Human & Experimental Toxicology

Gene expression profiling data can be used in toxicology to assess both the level and impact of toxicant exposure, aligned with a vision of 21st century toxicology. Here, we present a whole blood-derived gene signature that can distinguish current smokers from either nonsmokers or former smokers with high specificity and sensitivity. Such a signature that can be measured in a surrogate tissue (whole blood) may help in monitoring smoking exposure as well as discontinuation of exposure when the primarily impacted tissue (e.g., lung) is not readily accessible. The signature consisted of LRRN3, SASH1, PALLD, RGL1, TNFRSF17, CDKN1C, IGJ, RRM2, ID3, SERPING1, and FUCA1. Several members of this signature have been previously described in the context of smoking. The signature translated well across species and could distinguish mice that were exposed to cigarette smoke from ones exposed to air only or had been withdrawn from cigarette smoke exposure. Finally, the small signature of only 11 genes could be converted into a polymerase chain reaction-based assay that could serve as a marker to monitor compliance with a smoking abstinence protocol.

Although mining plays a prominent role in the economy of South Africa, it is associated with many chemical hazards. Exposure to dust from mining can lead to many pathological effects depending on mineralogical composition, size, shape and levels and duration of exposure. Mining and processing of minerals also result in occupational exposure to toxic substances such as platinum, chromium, vanadium, manganese, mercury, cyanide and diesel particulate. South Africa has set occupational exposure limits (OELs) for some hazards, but mine workers are still at a risk. Since the hazard posed by a mineral depends on its physiochemical properties, it is recommended that South Africa should not simply adopt OELs from other countries but rather set her own standards based on local toxicity studies. The limits should take into account the issue of mixtures to which workers could be exposed as well as the health status of the workers. The mining industry is also a source of contamination of the environment, due inter alia to the large areas of tailings dams and dumps left behind. Therefore, there is need to develop guidelines for safe land-uses of contaminated lands after mine closure.

Skin sensitization associated with allergic contact dermatitis is a common health problem and is an important consideration for toxicologists in safety assessment. Historically, in vivo predictive tests have been used with good success to identify substances that have the potential to induce skin sensitization, and these tests formed the basis of safety evaluation. These original tests are now being replaced gradually either by in vitro assays or by further refinements of in vivo methods such as the local lymph node assay. Human data have also been available to inform classification decisions for some substances and have been used by risk managers to introduce measures for exposure reduction. However, humans encounter hazards in the context of exposure rather than in the form of intrinsic hazards per se, and so in this article, we have examined critically the extent to which human data have been used to refine classification decisions and safety evaluations. We have also evaluated information on the burden of human allergic skin disease and used this to address the question of whether, and to what extent, the identification and evaluation of skin sensitization hazards has led to an improvement of public and/or occupational health.

A key aim of toxicology is the prevention of adverse effects due to toxic hazards. Therefore, the dissemination of toxicology research findings must confront two important challenges: one being the lack of information on the vast majority of potentially toxic industrial chemicals and the other being the strict criteria for scientific proof usually required for decision-making in regard to prevention. The present study ascertains the coverage of environmental chemicals in four volumes of Human & Experimental Toxicology and the presentation and interpretation of research findings in published articles. Links in SciFinder showed that the 530 articles published in four selected volumes between 1984 and 2014 primarily dealt with metals (126 links) and other toxicants that have received substantial attention in the past. Thirteen compounds identified by US authorities in 2006 as high-priority substances, for which toxicology documentation is badly needed, were not covered in the journal issues at all. When reviewing published articles, reliance on p values was standard, and non-significant findings were often called ‘negative.’ This tradition may contribute to the perceived need to extend existing research on toxic hazards that have already been well characterized. Several sources of bias towards the null hypothesis can affect toxicology research, but are generally not considered, thus adding to the current inclination to avoid false positive findings. In this regard, toxicology is particularly prone to bias because of the known paucity of false positives and, in particular, the existence of a vast number of toxic hazards which by default are considered innocuous due to lack of documentation. The Precautionary Principle could inspire decision-making on the basis of incomplete documentation and should stimulate a change in toxicology traditions and in toxicology research publication.

Uncertainty is the central element in insurance. This article examines how insurers evaluate and price risks that can present very high levels of uncertainty, and which many underwriters regard as especially hazardous in insurance terms. These are the risks associated with new medical devices, new pharmaceutical products and others substances for human consumption, such as food additives. Insurance is likely to be needed for these products both during their research and development phases, including insurance for clinical trials, and also once the device, drug or other substance gains approval and is in regular use.

The article examines the types of insurance that are available to cover these risks, the organizations that provide insurance and how the insurance is organised. It discusses the basic principles that insurers use to price insurance before considering the difficulties presented by novel and complex risks generally. The article concludes with a description of the techniques that insurers employ to analyse and price the particular risks that are our subject and a discussion of how underwriters seek to overcome the special problems associated with them.

We introduced Evidence-based Toxicology (EBT) in 2005 to address the disparities that exist between the various Weight-of-Evidence (WOE) methods typically applied in the regulatory hazard decision-making arena and urged toxicologists to adopt the evidence-based guidelines long-utilized in medicine (i.e., Evidence-Based Medicine or EBM). This review of the activities leading to the adoption of evidence-based methods and EBT during the last decade demonstrates how fundamental concepts that form EBT, such as the use of systematic reviews to capture and consider all available information, are improving toxicological evaluations performed by various groups and agencies. We reiterate how the EBT framework, a process that provides a method for performing human chemical causation analyses in an objective, transparent and reproducible manner, differs significantly from past and current regulatory WOE approaches. We also discuss why the uncertainties associated with regulatory WOE schemes lead to a definition of the term “risk” that contains unquantifiable uncertainties not present in this term as it is used in epidemiology and medicine. We believe this distinctly different meaning of “risk” should be clearly conveyed to those not familiar with this difference (e.g., the lay public), when theoretical/nomologic risks associated with chemical-induced toxicities are presented outside of regulatory and related scientific parlance.

Perceptions of the effects on health of air pollutants have changed dramatically over the past thirty five years. It is now clear that current, historically low, concentrations of air pollutants have significant effects on health and that these effects bear most heavily on deaths and illness caused by cardiovascular diseases. Epidemiological studies have provided the evidence for these conclusions; toxicological studies have provided explanations, not yet complete, for these effects. Most emphasis has been placed on the effects of airborne particles and the evidence for their effects is convincing. Less attention has been paid to the effects of gaseous air pollutants: it may be that their effects have been, and are, under-estimated. Recent work has allowed the effects on health of air pollutants to be quantified at both a national and global scale. This work has led to the realization that the effects are large and that air pollutants continue to pose an important threat to health.

A critical evaluation of several recent regulatory risk assessments has been undertaken. These relate to propyl paraben (as a food additive, cosmetic ingredient or pharmaceutical excipient), cobalt (in terms of a safety-based limit for pharmaceuticals) and the cancer Threshold of Toxicological Concern as applied to food contaminants and pharmaceutical impurities. In all cases, a number of concerns can be raised regarding the reliability of the current assessments, some examples being absence of data audits, use of single-dose and/or non-good laboratory practice studies to determine safety metrics, use of a biased data set and questionable methodology and lack of consistency with precedents and regulatory guidance. Drawing on these findings, a set of recommendations is provided to reduce uncertainty and improve the quality and robustness of future regulatory risk assessments.

Despite remarkable advances over the past 35 years in the field of toxicology generally, and the development of a vast body of knowledge detailing the nature and degree of many human and environmental toxicological risks, the excessive fear of anything connected with chemicals that some refer to as “chemonoia” persists. So too, unfortunately, does the rationalist belief that once the facts are all in, everyone will agree on what those facts say. This article examines the roots of what is essentially a cultural conflict, explains what various bodies of social science research reveal about the psychological roots of that conflict, and offers suggestions on how to move forward.

Since the approval of insulin as the first recombinant therapeutic protein, the prominence of biologic therapies in drug development has grown significantly. Many modalities beyond traditional biologics are now being developed or explored for various indications with significant unmet medical needs. From early traditional replacement proteins to more recent, highly engineered antibodies, oligonucleotides, fusion proteins, and gene constructs, biologic agents have delivered life-changing therapies, despite often having scientifically and technically challenging development programs. This brief review outlines some of the major biotherapeutic classes and identifies the advantages and challenges with the development of these products.

In this review, current issues and opportunities in food safety assessment are discussed. Food safety is considered an essential element inherent in global food security. Hazard characterization is pivotal within the continuum of risk assessment, but it may be conceived only within a very limited frame as a true alternative to risk assessment. Elucidation of the mode of action underlying a given hazard is vital to create a plausible basis for human toxicology evaluation. Risk assessment, to convey meaningful risk communication, must be based on appropriate and reliable consideration of both exposure and mode of action. New perspectives, provided by monitoring human exogenous and endogenous exposure biomarkers, are considered of great promise to support classical risk extrapolation from animal toxicology.

The Asian Society of Toxicology (ASIATOX), which consists of the seven national toxicology member societies of Japan, Korea, China, Taiwan, Thailand, Singapore, and Iran, now boasts of more than 3,000 members from a variety of industries, academia, and regulatory organizations. ASIATOX congresses are spaced three years apart and rotated among the member societies. In 1995, ASIATOX joined the International Union of Toxicology (IUTOX) as a regional society, and now serves as the scientific voice of toxicology in Asia under the IUTOX umbrella. Since its inauguration, the society has worked diligently to handle matters deemed essential to promoting the vision set fourth by its founders. Future perspectives of ASIATOX include the establishment of education and training programs, and the certification and accreditation of toxicologists. As the leading voice of toxicology in Asia, the society seeks to extend knowledge of toxicological issues to developing nations in Asia based on the following missions and goals: (1) to provide leadership as a worldwide scientific organization that objectively addresses global issues involving the toxicological sciences, (2) to broaden the geographical base of toxicology as a discipline and profession to all countries of the world, and (3) to pursue capacity building in toxicology, particularly in developing countries, while utilizing its global perspective and network to contribute to the enhancement of toxicology education and the career development of young toxicologists.

Despite efforts to eliminate the use of animals in testing and the availability of many accepted alternative methods, animals are still widely used for toxicological research and testing. While research using in vitro and computational models has dramatically increased in recent years, such efforts have not yet measurably impacted animal use for regulatory testing and are not likely to do so for many years or even decades. Until regulatory authorities have accepted test methods that can totally replace animals and these are fully implemented, large numbers of animals will continue to be used and many will continue to experience significant pain and distress. In order to positively impact the welfare of these animals, accepted alternatives must be implemented, and efforts must be directed at eliminating pain and distress and reducing animal numbers. Animal pain and distress can be reduced by earlier predictive humane endpoints, pain-relieving medications, and supportive clinical care, while sequential testing and routine use of integrated testing and decision strategies can reduce animal numbers. Applying advances in science and technology to the development of scientifically sound alternative testing models and strategies can improve animal welfare and further reduce and replace animal use.

Predictive toxicology plays a critical role in reducing the failure rate of new drugs in pharmaceutical research and development. Despite recent gains in our understanding of drug-induced toxicity, however, it is urgent that the utility and limitations of our current predictive tools be determined in order to identify gaps in our understanding of mechanistic and chemical toxicology. Using recently published computational regression analyses of in vitro and in vivo toxicology data, it will be demonstrated that significant gaps remain in early safety screening paradigms. More strategic analyses of these data sets will allow for a better understanding of their domain of applicability and help identify those compounds that cause significant in vivo toxicity but which are currently mis-predicted by in silico and in vitro models. These ‘outliers’ and falsely predicted compounds are metaphorical lighthouses that shine light on existing toxicological knowledge gaps, and it is essential that these compounds are investigated if attrition is to be reduced significantly in the future. As such, the modern computational toxicologist is more productively engaged in understanding these gaps and driving investigative toxicology towards addressing them.

Idiosyncratic drug reactions can be extremely severe and are not accounted for by the regular pharmacology of a drug. Thus, the mechanism of idiosyncratic drug–induced liver injury (iDILI), a phenomenon that occurs with many drugs including β-lactams, anti-tuberculosis drugs and non-steroidal anti-inflammatories, has been difficult to determine and remains a pressing issue for patients and drug companies. Evidence has shown that iDILI is multifactorial and multifaceted, which suggests that multiple cellular mechanisms may be involved. However, a common initiating event has been proposed to be the formation of reactive drug metabolites and covalently bound adducts. Although the fate of these metabolites are unclear, recent evidence has shown a possible link between iDILI and the adaptive immune system. This review highlights the role of reactive metabolites, the recent genetic innovations which have provided molecular targets for iDILI, and the current literature which suggests an immunological basis for iDILI.