Regulatory Toxicology in the European Union

Tim Marrs, Kevin Woodward, Tim Marrs, Kevin Woodward

• Publisher: Royal Society of Chemistry
• Year: 2018
• ISBN:
  9781788014045
• Edition: 1
• Topic: Medicina
• Subtopic: Toxicología

Consumer and environmental protection depend on the careful regulation of all classes of chemicals. Toxicology is the key science used to evaluate safety and so underpins regulatory decisions on chemicals. With the growing body of EU legislation involved in chemical regulation, there is a concomitant need to understand the toxicological principles underlying safety assessments

Regulatory Toxicology in the European Union is the first book to cover regulatory toxicology specifically in Europe. It addresses the need for a wider understanding of the principles of regulatory toxicology and their application and presents the relationship between toxicology and legislative processes in regulating chemical commodities across Europe. This title has a broad scope, covering historical and current chemical regulation in Europe, the role of European agencies and institutions, and also the use of toxicology data for important classes of chemicals, including human and veterinary medicines, animal feed and food additives, biocides, pesticides and nanomaterials. This book is therefore extremely pertinent and timely in the toxicology field at present.

This book is an essential reference for regulatory authorities, industrialists, academics, undergraduates and postgraduates working within safety and hazards, toxicology, the biological sciences, and the medicinal and pharmaceutical sciences across the European Union.

CHAPTER 1

Introduction and General Aspects of Risk Assessment

Timothy C. Marrs^a and Robert L. Maynard,^b

^a Edentox Associates, UK[email protected]

^b University of Birmingham, UK[email protected]

1.1 History of Regulation in the European Union (EU)

Regulatory toxicology is to toxicology as military music is to music (Sir Colin Berry, 2014).

The European Union (EU) has its origins in the European Coal and Steel Community (ECSC), created in 1951 under the Treaty of Paris and comprising the German Federal Republic, France, Italy and the three Benelux countries (the Netherlands, Belgium and Luxemburg). The ECSC essentially created a common market in respect of coal and steel. The European Economic Community (EEC), formed by the same countries under the Treaty of Rome in 1958, extended the common market to other goods and, to some extent, to services. Since then, the EEC has been steadily enlarged, and the Maastricht Treaty effectively created the EU from its predecessor, the EEC, in 1993. The need for common standards in traded goods, largely to remove barriers to inter-community trade, required the development of common toxicological standards, and it has also been thought desirable to have common standards of worker safety (including toxicological aspects thereof) and common environmental standards.¹

Before the EU and its predecessors existed, the individual member states had their own regulations relating to toxicology, but such regulations varied from country to country. Legislation regulating chemicals started in the 19th century: the 1863 United Kingdom (UK) Alkali Act² is often said to be one of the first pieces of such legislation, although there had been various earlier attempts at smoke abatement (see also Brimblecomb).³ The Pharmacy Act,⁴ which was the first attempt in the UK to control poisons, was a result of the Bradford sweets poisoning: this was the accidental arsenic poisoning of more than 200 people in Bradford, England, in 1858, with 20 fatalities. Another important UK statute, the Sale of Food and Drugs Act⁵ was intended inter alia to prevent adulteration of food. At this time, methods of analysis were primitive compared with those available in the 20th century, and only gross contamination could be detected. In many countries, the thalidomide disaster was the impetus towards modern regulation of pharmaceuticals and, in the UK, resulted in the Medicines Act 1968.⁶ Thalidomide, which was developed in Germany, also had adverse effects there: in 1964, the Bundestag made the testing of new drugs compulsory by amendment⁷ of the West German Drug Law of 1961,⁸ and this was followed by the West German Drug Law of 1978.⁹ Also, many countries, notably France, established systems for pharmacovigilance. Thus, in France, a Centre National de Pharmacovigilance was created by the Conseils de l’ordre des pharmaciens et des médecins (pharmacists and doctors) in 1973. In 1976, the pharmacovigilance system became more official with a decree (arrêté du 2 décembre 1976) to establish pharmacovigilance regulations.¹⁰ In 1982, the decree n°82-682 (30th July 1982) established the structures and organisation of pharmacovigilance in France.¹¹ Twenty-eight centres were created in the pharmacology/toxicology departments of university hospitals (the number has since been increased). In 2005, a new decree (arrêté du 28 avril 2005) created the practice of Good Pharmacovigilance Practice in France.¹²

1.2 Philosophical Aspects of Risk

Many factors seem to influence people’s attitude to risk, including familiarity, control of their own exposure to risk and novelty of the risk. Some of these are discussed in Living with risk: the British Medical Association guide.¹³ These factors have to be taken into account by any regulatory regime, although the aim is always the same; namely, to protect the public, workers, consumers and the environment.

1.3 Types of Regulatory Regime

Diggle¹⁴ discussed the various types of regulatory regimes that exist. Premarketing approval systems (also called authorisation or licensing systems) require the organisation wishing to market a substance to first gain approval from the regulatory authority. This is the system under which pharmaceuticals, both those for humans and for other animals, are regulated. A similar system is used for pesticides and biocides. Here, the role of the regulatory authority is to decide whether a substance is sufficiently safe to be marketed or that the benefits outweigh the risks; although, with some substances, e.g. pesticides, a working assumption is made that no individual benefit accrues to people. This is further discussed below. Another type of system is a notification scheme whereby the regulatory authority must be notified of the use, marketing or trading of a substance. Often, the requirements of this type of scheme become more rigorous the more the substance is produced or traded. Yet a further type of regulation applies to existing situations, such as air pollution. Here, the main roles of the regulatory regime are setting standards and risk mitigation.

1.4 Quality of Data

Robust regulation depends on good data. Evidence relating to the toxicological effects, or lack of such effects, of compounds or products subject to regulation comes from two main sources:

• (1) Proprietary data, comprising reports of work undertaken by, or on behalf of, the producers of the compounds.
• (2) Studies in the peer-reviewed literature in which studies are reported by (in most cases) independent workers.

1.4.1 Proprietary Data Versus Studies in the Peer-reviewed Literature

Some take the view that proprietary data should be ignored and only studies in the peer-reviewed literature evaluated; others consider that only Good Laboratory Practice (GLP)-compliant studies, conducted according to regulatory guidelines, should be evaluated. Both types of study have potential strengths and weaknesses,^15,16 but the present authors are strongly of the opinion that both types of data should be evaluated if of sufficient quality. Failure to do so could result in the ludicrous situation where, if one insisted only on data from GLP-compliant facilities, data on human poisonings would have to be ignored, as would many animal studies from reputable university departments or other research institutes. Conversely, poorly conducted studies in the peer-reviewed literature would be taken as valid, but a proprietary study, which was GLP-compliant and undertaken to internationally-agreed guidelines, looking at the same endpoint would have to be ignored. Science is a search for the truth, difficult enough in all circumstances, but particularly difficult when an absolutist view is taken of particular sorts of data. As Charles Darwin said, “scientific man ought to have no wishes, no affections, a mere heart of stone”.¹⁷ In fact, the greatest enemy of prejudice in science is facts from well-conducted studies.

Attempts have been made to grade scientific information by quality; for example, that of Klimisch and colleagues.¹⁸

An EU Regulation that takes an absolutist approach is regulation 1107/2009, which firmly states that “In relation to human health, no collected data on humans should be used to lower the safety margins resulting from tests or studies on animals.” This regulation concerns pesticides, an area where the use of human experimental data has been particularly controversial (see below).¹⁹

Although studies in the peer-reviewed literature are usually not paid for by industry, journals increasingly require declarations of conflicts of interest; those declared are generally financial. But other, non-financial, conflicts of interest may occur (see discussion by Purchase²⁰). Moreover, non-governmental organisations (NGOs) that take the view that only studies in the peer-reviewed literature can be trusted may have their own interests, which they may wish to protect. Leonard²¹ points out that many NGOs, which purport to represent the general population, are highly dependent on national government or EU money – though, of course, this no more implies an inability take a detached and disinterested view of issues than it does in the case of research workers (see also Pigeon²²). Moreover, NGOs may have agendas other than public health – for example, anti-globalisation, anti-capitalism, opposition to intensive farming, dislike for certain companies etc. – but tend to project their concerns as concerns for public health. The habit of certain NGOs of attacking authors ad hominem and/or their source of funding, rather than addressing the science, is to be deplored.

In fact, few people are truly disinterested, and we all have our prejudices. Thus, with publications in the peer-reviewed literature, it should be reflected that benefits, including recognition and promotion, might accrue to the workers as a result of publication. It should also be recalled that peer-review is not a fool-proof, error-free, process in that reviewers are, to a large extent, dependent on the honesty of those submitting work for review. If such honesty is lacking, then peer-reviewers can be misled and the process of quality assurance fails (instances of retraction of papers in the peer-reviewed literature are discussed below). The glaring problem with peer-review, as used by scientific journals, is the general inability of reviewers to access raw data. Further, when comparing the two sources of data, it should be remembered that the producers of compounds stand to lose a great deal, in terms of reputation and finance, should their submissions turn out to be flawed. No ethical producer stands to gain by marketing a compound which has not been rigorously tested or for which the results of such tests have been falsified. Quite apart from anything else, clearance of regulatory hurdles using false data would be unlikely to protect producers against lawsuits, at least in common-law countries.

1.4.2 Proprietary Data

As discussed above, the value of work published in the peer-review literature is sometimes stressed, to the disadvantage of the work provided to regulators in the proprietary literature. Such comparisons are based on the perception that the proprietary literature is likely to be biased in favour of the products studied in that industry, which in turn, is paying for the study; however, many studies are carried out by contract toxicology houses, who have no financial interest in the regulatory consequences of the results of their studies (as long as they get paid!). Whether such criticism of the proprietary literature is justified is thus open to question. It is also perceived, perhaps wrongly, that proprietary data are more difficult to access than those published in the open literature. This has led to data being described as being within the grey literature, although such data can often be accessed through national and international regulatory bodies.

1.4.2.1 Good Laboratory Practice

In the 1970s, there were scandals involving scientific misdeeds and fraud at toxicology laboratories, the best known case involving the firm Industrial Bio-Test (IBT), and a result was the establishment of GLP regulations by the US Food and Drug Administration (FDA), finalized in 1979. In 1983, the US Environmental Protection Agency (EPA) established similar guidelines for pesticide toxicology studies and, in 1989, extended them to cover all research data submitted for the purposes of pesticide registration. Because studies are designed to support marketing in multiple jurisdictions, GLP was widely adopted throughout the world. GLP makes falsification of data very difficult and provides a paper-trail, as do other requirements of GLP such as the retention of data, samples and specimens. However, the efficacy of GLP depends crucially on a good quality incorruptible GLP inspectorate. See also Marshall²³ and Seiler.²⁴

1.4.2.2 Guidelines

In addition to the requirement for GLP, with many regulatory regimes, unless there is a good scientific justification for deviation, there is an obligation that studies be carried out in accordance with guidelines such as those produced by the Organisation for Economic Co-operation and Development (OECD) or, for pharmaceutical toxicology, the International Council on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). In addition to the latter, there is a veterinary equivalent, the International Cooperation on Harmonisation of Technical Requirements for Registration of Veterinary Medicinal Products (VICH). Also, most EU regulatory bodies have their own test guidelines. The OECD is based in Paris, whereas ICH and VICH are nomadic, although they have permanent secretariats. ICH is located in Switzerland; VICH is based at Health for Animals, Brussels.

At t...