studies. However, for those who seek specialist training in environmental or ecotoxicology, diplomas in subjects such as pollution science, pesticide science or waste management are also now available. But remember - whichever route you choose to follow, once you have qualified, then becoming a Member of the British Toxicology Society is not only an excellent way of keeping up-to-date in toxicology, but also of obtaining important information on further training and qualification requirements - and career opportunities. For an up-to-date guide to courses and related subjects in the UK, please visit the British Toxicology Society web-site at

5 Toxicologist The industrial toxicologist plays a vital role in developing effective, and safe, products such as pharmaceuticals, petrochemicals, pesticides, cosmetics, food and drink, household products - and even radioactive materials for medical diagnosis. With the current emphasis by manufacturers and government alike on protecting production workers, consumers and the environment, all new products and their constituents must be carefully checked for any toxic potential. Of course, any production process can also be inadvertently contaminated with toxic materials, so toxicologists must be employed to test products during - and after - their manufacture. How extensively any product is tested will depend on factors such as its intended use, how much is used, and for how long. For example, a new drug will be tested much more intensely than a component of a highly specialised alloy. Career opportunities for industrial toxicologists occur in a wide range of companies, although exactly how many - and with which skills - are employed will depend largely on the company s size and their range of products. For example, a large company might employ several specialising in topics such as genetics and reproductive toxicology, pathology, clinical biochemistry, toxicokinetics, occupational hygiene, ecotoxicology or clinical toxicology. Often, an industrial toxicologist will work closely with regulatory authorities to ensure that a company s products and production processes conform to local, national and international regulations. Ecotoxicologist On the other hand, a small company might employ only one industrial toxicologist, but he or she would probably be more of a generalist. Toxicologists are also employed by contract research laboratories, which perform toxicity studies for other companies, large and small. These laboratories conduct studies in a wide range of specialities and consequently offer numerous different careers in toxicology.

6 Toxicologists and drug development Any newly-prepared material, whether an industrial chemical, a drug, or a household product, must - for safety s sake - be considered to have a toxic potential until proven otherwise. But since toxicity is a very broad-based concept and can appear in many guises, how does a toxicologist investigate a toxicological profile? Ecotoxicologist An ideal example is that of a new drug, because before it can be used to treat a disease, its safety must be proved in a series of in vivo and in vitro laboratory tests. To some extent, the nature of these tests is governed by the information required by regulatory authorities such as the Department of Health in the United Kingdom, or the Food and Drug Administration (FDA) in the USA. These authorities will then give the final permission for a new drug to be used, after the preliminary results have been obtained and the risk to humans exposed to the drug has been carefully assessed. In order to assess such risk for a new drug accurately, the toxicologist must be able to understand and evaluate data in several ways: Knowing the toxicity of similar drugs may eliminate or at least reduce the need for tests on the new drug; in vivo and in vitro tests may quickly indicate whether the new drug causes skin and/ or eye irritation, or is mutagenic. It is important to take into account the drug s pharmacological action, which in exaggerated form may cause its toxicity. For this reason, it s particularly important to understand sex- and species-related differences in pharmacology. Since toxicity may be due to the effects of either the parent drug or its metabolite(s), it is also important to appreciate species differences in drug metabolism and disposition - and particularly how these relate to man. A new drug may adversely affect the body s organs after either single or multiple dosing; these may appear as changes in clinical condition, altered blood drug levels and/or organ function. For example, liver damage may cause raised serum enzyme levels, kidney damage may affect the urine s constituents, and cardiovascular disturbances may cause changes in blood cell parameters. Such changes in function may, or may not, be accompanied by structural changes that are visible by eye, or through the microscope. Any changes which are not immediately understood may represent a potential hazard to man, and must be investigated more closely. Carefully selected biochemical, immunological, molecular biological or specialised microscopic techniques may help to assess any immediate hazard. Where a drug is intended for long-term therapy, it is important to assess its carcinogenic potential, initially by using short-term in vitro assays that detect direct DNA damage. True carcinogenic potential, however, can only be reliably assessed by long-term exposure of animals. When - and only when - this plethora of experimental data has been collected, the toxicologist can make a full assessment of the new drug s toxicity - and balance its potential benefits against any inherent risk that may occur during treatment.

7 Toxicologist The academic toxicologist s work is characterised not only by its variety, but also by the excitement and stimulation that it can provide. Much of his or her time is spent in lecturing and practical instruction, where there s a lively, friendly and satisfying working environment. Each academic year a new challenge begins - with a year-end reward as the students qualify. As well as the teaching the academic toxicologist spends a lot of time in the laboratory. Increasingly, this research is conducted in collaboration with industry, although UK Research Councils and independent charities fund much work. Many research programmes - such as investigating the biochemical mechanisms by which a toxic agent exerts its damaging effect - are fundamental in nature and utilise a number of increasingly complex techniques and disciplines such as: Computer-assisted systems can link the structure-activity relationship of a toxic material with the pathological changes seen in affected tissues. Gene-array technologies that can provide vast amounts of information on the expression of many thousands of genes in response to a toxic chemical/drug. Techniques in recombinant DNA and cell biology, and the use of transgenic models have helped enormously in the understanding of toxicology - and will continue to do so. Ecotoxicologist By publishing data, improved communications among toxicologists allows rapid and effective progress in the design of new materials, such as selective pesticides, or medicines for safe, effective therapy against disease. Of course, management ability is important too. Toxicology is a practical subject that needs a well-developed, well-organised and well-equipped laboratory - plus a capable research team. In fact, it s possible to develop a centre of excellence in toxicological research which will provide the opportunity to interact with other scientists, perhaps at international meetings. There are also increasing links between academia, industry and government. Today, these institutions often work hand-in-hand, so that data obtained within academia can complement the often more applied findings of industry, helping to protect man and the environment. Many academic toxicologists also serve on Government advisory committees where they provide an independent, expert source of advice on the safety of chemicals.

8 Toxicologist Typically, the clinical toxicologist is a medically-qualified graduate, who has specialist knowledge of the adverse effects of drugs and other chemicals in humans - and especially how to treat poisoning by such materials. Most clinical toxicologists work in hospitals, and have close links with university clinical pharmacology departments. Ecotoxicologist At any one time, the clinical toxicologist may be responsible for solving a variety of problems: Treating patients who have been poisoned with a drug or other material either accidentally or intentionally. Providing (via a poisons information service) advice to colleagues on the management of poisoned patients. Interpreting and applying the results of analyses performed in poisoned patients. Collating and assessing data on the adverse effects of prescribed drugs. Training in, and teaching of, toxicology at both undergraduate and postgraduate levels. Nowadays, the clinical toxicologist is also increasingly invited to advise on the environmental issues and occupational hazards associated with new chemicals. To do this well requires a comprehensive clinical training, since there may often be an alternative, clinically-based, rather than toxicologically-based explanation for an unusual symptom presented or for some abnormal results obtained from a clinical investigation. Because this can cause confusion, the clinical toxicologist may often become involved in the medico-legal aspects of toxicology.

9 Toxicologist The forensic toxicologist deals mainly with medico-legal aspects of drugs and poisons, his or her main responsibilities being to establish and explain the circumstances of legal cases where drugs or other chemicals are implicated. These can range from simple drink driving cases to fatal accident, suicide and murder investigations where deliberate or accidental poisoning is suspected. Since the forensic toxicologist may need to demonstrate evidence of drug intake, he or she must be able to isolate, identify and quantify toxic substances in biological materials. This involves using modern analytical procedures, from immunoassays to identify groups of drugs to sophisticated chromatographic and spectrometric assays to measure very small amounts of drugs - often in very small biological samples. Often, he or she may be called by the Courts as an expert witness to identify a drug, to say how much was found, when the drug entered the body, and by which route. They may also be asked whether measured drug levels could account for a clinical condition, or whether the drug was taken as a therapeutic dose, or as an accidental or intentional overdose. In order to do this, the forensic toxicologist must be able to assess the significance of analytical data, to identify relationships between drug levels and clinical response, and to recognise how the drug s metabolism can affect its concentrations and pharmacological effect. But factors such as drug interactions, tolerance, age-related effects and inter-individual differences, which might also affect drug response, must also be taken into account. Ecotoxicologist Clearly, with so many different types of legal case, forensic toxicology can provide an ideal scientific challenge, with career opportunities in the Home Office Science Service, private forensic laboratories and in hospital departments of forensic medicine.

10 Ecotoxicologist Ecotoxicology - which studies the toxic effects of chemicals on the environment - is a science that has emerged only recently. Although the ecotoxicologist studies the immediate effect on individual organisms, his or her ultimate interest is the effect on populations, and on ecosystems. Ecotoxicologist In this respect, sub-lethal effects, such as changes in behaviour or in reproductive efficiency, may be much more important than any lethal effect. Typically, the ecotoxicologist will be concerned with aspects such as: Tracing the movement of pollutants through terrestrial and aquatic food chains. Following the metabolism and bioaccumulation of these pollutants in food chains. Identifying population changes after exposure to pollutants; particularly genetic changes, such as the development of resistance to pesticides in insects. Monitoring the physiological and biochemical responses of organisms to pollutant exposure, which may reflect a toxic effect. Undertaking detailed ecological and toxicological studies of invertebrates and fish in polluted rivers and estuaries. Although the ecotoxicologist s main task is to develop models which can be used to predict the fate and effects of chemicals within an ecosystem, it may take many years to achieve results. This is because ecosystems are extremely complex - there are very often major variations in the way that the different species respond to pollutants. Often, to produce successful ecotoxicological research, there must be a very close cooperation between those ecologists working in the field, often on behalf of organisations whose aim is to protect the environment, and those in the laboratory who may have the latest techniques of biochemical toxicology and chemistry at their disposal.

11 Toxicologist Each day, the regulatory toxicologist - who generally will work for the government - may face a battery of questions relating to hazards within the environment, to which the public and politicians alike will expect clear, and certainly informative, answers An example would be: Do the toxicological data provided by a company on a new product satisfy the legal requirements such that a product license or other marketing authority can be issued? Are there as yet unrecognised behavioural effects in factory workers exposed to solvents - and can they somehow be measured in order to set safe exposure limits? What action can be taken when food is deliberately contaminated with mercury or cyanide - especially without knowing when or where the next episode of tampering will occur? What standards of testing should be adopted for chemicals which have been used for many years, but were first used before toxicology and toxicity testing were fully developed? Unfortunately, in many cases, the regulatory toxicologist may not initially be provided with sufficient information to assess such hazards, and so to provide a solution for a problem must rely on his or her knowledge of different toxicological mechanisms - and how these can be applied to different species, including man. Ecotoxicologist Often, however, it may be insufficient to make a straightforward assessment of a hazard, and the regulatory toxicologist will be required to predict the degree of risk to the general public in a given situation. So this is where a little diplomacy is useful in order to communicate effectively with - and to help educate - the public, because one individual s idea of risk may be very different from another s! Of course, applying toxicological science to such a wide variety of problems is rather more than a matter of careful judgement - it also forms the basis of a fascinating and varied career.

12 Toxicologist Most of the chemicals that we use routinely - such as drugs, veterinary products, cosmetics, food and food additives, pesticides and household products - can be called industrial chemicals at some point in their manufacture, use and disposal. Ecotoxicologist The occupational toxicologist is concerned with both the potential toxicity of such materials, and with the toxicity of products which contain them and, ultimately, of any waste formed from them. In fact, the occupational toxicologist spends most of his or her time assessing the effects of such chemicals on human health, on ensuring safe working conditions for the people producing them, or advising people on how they can be safely handled. Occasionally, the occupational toxicologist might be asked to advise on how to treat patients after they have been accidentally exposed to a chemical, or what precautions should be taken if the chemical has been accidentally released into the environment. This advice would be based on previous experience in dealing with such a situation, perhaps in combination with that from laboratory studies in which animals were exposed to the chemical in question. Often, government regulations concerning the use of a new chemical will require specific information on how it may affect a person s health. So the toxicologist will be asked to evaluate existing toxicological data - and may also need to organise new studies to obtain the necessary evidence. Although the occupational toxicologist may be involved with a very wide range of industrial chemicals, it is impossible for him or her to be an expert on them all, so they will often concentrate on the regulatory and toxicity requirements of just one type. However, it is very important that they can recognise the potential dangers of simultaneous exposure to more than one type of chemical.

13 The British Toxicology Society Speciality Groups The following sub-groups are just examples of some of the areas the British Toxicology Society (BTS) members have organised into sub-speciality areas. The grouping of these fields enables greater in-depth discussions between like-minded toxicologists and facilitates the arrangement of meetings focussed to that particular field of toxicology. Speciality Sections are endorsed by the BTS Executive upon demonstration of adequate interest amongst the membership. Neurotoxicology Amongst the several target organ-defined sub-disciplines within toxicology, neurotoxicology is one of the most specialised. This is because the techniques needed both to detect and also to understand neurotoxicology are very specific. Many neurotoxic chemicals disrupt function but are not cytotoxic, so standard tests for cytotoxicity only tell half of the story. Nearly all neurotoxic chemicals are very selective, and damage just one or two specific components of the nervous system such as peripheral cholinergic synapses or brain myelin. This means that it is easy to miss neurotoxicity unless one looks carefully. The reasons for this selectivity are mostly unknown, and a better understanding of selectivity is a major goal for neurotoxicologists. The nervous system is a very important target, since even minor damage can alter quality of life and earning potential. Someone with a 90% functioning kidney or liver can live a perfectly normal life, but a 90% functioning brain may limit its owner severely. The adult brain has very little capacity for repair. A final complication is that subtle impairments of nervous system function may be caused by poor upbringing or education, alcohol abuse, or many other social factors in addition to neurotoxicity. This means that adverse effects in the human population can be very difficult to investigate, and to attribute to particular causes. The other major challenge to neurotoxicologists is to develop better and more specific diagnostic tools to recognise neurotoxicity when it does happen, and to distinguish it from the normal background level of human stupidity. Most neurotoxicologists have a training in general neuroscience, with neurochemistry predominating, but some understanding of all of neuroscience (neuro-anatomy, physiology and psychology) is vital. Then comes basic toxicology, since the nervous system is still subject to the fundamentals of dose-response, pharmacokinetics, exposure assessments, strain and species variability, and all the other factors important for every kind of toxicology. Employment is usually in relation to pharmaceuticals (many either target the nervous system or produce neurotoxic side-effect) or pesticides (most of which are designed to attack the nervous system), but most large organisations with toxicologists need someone who understands neurotoxicology. The brain expresses a greater proportion of the genome than any other organ, so if you are not daunted by a major challenge, neurotoxicology is the career for you.

14 Immunotoxicology Immunotoxicology describes the study of the adverse health effects that may result from the interaction of chemicals with the immune system. Two broad areas of interest can be identified: immunotoxicity and allergy. The former is defined as xenobiotic-induced perturbations to one or more components to the immune system such as to cause altered or suppressed immune function associated with compromised host resistance to infectious and/or malignant disease. In contrast, allergy is best defined as the adverse effects that may result from the stimulation of a specific immune response. The challenges for immunotoxicologists are to define at the cellular and molecular levels the mechanisms through which chemicals may interact with the immune system such as to impair normal immunological function, and to characterise the conditions under which allergic sensitization is induced and allergic reactions provoked. A clearer understanding of the interactions of xenobiotics with the immune system will provide the foundations for the development and application of improved methods for the identification of immunotoxicants and allergens and for defining their potential risk to human health. Safety Pharmacology There are three main types of pharmacology studies carried out in pharmaceutical research and development. Primary pharmacodynamic studies are concerned with identifying the desired properties of a substance, which will be responsible for its therapeutic action in the clinic. Secondary pharmacodynamic studies (sometimes known as general pharmacology) are concerned with the mode of action and/or effects of a substance, which are not directly related to its therapeutic application. Safety pharmacology studies are carried out to identify the potential undesirable pharmacodynamic effects of a substance on physiological functions. A key difference between safety pharmacology and toxicology studies is that the former concentrate on the effects of a substance on physiological function, whereas the latter tend to concentrate on effects on structure. There are of course areas of overlap between safety pharmacology and toxicology, and one does not replace the other they are complementary disciplines in nonclinical safety assessment. Data from safety pharmacology studies are used for several purposes in the research and development process. When the studies are carried out sufficiently early they can be a useful candidate selection tool, allowing the identification of potential problems with a compound before the formal development process begins. Since the studies give information on the effects of a substance on physiological function, they provide useful information to the clinicians who will conduct early studies in humans, indicating to them the sorts of effects they might see. As well as providing important safety data that will help protect humans from the adverse effects of a substance, safety pharmacology studies are required as part of a regulatory submission for a product license. An indication of the increasing status of safety pharmacology in the drug development process is its adoption as an ICH topic (International Conference on Harmonisation an attempt to get global approval on which tests to undertake at what stage in the drug development process).

15 Toxicology The Toxicology Speciality Section is a forum for toxicologists who are particularly concerned with the hazards and risks to health of chemicals encountered in a working situation. Toxicologists within several of the categories described earlier - occupational, industrial, university and regulatory toxicologists - might or will be involved in the occupational arena. The section also brings in those from other disciplines whose work interacts with toxicology in the occupational context, such as occupational hygiene, epidemiology, occupational medicine and biological monitoring. Both short-term (including accidents) and long-term exposure situations are relevant and all aspects of toxicology are of potential interest. The inhalation and dermal exposure routes are particular concerns and site-of-contact effects to the skin, eyes and respiratory tract are as frequent an issue as the consequences of systemic absorption and distribution. The occupational environment has distinctive features in terms of the characteristics of those exposed, the nature and pattern of their exposure and the historical progression of the surrounding culture and regulatory framework. Toxicology of biotechnology products The development of recombinant DNA, large-scale cell culture technologies, and advances in synthetic DNA and protein chemistry has introduced a wide range of potential pharmaceutical products including cytokines, hormones, growth factors, monoclonal antibodies and gene therapy products. Recombinant DNA technology is also impacting on food and agriculture. Fifteen years after the initial creation of transgenic plants, the first commercial products are now arriving at the market place. The complex structural and biological characteristics of biotech products, dictate different approaches to their non-clinical safety evaluation. Knowledge gained from non-clinical and clinical evaluation of some of the early biotech products has demonstrated that toxicological evaluation of these products requires a case-by-case and mechanistic-based approach. The safety evaluation of genetically modified crops departs significantly from conventional toxicology. For many reasons, conventional toxicology studies on the whole food are unlikely to give rise to meaningful data. The evaluation of GM crops therefore starts from a position of comparing that crop with its conventional counterpart which, on the basis of long term usage, has traditionally been accepted as safe. Subsequent studies are then determined, on a case by case basis, once both intended and unintended secondary effects of the genetic modification have been identified and characterised. In practice, this often means that there needs to be an evaluation of the potential health effects due to new protein(s) expressed in the crop. In addition to this, the safety evaluation also demands a thorough characterisation of the molecular events leading to the production of the GM crops. For an up-to-date guide to courses and related subjects in the UK, please visit the British Toxicology Society web-site at

16 Designed by Visual Communications Glaxo Wellcome on behalf of the British Toxicology Society printed by Hensal Press Ltd