ECVAM-ICCVAM: prospects for future collaboration

The level and complexity of testing for hazard and risk assessment of marketed products and environmental agents has increased substantially over time, resulting in the use of greater numbers of both animals and humans for testing. Today, industry and regulatory bodies worldwide face increasing pressures to demonstrate responsible utilisation of laboratory animals, to limit their use, and to employ alternative non-animal tests. Institutions have also been established to identify, encourage development of, conduct research on, and validate new, improved, and surrogate test methods that will reduce and replace animal use. Two such organisations are ECVAM and the Interagency Coordinating Committee for the Validation of Alternative Methods (ICCVAM). As the evolutionary changes occurring in the field of toxicology result in an unprecedented increase in the introduction of alternative methodologies, these will strain the capacities of such alternative methods institutions. That realisation is causing a shift in thinking and creating an impetus to seek approaches by which to collaborate and develop more-efficient operational procedures for the validation and regulatory acceptance of alternative methods. Similarities in objectives, functions, scientific standards, and commitment to the principles of validation and animal welfare support the value of a cooperative arrangement between ECVAM and ICCVAM, to minimise duplication of effort, maximise productivity, and influence the international adoption of alternative tests. Opportunities for ECVAM-ICCVAM collaboration are discussed, which illustrate the feasibility and potential benefits of such a partnership.     

SYSTEMIC FUNGICIDES INTRODUCTION

The idea of controlling plant diseases by introducing curative chemicals into the plant goes back many years. All the early work, which has been reviewed by Müller (1926), was of an empirical nature and although claims were made from time to time that particular treatments were effective, no clear and reliable method ever became established for controlling a plant disease by internal therapy. Within the last few decades, however, such treatment for certain animal diseases with substances possessing antibacterial properties has given spectacular results. This success in the animal led to a renewed interest in the control of plant diseases by similar means, though it was of course recognized that the animal, with its circulating blood system capable of carrying chemicals rapidly to all tissues, is very different from the plant.     

Happy Chickens Lay Tastier Eggs: Motivations for Buying Free-range Eggs in Australia

Recent public interest in so-called “ethical” food production, and in particular the welfare of intensively housed farm animals, has been linked to an increase in sales of free-range eggs in several countries including Australia. Animal activist groups around the world have campaigned for the abolition of caged-egg production, retailers and large food companies are now sourcing less of these products, and governments in various locales have placed restrictions on caged-egg production. In addition, the recent focus on food production and preparation in popular culture including books, films, and television has made these practices, including those associated with eggs, more transparent to mainstream audiences. Previous studies have examined consumers’ willingness-to-pay for free-range eggs, and community attitudes to animal welfare, but there has been little qualitative work that unpacks a key assumption which underlies much discussion of these issues: that free-range egg purchases are primarily or solely linked to consumers’ desires to have egg production systems changed from intensive to free-range. This paper analyses qualitative research undertaken in Australia that explores consumers’ motivations for buying free-range (or cage-free) eggs, which was part of a larger study examining ethical foods. Qualitative analysis of focus groups and interviews involving 73 participants revealed that free-range and cage-free eggs are perceived as being better quality, more nutritious, and safer, and having better sensory characteristics, than caged eggs. In response to open-ended questions, free-range and cage-free eggs were mentioned much more frequently than free-range meats, and were described as easy to identify and affordable, compared with other products with humane production claims. Several participants even had begun keeping their own hens in order to have an alternative to purchasing caged (or expensive free-range) eggs. Although caged-egg production was described by many participants as cruel, the desire to purchase free-range eggs was more often described in connection to efforts to avoid “industrialized” food than in relation to taking a stance on the issue of caged-hen welfare.     

A report on methods to reduce,refine and replace animal testing in industrial toxicology laboratories

The Committee to Promote Principles of Reduction, Refinement and Replacement of Animal Testing in Industrial Toxicology Laboratories was established in 1987 to work toward industrywide improvements in laboratory animal testing methods. The committee's goals are to gather information about effective nonanimal testing techniques and other methods of conserving and improving the care of laboratory animals, to work toward the systematic validation of nonanimal alternatives, and to disseminate useful information about progressive programs and policies throughout the industrial toxicology community. This is the first in a continuing series of reports the committee plans to produce as part of an ongoing program to promote communication among industrial toxicologists about successful methods of reducing, refining and replacing animal testing. Here are some of the report's major findings: (1) Animal care and use committees charged with the oversight of laboratory animal use are a universal practice at the companies surveyed. (2) Significant reductions in the number of animals used for acute toxicity testing have taken place at all the companies during the last 5- to 10-year period. (3) Structure-activity relationships (predicting a test compound's properties based on the known properties of familiar chemicals with similar structures) are widely used to minimize, but not replace, the use of animals. (4) Tissue and organ culture systems are being used with increasing frequency for screening and mechanistic studies, but are not completely replacing animal evaluations as a final step. (5) There is a pressing need for the systematic and scientifically sound validation of nonanimal alternative techniques to reduce the use of animals in toxicology testing while satisfying requirements for the protection of public safety.     

A survey of stakeholder organisations on the proposed new European chemical policy

In February 2001, the European Commission published a White Paper proposing that a single new system of chemical regulation should be applied throughout the Member States of the European Union. The proposed Registration, Evaluation and Authorisation of Chemicals (REACH) system was to include both new and existing chemicals, with the aim of ensuring that sufficient pertinent data were made available to enable human health and the environment to be protected. The policy was founded on the principle of sustainable industrial development, and ambitiously attempted to incorporate the needs and views of key stakeholder organisations, such as industry, trade associations, consumer groups, environmentalists, animal welfarists and Member State governments. During the period between the publication of the White Paper and the on-line publication of consultation documents, as part of a public consultation exercise, in May 2003, many of these key stakeholder organisations produced material in support of or critical of the White Paper, either in part or as a whole. In this paper, we have attempted to review this extensive material and to present it in the context of the current chemical regulatory system that the REACH system will replace. Emphasis is placed on the impact of the new policy on the number of animals used in the testing regimes within the REACH system and the inclusion of alternative methods into the legislation. Although supportive of the overriding aims of the new policy, FRAME believes that the fundamental concept of a risk-free environment is flawed, and that the new REACH system will involve the unjustifiable use of millions of laboratory animals. The new policy does include alternative methods, particularly for base set substances. Nevertheless, alternative testing methods that are already available have been excluded and replaced with outdated in vivo versions. There is also insufficient detail with regard to the further development and validation of alternative methods, particularly for substances of high concern, such as endocrine disrupters or reproductive toxins, for which no alternative testing methods currently exist.     

A survey of stakeholder organisations on the proposed new European chemicals policy

In February 2001, the European Commission published a White Paper proposing that a single new system of chemical regulation should be applied throughout the Member States of the European Union. The proposed Registration, Evaluation and Authorisation of Chemicals (REACH) system was to include both new and existing chemicals, with the aim of ensuring that sufficient pertinent data were made available to enable human health and the environment to be protected. The policy was founded on the principle of sustainable industrial development, and ambitiously attempted to incorporate the needs and views of key stakeholder organisations, such as industry, trade associations, consumer groups, environmentalists, animal welfarists and Member State governments. During the period between the publication of the White Paper and the on-line publication of consultation documents, as part of a public consultation exercise, in May 2003, many of these key stakeholder organisations produced material in support of or critical of the White Paper, either in part or as a whole. In this paper, we have attempted to review this extensive material and to present it in the context of the current chemical regulatory system that the REACH system will replace. Emphasis is placed on the impact of the new policy on the number of animals used in the testing regimes within the REACH system and the inclusion of alternative methods into the legislation. Although supportive of the overriding aims of the new policy, FRAME believes that the fundamental concept of a risk-free environment is flawed, and that the new REACH system will involve the unjustifiable use of millions of laboratory animals. The new policy does include alternative methods, particularly for base-set substances. Nevertheless, alternative testing methods that are already available have been excluded and replaced with outdated in vivo versions. There is also insufficient detail with regard to the further development and validation of alternative methods, particularly for substances of high concern, such as endocrine disrupters or reproductive toxins, for which no alternative testing methods currently exist.     

The evolution of teratological testing

The beginnings of mammalian experimental teratology in this century are briefly reviewed and it is noted that prior to 1960 a degree of sophistication in concept and technology had already been achieved. Thus, contrary to claims that teratology had its beginning with the thalidomide catastrophe, a modest but expanding activity and body of knowledge already existed before this unfortunate event. This activity and this knowledge, however, were largely confined to academic and research institute laboratories and made little impact on the agencies in medicine, government and industry which oversaw public health and safety and set policies intended to preserve them. No individual, group, or agency can rightly be blamed for not having sooner brought together the concepts and methodology needed for meaningful animal testing and the regulatory insignt and experience needed intelligently to apply test data to human safety evaluation and experience needed intelligently to apply test data to human safety evaluation. To accomplish this liaison seems to have required the largest toxicological catastrophe yet recorded in human history. The major events leading to formulation of the first standardized guidelines are reviewed, but it is emphasized that even today the best animal testing can only provide a limited statement of probability regarding human risk vis-à-vis safety.     

Ocular safety: a silent (in vitro) success story

Ocular irritation testing has been one of the animal test methods most criticised by animal welfare advocates. Additional criticism has arisen from within the scientific community, based on the variability of the animal test results and the questionable relevance of the extremely high dose levels employed. As a result, the Draize eye irritation test has been one of the main targets for in vitro replacement. Despite extensive efforts, however, there is still no in vitro method that is fully validated as a regulatory replacement. In spite of this, many individual companies are using diverse in vitro ocular irritation tests to gain important safety and efficacy information about their products and raw materials, eliminating the need for animal testing in the process. This is done in a safe fashion by applying intelligent testing paradigms. ECVAM has played a major role in this success, through its many programmes that have emphasised the importance of understanding the true toxicological need, and then using in vitro tests to provide that information. Thus, even in the absence of a successfully validated regulatory assay, the desired result of reducing animal testing is being met.     

Systematic reviews of animal experiments demonstrate poor human clinical and toxicological utility

The assumption that animal models are reasonably predictive of human outcomes provides the basis for their widespread use in toxicity testing and in biomedical research aimed at developing cures for human diseases. To investigate the validity of this assumption, the comprehensive Scopus biomedical bibliographic databases were searched for published systematic reviews of the human clinical or toxicological utility of animal experiments. In 20 reviews in which clinical utility was examined, the authors concluded that animal models were either significantly useful in contributing to the development of clinical interventions, or were substantially consistent with clinical outcomes, in only two cases, one of which was contentious. These included reviews of the clinical utility of experiments expected by ethics committees to lead to medical advances, of highly-cited experiments published in major journals, and of chimpanzee experiments--those involving the species considered most likely to be predictive of human outcomes. Seven additional reviews failed to clearly demonstrate utility in predicting human toxicological outcomes, such as carcinogenicity and teratogenicity. Consequently, animal data may not generally be assumed to be substantially useful for these purposes. Possible causes include interspecies differences, the distortion of outcomes arising from experimental environments and protocols, and the poor methodological quality of many animal experiments, which was evident in at least 11 reviews. No reviews existed in which the majority of animal experiments were of good methodological quality. Whilst the effects of some of these problems might be minimised with concerted effort (given their widespread prevalence), the limitations resulting from interspecies differences are likely to be technically and theoretically impossible to overcome. Non-animal models are generally required to pass formal scientific validation prior to their regulatory acceptance. In contrast, animal models are simply assumed to be predictive of human outcomes. These results demonstrate the invalidity of such assumptions. The consistent application of formal validation studies to all test models is clearly warranted, regardless of their animal, non-animal, historical, contemporary or possible future status. Likely benefits would include, the greater selection of models truly predictive of human outcomes, increased safety of people exposed to chemicals that have passed toxicity tests, increased efficiency during the development of human pharmaceuticals and other therapeutic interventions, and decreased wastage of animal, personnel and financial resources. The poor human clinical and toxicological utility of most animal models for which data exists, in conjunction with their generally substantial animal welfare and economic costs, justify a ban on animal models lacking scientific data clearly establishing their human predictivity or utility.     

In vivo detoxification of Fusarium toxins

Fusarium toxins are of great practical relevance in animal feeding since they may occur in toxicologically relevant concentrations. Therefore, many attempts have been made to find ways to detoxify contaminated feedstuffs or diets in order to cope with the problem. The supplementation of contaminated diets with detoxifying agents seems to be easily feasible, and in vitro results seem to be convincing. According to the Guideline 87/153/EEC of the Council of the European Communities, efficacy has to be proven by using an experimental design justified by the claims for use of the additive. In a review of the literature, only a few studies investigated specific parameters that could clearly reflect the claimed mode of action of the additives, and those demonstrated no measurable detoxifying effects. The majority of investigations focused on rather non-specific performance parameters, while many of these applied incomplete experimental designs. Nevertheless, most of the experiments did not demonstrate preventive effects. It is concluded that testing of currently available detoxifying agents did not follow the Council Directive in style and since the claim for their use was not proven. The application of complete two by two factorial experimental designs, the investigation of mycotoxins and/or metabolites in physiological samples as specific parameters and the verification of the specificity of the detoxifying agent is recommended for future in vivo investigations.     

Physician attitudes towards pharmacological cognitive enhancement: safety concerns are paramount

The ethical dimensions of pharmacological cognitive enhancement have been widely discussed in academic circles and the popular media, but missing from the conversation have been the perspectives of physicians - key decision makers in the adoption of new technologies into medical practice. We queried primary care physicians in major urban centers in Canada and the United States with the aim of understanding their attitudes towards cognitive enhancement. Our primary hypothesis was that physicians would be more comfortable prescribing cognitive enhancers to older patients than to young adults. Physicians were presented with a hypothetical pharmaceutical cognitive enhancer that had been approved by the regulatory authorities for use in healthy adults, and was characterized as being safe, effective, and without significant adverse side effects. Respondents overwhelmingly reported increasing comfort with prescribing cognitive enhancers as the patient age increased from 25 to 65. When asked about their comfort with prescribing extant drugs that might be considered enhancements (sildenafil, modafinil, and methylphenidate) or our hypothetical cognitive enhancer to a normal, healthy 40 year old, physicians were more comfortable prescribing sildenafil than any of the other three agents. When queried as to the reasons they answered as they did, the most prominent concerns physicians expressed were issues of safety that were not offset by the benefit afforded the individual, even in the face of explicit safety claims. Moreover, many physicians indicated that they viewed safety claims with considerable skepticism. It has become routine for safety to be raised and summarily dismissed as an issue in the debate over pharmacological cognitive enhancement; the observation that physicians were so skeptical in the face of explicit safety claims suggests that such a conclusion may be premature. Thus, physician attitudes suggest that greater weight be placed upon the balance between safety and benefit in consideration of pharmacological cognitive enhancement.     

Ecotoxicity testing: science, politics and ethics

Animal welfare organisations have long been concerned about the use of animals for ecotoxicity testing. Ecotoxicity testing is a necessary part of the statutory risk assessment of chemicals that may be released into the environment. It is sometimes also carried out during the development of new chemicals and in the investigation of pollution in the field. This review considers the existing requirements for ecotoxicity testing, with particular reference to practices in the European Union, including the recent REACH system proposals, before discussing criticisms that have been made of existing practices for environmental risk assessment. These criticisms have been made on scientific and ethical grounds, as well as on questions of cost. A case is made for greater investment in the development of alternative testing methods, which could improve the science, as well as serving the cause of animal welfare. It has frequently been suggested that the statutory requirements for environmental risk assessment are too rigid and bureaucratic. A case is made for flexibility and the greater involvement of scientists in the risk assessment procedure, in the interests of both improved science and improved animal welfare.     

Extrapolating Antifungal Animal Data to Humans—Is It Reliable?

This article aimed to review animal models of antifungals and identifies human literature to assess if the extrapolation of results is reliable. Animal studies have helped identify area under the concentration curve to minimum inhibitory concentration ratio targets for new drugs and formulations such as isavuconazole and delayed-release posaconazole that have translated to successful outcomes in humans. Models have also been influential in the identification of possible combination therapies for the treatment of aspergillosis, such as voriconazole and echinocandins. However, challenges are endured with animal models when it comes to replicating the pharmacokinetics of humans which has been exemplified with the newest itraconazole formulation. Additionally, animal models have displayed a survival benefit with the use of iron chelators and amphotericin for mucormycosis which was not demonstrated in humans. Animal models have been a staple in the development and optimization of antifungal agents. They afford the ability to investigate uncommon diseases, such as invasive fungal infections, that would otherwise take years and many resources to complete. Although there are many benefits of animal models, there are also shortcomings. This is why the reliability of extrapolating data from animal models to humans is often scrutinized.     

Allen Denver Russell Memorial Lecture, 2006. The use of microbicides in infection control: a critical look at safety, testing and applications

Microbial pathogens continue as major threats to health. Indeed, many ongoing societal changes are enhancing our vulnerability and exposure to several frank and opportunistic pathogens. This, together with rampant antimicrobial resistance and reduced prospects for newer drugs and vaccines, is forcing a higher reliance on microbiocides in infection prevention and control. That this reliance may not be well-founded becomes apparent from a closer look at current ways of testing and registering microbiocides, their label claims as well as human and environmental safety of certain widely used microbicidal chemicals. Many methods to test microbiocides for registration are flawed and/or entail test conditions irrelevant to field use. Pathogens listed on product labels may not be among those amenable to interruption through microbiocide use. The wide variations and discrepancies in existing national/regional regulations for registering microbiocides for sale stifle innovation. This is a critical look at the above-mentioned issues with emphasis on chemicals meant for use on environmental surfaces and medical devices. It highlights better ways to test microbiocides and to attain global harmonization of testing and product registration. It also details the known and potential dangers of microbiocide use and what to consider in choosing such formulations for optimal safety and effectiveness. End users are advised to be more critical and prudent in the selection and application of microbicidal chemicals, manufacturers are encouraged to explore infection control products and technologies that are safer in the workplace and for the environment, and regulators are urged to review and update the requirements and procedures for premarket review of microbiocide efficacy data and label claims. Independent investigations are also urgently needed to document the proportion of nosocomial infections that would be amenable to prevention through chemical disinfection of environmental surfaces.     

Identification of genetic susceptibility to common diseases: the case for regulation

There is, and will continue to be, pressure to disseminate and market population-wide availability of genetic susceptibility tests for common, complexly determined diseases. Many of the claims for such genetic screening tests are made by parties who stand to gain: laboratories, service providers, biotechnology firms, scientists working in genetics. Despite the fact that there is little or no evidence to support the claims of benefit, the current lack of appropriate regulation means there is a danger that promotion and advertising will nevertheless be successful in marketing such testing. Some suggestions as to the content of possible regulation are made, and some impediments to the implementation of regulation are discussed.     

Chemical dependency and drug testing in the workplace.

Urine testing for drug use in the workplace is now widespread, with the prevalence of positive drug tests in the work force being 0% to 15%. The prevalence of marijuana use is highest, and this can be reliably tested. Though it is prudent to rid the workplace of drug use, there is little scientific study on the relationship of drug use and workplace outcomes, such as productivity and safety. Probable-cause testing and preemployment testing are the most common applications. Random testing has been less accepted owing to its higher costs, unresolved legal issues, and predictably poor test reliability. Legal issues have focused on the right to policy, discrimination, and the lack of due process. The legal cornerstone of a good program is a policy that is planned and agreed on by both labor and management, which serves both as a contract and as a procedure in which expectations and consequences are known. The National Institute on Drug Abuse is certifying laboratories doing employee drug testing. Testing methods when done correctly are less prone to error than in the past, but screening tests can be defeated by adulterants. Although the incidence of false-positive results is low, such tests are less reliable when the prevalence of drug abuse is also low.     

Adaptable individuals and innovative lineages

This paper suggests (i) that while work on animal innovation has made good progress in understanding some of the proximate mechanisms and selective regimes through which innovation emerges, it has somewhat neglected the role of the social environment of innovation; a neglect manifest in the fact that innovation counts are almost always counts of resource-acquisition innovations; the invention of social tools is rarely considered. The same is true of many experimental projects, as these typically impose food acquisition tasks on their experimental subjects. (ii) That neglect is important, because innovations often pose collective action problems; the hominin species were technically innovative because they were also socially adaptable. (iii) In part for this reason, there remains a disconnect between research on hominin innovation and research on animal innovation. (iv) Finally, the paper suggests that there is something of a disconnect between the theoretical work on innovation in hominin evolution (based on theories of cultural evolution) and the experimental tradition on human innovation. That disconnect is largely due to the theoretical work retreating from strong claims about the proximate mechanisms of human cultural accumulation.     

Overview of marker vaccine and differential diagnostic test technology.

Recent advances in molecular biology, immunology, microbiology, genetics and microbial pathogenesis have lead to the development of a wide variety of new approaches for developing safer and more effective vaccines based on designs such as subunit vaccines, gene deleted vaccines, live vectored vaccines, and DNA mediated vaccines. Technology tools can be as basic as identifying naturally occurring strains with deletions that support differentiating infected from vaccinated animal (DIVA) needs or be based on higher technology developments such as improved protein expression and purification methods, transgenic plant- and plant virus-based antigen production, and novel adjuvants that target specific immune responses. These new approaches, when applied to the development of marker vaccines and companion diagnostic test kits hold tremendous potential for developing improved tools for eradication and control programs. Marker vaccines and companion diagnostic test kits must meet the established licensing requirements for purity, potency, safety and efficacy. Efficacy claims are based on evaluation of the level of protection demonstrated in host animal trials and may range from "prevents infection with (a specific agent)", to "for use as an aid in the reduction of disease due to (a specific agent)." The differences in claims and recommendations are a function of the variation in protection elicited by various vaccines. For designing effective eradication programs, vaccine efficacy characteristics such as for reducing susceptibility to infections and spread of infections must be well defined; similarly, diagnostic test performance characteristics (efficacy) must be determined. In addition to data to support efficacy claims, it is imperative that safety of production and use of vaccines be evaluated. During the design of marker vaccines and diagnostic tests, it is important to consider the application of appropriate technologies to improve the safety of these products. Use of recombinant technologies for production of vaccines and/or diagnostic test antigens can reduce the biosafety concerns during production and during use, including human exposure to zoonotic pathogens during production and use, and potential spread of foreign animal disease agents due to loss of biocontainment. In addition, vaccines may induce adverse reactions. It is important to determine the frequency of adverse events and to reduce the likelihood of induction of adverse reactions through proper design.     

Quality Control and Assurance: crucial for the sustainability of the applied phycology industry

The chemical and nutritional properties of microalgae are well known, which has led to an ever expanding industry for foods and dietary supplements both in terms of quantity and products. Little has been done to regulate or control quality and assurance in the applied phycology industry and it is known that it varies considerably. Nutritional aspects of produced biomass and consumption as dietary supplements have become issues of concern, especially since the industry is lucrative and fast growing. Various claims are made regarding dietary and food supplements that include health, nutrition, structure and functioning, many often unsubstantiated. Although quality is a subjective term many organisations are involved in testing, controlling and determining criteria. Today quality is more than just standards where it is an "integrated quality management approach" involving amongst others "hazard analyses and critical control points" (HACCP) practices. Microalgae are not recognised as a food or food supplement and they are also not categorised under herbals or botanicals, but as "other supplements". Produced microalgal biomass is subject to contamination from the entire range of contaminants and pathogens. Contamination of products by algal toxins in mixed culture populations also occurs. The industry has largely regulated itself, but there is considerable scope for improvement. There is a need for support and dissemination of information in the industry.     

Working together to respond to the challenges of EU policy to replace animal testing

This paper presents a personal perspective on efforts during the past 15 years to replace animal testing for assessing the safety of chemicals and products. It is based on an invited lecture--the FRAME Annual Lecture--given in October 2005, with the theme of "making progress by working together" (government-industry-academia-NGOs). Where we have achieved some successes, these have clearly been due to effective cooperation and collaboration between the relevant stakeholders. In recent times, there has not been this same level of active commitment and coordination. This needs to change, since, if we are to make good progress in the years to come in responding to the new challenges of the EU policy to replace animal testing, this will undoubtedly require us to work together, hopefully facilitated by effective leadership and coordination from the EU policy-makers themselves.