Beyond Poisons and Problems: Toxicology in Italy - ACS Publications


Apr 21, 2008 - Writing about toxicology in Italy is not as easy as writing about other disciplines. Honeymouth words would be unrealistic, hypercritic...
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APRIL 2008 VOLUME 21, NUMBER 4  Copyright 2008 by the American Chemical Society

Guest Editorial Beyond Poisons and Problems: Toxicology in Italy Writing about toxicology in Italy is not as easy as writing about other disciplines. Honeymouth words would be unrealistic, hypercritical skepticism would be ungenerous, and impersonal chronicle would be useless. We therefore decided to begin the writing of this editorial with a few honest statements that introduced the readers to verifiable facts and misfacts about toxicology in Italy. In our country, as everywhere else in the world, modern toxicology cuts across pharmacology, molecular biology, biotechnology, and clinical medicine. That said, we must confess that many members of our scientific community underestimate the versatility of toxicology or perceive it as a lack of identity rather than a strength. Some have even more negative feelings and look at toxicology as the science of accidental or intentional poisoning or other bizarre chemical events. Such misconceptions translate into facts and numbers. Between 1997 and 2006, there has been a lack of increase or a measurable decrease of affiliations to the Italian Society of Toxicology (SITOX), while in the same period “sister societies” (pharmacology, pathology, biochemistry, and molecular biology) enjoyed a gratifying trend toward measurable growth (1). Particularly disappointing is the comparison of toxicology with pharmacology, in spite of the fact that the two disciplines should cross-fertilize by definition. In inviting us to contribute our personal views of toxicology in Italy, the Editors surrendered to the magics of serendipity. They picked two personalities that fit well in the aforementioned blending of enthusiasm or coolness. One of us1 is a pharmacologist who has devoted his career to harmonizing toxicology with pharmacology. He has chaired toxicology societies and meetings 1 Paolo Preziosi, MD, FRC Path, is Professor Emeritus of Pharmacology at the Catholic University School of Medicine in Rome. His research interests focus on basic and regulatory pharmacology and toxicology. He has been President of the International Union of Toxicology (1989–1992), Italian Society of Toxicology (1979–1986), and Italian Society of Pharmacology (1990–1995). He is also a member of the Board as well as liaison–officer for the Word Health Organization and is an honorary member of several other societies for pharmacological (IUPHAR) and toxicological (Eurotox) sciences.

at both national and international levels and has regularly published in toxicology journals or books. The other one2 is pharmacologist as well, but he only occasionally attends toxicology meetings or submits to toxicology journals, although undoubtedly his research interests focus on toxicology issues. We hope that serendipity will help us to herald the feelings of colleagues who, like the two us, share an interest in toxicology as a science but have different commitments to promoting toxicology as a premiere discipline.

Our Past at Glance Is toxicology the science of poisoning? Of course it is, and our country has a spectacular tradition in this field. In looking back at our ancestors, we can easily retrieve the names of infamous “toxicologists” who twisted the course of history by poisoning rivals, competitors, husbands, wives, lovers, or just innocent bystanders. The Roman Emperor Nero, his mother Agrippina, the Borgias, and Catherine de’ Medici, were all highly talented “toxicologists”. Poison after poison and century after century, Italian “toxicologists” calmed down and moved to more respectable and peaceful activities. Bernardo Ramazzini (1633–1714) and Paolo Zacchia (1584–1659) set the scientific foundations of industrial and forensic toxicology, respectively, which gradually rose through the rank of academic disciplines. The first Department of Industrial Toxicology was founded by Luigi Devoto in Milan (1910) and contributed to disseminating knowledge and health policies in rapidly evolving northern Italy. The first Toxicology Division was founded by Giusto Coronedi at the University of Florence and subsequently headed by Mario Aiazzi Mancini, who is venerably remembered as a mentor of modern toxicology in our country. It took some time, but the 2 Giorgio Minotti, MD and oncologist, developed an interest in biochemical toxicology during his postdoctoral stage in Dr. Aust’s laboratory at Michigan State University. He is now Professor of Pharmacology at the University Campus Bio-Medico of Rome. His research focuses on the mechanisms of cardiotoxicity induced by antitumor drugs.

10.1021/tx8000847 CCC: $40.75  2008 American Chemical Society Published on Web 04/21/2008

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Italian way from conspiracies and poisons to modern toxicology could be said to have been successful.

Modern Toxicology in Italy: National and Supranational Bodies Contemporary Italian toxicology breaks down into three main areas, with some unavoidable overlap of one area with another: regulation, prevention and safety (food toxicology, ecotoxicology, and veterinary toxicology), and research. Forensic toxicology and clinical toxicology cut across these areas. Regulation and protection and safety are operated by national bodies, among which the National Health Institute (Istituto Superiore di Sanità, ISS) plays a leading role. The ISS has a long-standing tradition of independent toxicogical research in pharmaceutical chemistry and pharmacology, drug safety, prevention of infectious diseases, environmental hygiene, and identification and control of chemical and biological risk factors. As a logical readout of such numerous activities, the ISS (i) hosts a National Toxicology Advisory Committee that evaluates the carcinogenic, mutagenic, and reproductive consequences of human exposure to environmental agents; (ii) updates the National Inventory of Chemical Substances, a data bank on the hazards and risks related to existing chemicals; (iii) serves as a national coordinator of the Toxicology Testing Guidelines Program and a reference point for the Complementary Information Exchange Procedure; (iv) contributes scientific and technical activities organized by the European Union with reference to classification, labeling, preparation of test guidelines, and risk assessment for chemical substances or new chemical entities; (v) is a member of the European Union network of reference laboratories for monitoring pesticide residues in food and environmental matrices; and (vi) collaborates with the World Health Organization (WHO) in organizing research and training in veterinary public health and participates in WHO working groups that examine the risk profile of existing or new chemicals. The ISS is a public body with intellectual and administrative autonomy, but it also represents the technical and scientific body of the National Health System; as such, the ISS shares collaborations with the Ministry of Health, regional authorities, health care providers, and hospitals. Other toxicology-committed national bodies includesamong otherssthe National Agency for New Technologies, Energy, and the Environment (Ente per le Nuove Tecnologie, l’Energia e l’Ambiente, ENEA), the Italian National Research Council (Consiglio Nazionale delle Ricerche, CNR), and the National Research Council Water Research Institute. The ENEA operates under the authority of the Ministry of Industry in close collaboration with the Ministry of Universities and Research and the Ministry of the Environment; its frontline activities range from genetic toxicology (with a particular emphasis on the population’s biomonitoring policies) to reproductive and environmental toxicology. The CNR recently underwent an in-depth restructuring of its administrative and scientific framework. It does not run laboratories specifically devoted to “toxicological research”, but it does support toxicology-oriented projects or basic science projects that could develop methods and guidelines of interest to toxicologists (perhaps, this a good example of how good toxicology and toxicologists operate in the shadows of a big scientific infrastructure and miss an otherwise well-deserved visibility). The National Research Council Water Research Institute (Department of Applied Hydrobiology) is the ecotoxicology section of a CNR branch with expertise in monitoring and establishing quality standards for water. This institute is formally endorsed to determine acute or long-term effects of

industrial or environmental contaminants on aquatic organisms; it therefore develops methodologic approaches (e.g., QSARs) and regulatory policies to characterize the distribution, fate, and risk potential of persistent micropollutants in fish, surface waters, and soil. Of paramount importance is the activity of the Istituti Zooprofilattici Sperimentali (Experimental Institutes of Zooprophylaxis); they operate on behalf of the National Health System and provide laboratory information for veterinary medicine and safety control of feed stuffs or foodstuffs of animal origins. National bodies’ activities harmonize with logistic and technical resources of supranational organizations. Italy complies with REACH, a new European Community Regulation on chemicals and their safe use. The Ministries of Health and Environment, the Agency for the Protection of the Environment and Technical Services (APAT), and ISS will be important parties in the implementation of the REACH system. Our country is also home to one of five European Commissionsponsored Joint Research Centers (JRC). Located in Ispra, not too far from Milan, the Italian JCR operates the Institute for Health and Consumer Protection, which was created to support the European Union’s legislation on food and establish highquality analysis of food safety (analytical chemistry, molecular biology, pharmacology, and toxicology). Moreover, the Italian JCR operates the Institute for Environment and Sustainability (detection of pollutants and monitoring of water and air quality), the Institute for the Protection and Security of the Citizen (measures against against natural and technological risks), and the European Center for Validation of Alternative MethodsECVAM (optimization/minimization of animal models in biomedical research and regulatory acceptance of alternative in vitro methods). Rome hosts a division of the European Center for Environment and Health, a WHO subsidiary that focuses on health aspects related to the environment. Finally, it is a matter of pride that Parmasthe hometown of ham and cheeseshosts the headquarters of the European Food Safety Authority (EFSA), the keystone of the European Union’s risk assessment regarding food and feed safety. Professor Lucio Costa is a member of the Technical-Scientific Committee of EFSA.

Toxicology in Academics, Scientific Foundations, and Contract Laboratories Experimental toxicology is done primarily in departments or institutes of toxicology and/or pharmacology at schools of medicine, pharmacy, veterinary medicine, and biological sciences of the Italian academy network. In apologizing to colleagues whose work will not be cited because of space limitations, we quickly acknowledge highly reputed toxicological traditions at the Universities of Bologna (mechanisms of mutagenesis and carcinogenesis), Firenze (pathophysiology of oxygen free radicals), Genova (chemical genotoxicity/carcinogenicity), Milan (toxicological aspects of food additives and environmental contaminants, risk assessment, cell responses to toxic agents in the central nervous system and immune system, and toxicity of water pollutants), Pavia (metals toxicology, neurotoxicology), and Turin (hepatic uroporphyria from polyhalogenated chemicals, modulation of nitric oxide synthase by exogenous arginine and endotoxin, cytochrome P450, and halocarbons or haloethanes). The Istituto Mario Negri, a Milanbased nonprofit organization, similarly enjoys a long-standing tradition in toxicological research (metabolism and disposition of xenobiotics in animals, toxicity tests in isolated organs, mechanisms and mediators of drug-induced renal injury, and many other research lines).

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Clinical toxicology is studied primarily at the Universities of Florence, Pavia, and Padua, but centers for the diagnosis and treatment of acute intoxications are distributed all over the country. Particularly remarkable is the work done at the University of Pavia, where the National Toxicology Information Center serves as the coordinator of a national network of approximately 300 hospitals. It is operated full-time by personnel coversant in clinical toxicology, emergency medicine, anesthesiology, pharmacology, analytical chemistry, and occupational and environmental health. Centers for assistance to drug abusers are operated, among others, by pharmacologists at the Schools of Medicine of the Universities of Modena and “La Sapienza” in Rome. Industrial and forensic toxicology are studied primarily in institutes or departments of occupational or forensic medicine, respectively, often in harmonization with the national body Istituto Superiore di Prevenzione e Sicurezza sul Lavoro (ISPEL). Ecotoxicology is a focus in many faculties of natural sciences, as well as in the Department of Environmental Science and Primary Prevention of the ISS. Advice and scientific knowledge are also provided by the aforesaid APAT, which operates under the auspices of the Italian Ministry for Environment. Two important contract laboratories, the Rome Research Centre in Pomezia and the RBM in Ivrea, perform preclinical toxicology and safety assessments for pharmaceutical and food companies, as well as for academy units that outsource specialty studies.

Professional Societies Founded in 1966, SITOX promotes the dissemination of scientific, professional, and regulatory aspects of modern toxicology. The Society and its Executive Board are therefore structured to welcome phamacologists, veterinary toxicologists, occupational and forensic medicine experts, etc. SITOX sponsors annual postgraduate courses in toxicology, national meetings, and an official web site (http://www.sitox.org) with the names and affiliations of all research groups. A summary of the society’s activities (SITOX Informa) is available online and in a printed version. SITOX is a member of the Federation of the European Societies of Toxicology (EUROTOX) and the International Union of Toxicology (IUTOX). Cell Tox (Italian Association of in vitro Toxicology) was founded in 1991 with the mission of promoting the use of in vitro systems and new methods and techniques that traced the toxicity of xenobiotics at cellular and molecular levels. It organizes national congresses, continuing education courses, and specialty meetings.

So, What’s Wrong? We have described a dynamic network of regulatory bodies, research groups, and professional societies. So, what’s wrong with toxicology in Italy? The disappointing trend of affiliations to SITOX attests to problems of popularity rather than scientific credibility. There are some practical and conceptual facts that contribute to generating such a situation. For example, strategic funding to toxicology-oriented projects is quite limited in our country, putting many toxicologists in the unpleasurable position of competing for resources allocated to other disciplines. This is not the best way to improve the identity of toxicology as a stand-alone discipline. In the past, the Ministry of Universities and Research funded national program projects like “Cellular Mechanisms of Toxicity at the Level of Organs and Systems” (1981–1989) and “New Evaluation Approaches in Toxicology” (1989–1996). These projects involved some 300 scientists from 30 Italian university

laboratories in 19 different cities. The annual budget averaged 170000–200000 USD, not a big deal as compared to standards in northern Europe or the United States; nonetheless, these research programs fostered collaborative efforts in basic and translational toxicology and served the logical framework for putting toxicologists at work in their natural arena. There has been no follow-up to such programs, leaving toxicologists with the unmet aspiration to submit toxicology-oriented projects to expert panels and boards with verifiable expertise in toxicology. In the 1980s and 1990s, the CNR supported the 5 year finalized project “Toxicological Risk”, which was supervised by Biology and Medicine, Chemistry, or Agricultural Sciences Committees. This project involved more than 250 scientists from 60 Italian laboratories (academy, CNR, ISS, and nonprofit research associations), with an annual budget of about 700000 USD. Regrettably, it is now 8 years or so since the CNR gave up funding extramural research projects. We believe that the time has come to resuscitate funding programs that support toxicological research at a national level and generate a sense of identification that cannot be met by sporadic initiatives at a local level. The uncertain financial forecast of our country should not be perceived as an excuse to outside toxicology from the exclusive club of disciplines worthy of funding. Rough times dictate prioritized decisions, and toxicology should be felt as a priority. While struggling for funding resources, Italian toxicologists are also faced with the problem of publishing with a high impact factor. Our academic community identified journals’ impact factor as the most reliable index of quality in science, binding decisions on funding or career progression to the impact factor score of the applicant. There are very many articles dealing with the pros and cons of impact factor as a signature of good or bad science. We would not contribute a “me too” pamphlet on such a debate, but it is curious that our scientific community embraced the impact factor criterion much more vigorously than did the communities in northern Europe or in the United States. That said, we cannot ignore that toxicology journals score high but not as high as pharmacology or biochemistry or cancer journals (not to mention clinical medicine journals). Many toxicologists, therefore, submit their papers to other specialty journals that warrant a higher impact factor. This generates a vicious cycle, as the less we publish in toxicology journals, the less we improve the visibility of toxicology and its moral suasion on funding agencies. There are other signs and symptoms that attest to a decreasing visibility of toxicology as a stand alone discipline. Toxicology is formally considered part of the curricula of medicine and surgery, dentistry, pharmacy, medicinal chemistry, veterinary medicine, and biological sciences. In the school of medicine, however, the toxicology momentum is buried in relatively few teaching hours of the courses of pharmacology, occupational medicine, industrial medicine, or forensic medicine. Too many doctors therefore enter their clinical practice with a marginal appreciation of the importance of toxicology; needless to say, too few of them will develop an interest in toxicology as a prospective professional opportunity. There is more focus on toxicology in the faculties of pharmacy or medicinal chemistry, but the “interpretation” of the discipline is sometimes limited to overviewing the side effects of most common drugs. It is therefore regrettable but not completely unexpected that the Italian Ministry of Universities and Research terminated some postgraduate programs in toxicology. Cause-and-effect mechanisms for this and other decisions are left to the guesses of the reader, but vicious cycles can be seen here as well. Education in regulatory, experimental, or clinical toxicology survives

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through the meritorious activity of masters or doctoral courses, but this is quite indicative of how the education in toxicology is left to local initiatives rather than to well-structured national programs.

More Shadows or More Lights? The Italian toxicology community rests with healthy intellectual traditions and expertises (2), but excellence in science is counterbalanced by an undesired array of visibility and resource-related problems. The future is nonetheless brighter than obscure, as the legendary Italian capability to survive against all odds applies to toxicology as well. Thanks to the unfailing activity of Giorgio Cantelli Forti, Enzo Chiesara, Corrado Galli, Patrizia Hrelia, Pier Francesco Mannaioni, Luigi Manzo, Marina Marinovich, Piero Dolara, and other dedicated colleagues, SITOX keeps launching countless activities that foster collaborations and continued education programs. These are closely linked to the maintenance of RENTIC, a formal registry of certified Italian toxicologists. Affiliation to RENTIC is mandatory for Italian toxicologists to be registered at an European level. This having been said, much remains to be done for improving the perception of toxicology in the broader arena of preclinical and clinical disciplines. The time of poisons is over, as is the concept of the toxicologist as he who calculates LD50 values or other descriptive parameters. However, toxicologists are asked to stand up and proudly do what toxicologists should do. There are very many sunny pastures for the modern toxicologist, for example, toxicology-driven drug reengineering, drug composition assessment, clinical pharmacokinetics (not just preclinical toxicokinetics), and risk:benefit assessment of new

chemical entities in exploratory or observational trials (not just preclinical toxicology) (3, 4). Are we prepared for this new scenario? That is difficult to say, as we really never looked at these possibilities from the broader perspective of modern toxicology, and many of us actually refrain from qualifying ourselves as toxicologists. By having said that modern toxicology encircles very many disciplines, we should not leave this challenge without a try. Visibility will only come to the brave toxicologist. Paolo Preziosi Department of Pharmacology, Catholic UniVersity School of Medicine, Rome, Italy

Giorgio Minotti CIR and Drug Sciences, UniVersity Campus Bio-Medico of Rome, Italy Tel:011-39-06-225419109 Fax: 011-39-06-22541456 E-mail: [email protected]

References (1) Marinovich, M. (2006) Tossicologi, se ci siete. . . (Where are you, toxicologists. . .). SITOX Informa 9 (2), 1–3. (2) Preziosi, P., Dracos, A., and Marcello, I. (2003) Information resources in toxicologysItaly. Toxicology 190, 35–54. (3) Egner, P. A., Stansbury, K. H., Snyder, E. P., Rogers, M. E., Hintz, P. A., and Kensler, T. W. (2000) Identification and characterization of chlorin E4 ethyl ester in sera of individuals participating in the chlorophyllin chemoprevention trial. Chem. Res. Toxicol. 13, 900– 906. (4) Menna, P., Salvatorelli, E., and Minotti, G. Cardiotoxicity of antitumor drugs. Chem. Res. Toxicol. Accepted for publication.

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