Advances in selecting appropriate non-rodent species for regulatory toxicology research: Policy, ethical, and experimental considerations.

In vivo animal studies are required by regulatory agencies to investigate drug safety before clinical trials. In this review, we summarize the process of selecting a relevant non-rodent species for preclinical studies. The dog is the primary, default non-rodent used in toxicology studies with multiple scientific advantages, including adequate background data and availability. Rabbit has many regulatory advantages as the first non-rodent for the evaluation of reproductive and developmental as well as local toxicity. Recently, minipigs have increasingly replaced dogs and rabbits in toxicology studies due to ethical and scientific advantages including similarity to humans and breeding habits. When these species are not relevant, nonhuman primates (NHPs) can be used as the available animal models, especially in toxicology studies investigating biotherapeutics. Particularly, based on the phylogenetic relationships, the use of New-World marmosets can be considered before Old-World monkeys, especially cynomolgus with robust historical data. Importantly, the use of NHPs should be justified in terms of scientific benefits considering target affinity, expression pattern, and pharmacological cross-reactivity. Strict standards are required for the use of animals. Therefore, this review is helpful for the selection of appropriate non-rodent in regulatory toxicology studies by providing sufficient regulatory, ethical, and scientific data for each species.

Status of clinical toxicology education and ethics in medical care of poisoned patients in the Islamic Republic of Iran and a comparison with other countries.

Clinical toxicology is not recognized as a clinical speciality in Iran. After the chemical war gas attack by the Iraqi army against the Iranian troops in the 1980s, health professionals and Iranian authorities noticed the importance of this field in clinical medicine. Collaboration between the clinical toxicologists and toxicologists of pharmacy schools resulted in the establishment of the Iranian Society of Toxicology and Poisonings in 1991 and the National Board of Toxicology in 1993. Clinical toxicology fellowship was also formed as a joint collaboration between the toxicology and internal medicine boards in 2010. Medical doctors who specialized in clinical medicine are eligible to take the entrance examination of the fellowship. In spite of the advancement of clinical toxicology and increased number of acute poisonings and drug abuse, undergraduate teaching in this field is still lacking and being taught as part of the forensic medicine curriculum since 1952. There is a lack of an efficient national poison information and control centre (s) in Iran, and no action plan and practical efforts have been done for poisoning prevention. Therefore, the number of drug abuse and acute poisonings has increased over the past four decades and induced cultural, social and health problems. According to Iranian legal medicine organization reports, poisoning is the second-most occurring cause of unnatural death. The suicidal attempt is the most common method of acute poisoning in adults. Suicidal attempt including self-poisoning is not accepted in the Islamic point of view, and thus self-poisoning is mostly neglected and may not be treated appropriately in time in some regions of Iran. Accidental poisoning in children is also common in Iran and estimated to be between 20 000 and 25 000 cases annually over the recent years. In addition, social, cultural and economic problems have induced more health problems such as drug abuse and addiction even in children. Adulterated opium to lead for economic gaining has produced thousands of cases of lead poisoning over the past few years in nearly all opium addicts, which is still a major health problem in Iran. Ban on alcoholic beverages leads some people to make their own home-made spirits, which is unfortunately contaminated with methanol. Thousands of cases of methanol poisoning and even some epidemics have occurred over the past four decades in some parts of the country. Lack of availability of essential antidotes such as succimer and fomepizole has been a major problem for the effective treatment of poisoned patients. Despite the well-known fact that cases of poisoning and drug overdose constitute a significant proportion of hospital admissions in some developing countries, clinical toxicology education and medical care of the poisoned patients are lacking. Therefore, policymakers and health authorities should realize the importance of toxicology in clinical medicine. The Iranian Ministry of Health, medical care and Medical Education should implement clinical toxicology courses for medical students; establish effective national poisons information and control centres and advance clinical toxicology services for appropriate management of poisoned patients to improve public health and the overall health policy goals.

Ethics and Medical Toxicology Research.

Optimizing care in medical toxicology necessitates designing and conducting ethical research. Nevertheless, the context of medical toxicology can make clinical research ethically challenging for a variety of reasons: medical toxicology is typified by relative rare conditions; making precise and rapid diagnoses is often fraught with uncertainty; emergent and urgent clinical exigencies make consent difficult or impossible; and some exposures are stigmatized or related to illegal activities that can compromise collecting accurate data from patients. In this paper, we examine some of the ethical issues in medical toxicology research that are especially salient in effort to promote optimal research in the field. The particular issues to be addressed are as follows: (1) rare conditions and orphan agents, (2) randomization and control arms, (3) inclusion and exclusion criteria, (4) outcome measures, (5) consent, (6) confidentiality, (7) registries, (8) oversight, and (9) transparency and reporting. Thinking about these ethical issues prospectively will help researchers and clinicians appropriately navigate them.

Risk, Uncertainty and Precaution in Science: The Threshold of the Toxicological Concern Approach in Food Toxicology.

Environmental risk assessment is often affected by severe uncertainty. The frequently invoked precautionary principle helps to guide risk assessment and decision-making in the face of scientific uncertainty. In many contexts, however, uncertainties play a role not only in the application of scientific models but also in their development. Building on recent literature in the philosophy of science, this paper argues that precaution should be exercised at the stage when tools for risk assessment are developed as well as when they are used to inform decision-making. The relevance and consequences of this claim are discussed in the context of the threshold of the toxicological concern approach in food toxicology. I conclude that the approach does not meet the standards of an epistemic version of the precautionary principle.

La docencia del área de Toxicología de la Universidad de La Laguna / The teaching of Toxicology at the University of La Laguna

La docencia de Toxicología en la Universidad de La Laguna (ULL) se integra en diversas Licenciaturas y Grados tales como Farmacia, Ciencia y Tecnología de los Alimentos (CTA), Medicina, Náutica y Transporte Marítimo y el Máster Oficial de Seguridad y Calidad de los Alimentos. En la Licenciatura de Farmacia en la ULL, el Área de Toxicología imparte la asignatura troncal Toxicología de 7 créditos y dos asignaturas optativas, Drogodependencias y Toxicología Clínica y Laboral, de 4,5 créditos cada una. En el Grado en Farmacia, se imparte la asignatura obligatoria de Toxicología (9 ECTS) y la asignatura optativa de Drogodependencias (6 ECTS). Asimismo, se imparte un total de 11 créditos en la Licenciatura de CTA quedando ésta extinguida en el curso académico 2013/2014. En la Licenciatura de Medicina, se imparte docencia de Toxicología en las asignaturas de Medicina Legal y Toxicología (asignado 1 crédito) y Toxicología clínica (4,5 créditos) mientras que en el Grado de Medicina se integra en las asignaturas Farmacología, anestesia y tratamiento del dolor (9 ECTS) y Aspectos éticos, aspectos legales y aspectos humanísticos de la Medicina (6 ECTS). En ellas, la Toxicología tiene asignado 1 y 0,5 ECTS, respectivamente. La Licenciatura de Náutica y Transporte Marítimo, la docencia de Toxicología se engloba en una asignatura obligatoria mientras que en el Grado en Ingeniería Radioelectrónica se incluye en una asignatura optativa (3 ECTS). En la docencia de Postgrado, la Toxicología se imparte en el Máster Oficial en Seguridad y Calidad de los Alimentos desde dos módulos con 6 ECTS cada uno de ellos (AU)

The Toxicology Department at the University of La Laguna (ULL) offers courses included in the curricula of several degrees such as Pharmacy, Food Science and Technology, Medicine, Marine and Maritime Transport, and Food Safety and Quality Master program. In the Bachelor of Pharmacy at ULL that will end in 2014/2015, the Toxicology Department offers the mandatory subject "Toxicology", with 7 credits, as well as two optional subjects ("Clinical and Professional Toxicology", and "Drug Addiction"), with 4.5 credits each. In the Degree in Pharmacy, the "Toxicology" course is a compulsory subject worth 9 credits in the European Credit Transfer System (ECTS) and the optional "Drug Addiction" subject remains, and will be worth 6 ECTS. The Toxicology Department also gives a total of 11 credits in the Food Science and Technology Bachelor that will end in the academic course 2013/2014. In the Bachelor of Medicine, Toxicology is taught in two courses: "Pharmacology, anesthesia and pain management" (9 ECTS, of which 1 ECTS is for toxicology) and "Ethical, legal and humanistic aspects of medicine" (6 ECTS, of which 0.5 ECTS is for toxicology). In the Bachelor of Nautical and Maritime Transport, Toxicology is included in a mandatory subject while in the Bachelor of Radio Electronics Engineering, Toxicology is an optional subject (3 ECTS). As for postgraduate teaching, Toxicology is taught in the Master program in Food Safety and Quality, in two modules of 6 ECTS each (AU)

Taking action on developmental toxicity: scientists' duties to protect children.

BACKGROUND: Although adaptation and proper biological functioning require developmental programming, pollutant interference can cause developmental toxicity or DT. OBJECTIVES: This commentary assesses whether it is ethical for citizens/physicians/scientists to allow avoidable DT. METHODS: Using conceptual, economic, ethical, and logical analysis, the commentary assesses what major ethical theories and objectors would say regarding the defensibility of allowing avoidable DT. RESULTS: The commentary argues that (1) none of the four major ethical theories (based, respectively, on virtue, natural law, utility, or equity) can consistently defend avoidable DT because it unjustifiably harms, respectively, individual human flourishing, human life, the greatest good, and equality. (2) Justice also requires leaving "as much and as good" biological resources for all, including future generations possibly harmed if epigenetic change is heritable. (3) Scientists/physicians have greater justice-based duties, than ordinary/average citizens, to help stop DT because they help cause it and have greater professional abilities/opportunities to help stop it. (4) Scientists/physicians likewise have greater justice-based duties, than ordinary/average citizens, to help stop DT because they benefit more from it, given their relatively greater education/consumption/income. The paper shows that major objections to (3)-(4) fail on logical, ethical, or scientific grounds, then closes with practical suggestions for implementing its proposals. CONCLUSIONS: Because allowing avoidable DT is ethically indefensible, citizens---and especially physicians/scientists---have justice-based duties to help stop DT.

[The challenges of the ethics of personalism to clinical toxicology]. / Etyka personalistyczna wobec wyzwan toksykologii klinicznej.

The fields of philosophical anthropology and the ethics of personalism overlap in the area of many difficult personal situations involving clinical toxicology. These therapeutic situations need an integral, multidimensional, and personal approach for both the patient and the toxicologist. This means that man is treated not only as a physical (biological) being but also there is an appreciation for the mental sphere, which includes rational, emotional, and spiritual elements while not forgetting that the human person is also part of the human community. Studying such an individual's personal decision as suicide, we must realize that it's not just physiological or biochemical poisons but also includes the poisoning of the psyche, as well as poisoning relationships with loved ones (family), poisoning social relations (in school or the workplace) and poisoning the spirit, in other words, there is no meaning in life itself, nor the meaning of God's existence, nor the meaning of faith, hope and love. Not only is there a greater "variety of poisons" than before, they are much more extensive and deep. For example, we can name environmental pollution, industrial poisons, chemical waste, genetic modification, powerful medications, or even the toxic social environment of evil ideas, malicious manipulation of the human mind (destructive religious sects). In approaching the challenges of clinical toxicology, the doctor must not only be a specialist in chemistry, biochemistry and pharmacology. What then is of future of toxicology because of this human dimension (anthropological, ethical and spiritual) of this teaching? As today marks the occasion of the 45th anniversary of the Clinic of Toxicology CM UJ, should we shape the ethos of young doctors who want to deal with toxicology seriously?

Challenges of using pluripotent stem cells for safety assessments of substances.

Various European Union (EU) legislations request the use of in vitro tests for toxicological evaluations in order to increase the safety of consumer and patients but also to reduce the number vertebrates. The review provides a brief overview on EU legislations in place but without further interpretation. At present several ongoing EU projects address the need of developing predictive in vitro tests including projects assessing the potential of human embryonic stem cell (hESC) lines as basis for a range of toxicity tests. Tests based on human cells would avoid interspecies variations and as such predict more precisely adverse effects to the human body. However, the ethical situation on the use of toxicity tests based on hESCs is still under debate since no harmonization within Europe on the use of hESC lines has been achieved yet. A mutual acceptance of toxicity tests based on hESCs for regulatory applications is therefore challenging. Recent reports on the establishment of induced pluripotent stem cells (iPSC) are pointing to a way out of this dilemma, since these cells have apparently very similar characteristics as hESCs and could serve as basis for the development of toxicity tests. A careful scientific comparison between pluripotent cells of different origin is now needed in order to make final judgments. In any case, the development of reliable and relevant in vitro toxicity tests based on human pluripotent cells requires additional quality assessments of critical parameter that are also summarized within the review.

An analysis of toxicology and medical journal conflict-of-interest polices.

Basic science and medical journals are increasingly requiring authors to disclose financial interests they have in the subject matter of contributed articles and letters. A comparison of journal conflict-of-interest (COI) policies can provide insight into published reports of low compliance rates and inconsistencies in disclosures by the same author found in different journals. The objective of this article is to compare the criteria, specificity, and scope of COI polices in toxicology and medical journals. We studied the COI policies of 47 toxicology and 180 medical journals catalogued in Ulrich's International Periodicals Directory for criteria of competing interests, types of submissions covered, monetary or time thresholds for reporting, and penalties for violations. Indicators were constructed for rating policy specificity, author discretion, and policy scope. Written COI policies were found in 87% if the toxicology and 84% of the medical journals; 15% and 28% of the toxicology and medical journals, respectively, were explicit about the type of content covered by the policy; 20% and 29%, respectively, included a monetary threshold for reporting purposes; the level of author discretion for reporting COIs was found to be high in 46% of the toxicology and 41% of the medical journals respectively. The level of specificity for more than 75% of the written journal COI policies for both fields was minimal or practically nil, and the scope of more than 80% of the policies was minimal to narrow. Lack of specificity, high author discretion, and restricted scope were found to be prevalent among COI policies of toxicology and medical journals.

The human repeated insult patch test in the 21st century: a commentary.

The human repeated insult patch test (HRIPT) is over half a century old, but is still used in several countries as a confirmatory test in the safety evaluation of skin sensitizers. This is despite the criticism it receives from an ethical perspective and regarding the scientific validity of such testing. In this commentary, the HRIPT is reviewed, with emphasis on ethical aspects and where the test can, and cannot, contribute in a scientifically meaningful manner to safety evaluation. It is concluded that where there is a specific rationale for testing, for example, to substantiate a no-effect level for a sensitizing chemical or to ensure that matrix effects are not making an unexpected contribution to sensitizing potency, then rigorous independent review may confirm that an HRIPT is ethical and scientifically justifiable. The possibility that sensitization may be induced in volunteers dictates that HRIPTs should be conducted rarely and in cases where the benefits overwhelmingly outweigh the risk. However, for the very large majority of HRIPTs conducted concerning the risk of skin sensitization, there is neither scientific justification nor any other merit.

Ethical principles for hormesis policies.

At least two major choices have to be made in the ethical analysis of hormesis policies. The first is where to put the burden of proof when it is uncertain whether a particular hormesis effect exists or not. It is argued that the burden of proof will have to fall primarily on those who claim the existence of such an effect. The second issue arises when (positive) hormesis effects of a substance are weighed against negative effects of the same substance. A decision must then be made whether negative effects affecting one person can be outweighed by positive effects on another person or only by positive effects on that person herself. It is argued that risk-weighing for hormesis effects should be individualistic. This would mean that benefits for one person do not automatically outweigh negative effects on another person.