Generally, the assessment of hazard and risk to humans that might arise from exposure to chemical substances is based on the extrapolation from data generated in studies with experimental animals. The assumption is made that the effects observed in the animals would also be expressed in humans and, to account for uncertainties including intra- and interspecies variability, and more recently susceptible human subpopulations, assessment factors are applied in deriving 'safe' exposures for humans. This is usually done without testing the hypothesis in humans, as the default approach allows for humans to be more sensitive than the most susceptible animal species. However, for those substances where humans are not sensitive to the effects seen in the animal studies, this approach is conservative and may result in risk management measures being taken that are totally unwarranted. An alternative approach is proposed in this report for the evaluation of such substances. The view has been expressed by many leading researchers and regulatory organisations that an understanding of the molecular and cellular processes underlying toxicity and carcinogenicity allows a more scientifically-based risk assessment and, where such information is available and adequate, this should replace default approaches in assessing human risk. All mechanisms of toxicity can be described in terms of a sequence of events, each of which is critical to the manifestation of the toxic endpoint. To elucidate such a mechanism requires rigorous investigation to obtain a complete and detailed understanding of the process leading to a toxic effect. However, the complete elucidation of all the events leading to the effect is not essential for evaluating the species differences in sensitivity to a toxicant. To achieve this we can restrict our understanding to selected key events within the complete sequence of events. This concept, termed the 'mode of action' can be used for the evaluation of species specificity including human susceptibility. If it could be shown that one or more of the key events could not occur in humans, or could only occur to a much lesser extent, it could be assumed that the mode of action of the substance in question was not relevant to the assessment of human risk. In such cases departure from the default approach would be justified. This philosophy is illustrated by a number of well-studied examples for which the modes of action and corresponding key events have been established for effects that are not relevant to humans. A structured two-step 'mode of action' approach was developed to guide the evaluation of substances expressing toxicity suspected as being species-specific and of questionable relevance to humans. Advice is given on how to identify the key events in the mode of action of the toxicological effect, how to test the strength of the data on which the mode of action hypothesis is based and how to establish its relevance to humans. The extent to which new data will be required to associate a substance with an established mechanism of toxicity or mode of action will vary, depending on the existing knowledge of the role of toxicokinetics and toxicodynamics and of the understanding already available within that class of chemicals. The use of this approach to identify those substances which express toxicity in experimental animals via a mode of action that is not relevant to humans will enable a more scientifically objective assessment of risk in humans. Furthermore, adopting a 'mode of action' approach should considerably speed up the risk assessment process and avoid unnecessary animal experimentation. [Editor]

Formaldehyde is ubiquitous in indoor and outdoor air, and everyone is exposed to formaldehyde at some concentration daily. Formaldehyde is used to produce a wide array of products, particularly building materials; it is emitted from many sources, including power plants, cars, gas and wood stoves, and cigarettes; it is a natural product in come foods; and it is naturally present in the human body as a metabolic intermediate. Much research has been conducted on the health effects of exposure to formaldehyde, including effects on the upper airway, where formaldehyde is deposited when inhaled, and effects on tissues distant from the site of initial contact. The U.S. Environmental Protection Agency (EPA) released noncancer and cancer assessments of formaldehyde for its Intergated Risk Information System (IRIS) in 1990 and 1991, respectively. The agency began reassessing formaldehyde in 1998 and released a draft IRIS assessment in June 2010. Given the complexity of the issues and the knowledge that the assessment will be used as the basis of regulatory decisions, EPA asked the National Research Council (NRC) to conduct an independent scientific review of the draft IRIS assessment. In this report, the Committee to Review EPA's Draft IRIS Assessment of Formaldehyde first addresses some general issues associated with the draft IRIS assessment. The committee next focuses on questions concerning specific aspects of the draft assessment, including derivation of the reference concentrations and the cancer unit risk estimates for formaldehyde. The committee closes with recommendations for improving the IRIS assessment of formaldehyde and provides some general comments on the IRIS development process.

The new field of toxicogenomics presents a potentially powerful set of tools to better understand the health effects of exposures to toxicants in the environment. At the request of the National Institute of Environmental Health Sciences, the National Research Council assembled a committee to identify the benefits of toxicogenomics, the challenges to achieving them, and potential approaches to overcoming such challenges. The report concludes that realizing the potential of toxicogenomics to improve public health decisions will require a concerted effort to generate data, make use of existing data, and study data in new waysâ€"an effort requiring funding, interagency coordination, and data management strategies.

Bringing together the recent and relevant contributions of over 125 scientists from industry, government, and academia in North America and Western Europe, Alternative Toxicological Methods explores the development and validation of replacement, reduction, and refinement alternatives (the 3Rs) to animal testing. Internationally recognized scientist

Scientific Frontiers in Developmental Toxicology and Risk Assessment reviews advances made during the last 10-15 years in fields such as developmental biology, molecular biology, and genetics. It describes a novel approach for how these advances might be used in combination with existing methodologies to further the understanding of mechanisms of developmental toxicity, to improve the assessment of chemicals for their ability to cause developmental toxicity, and to improve risk assessment for developmental defects. For example, based on the recent advances, even the smallest, simplest laboratory animals such as the fruit fly, roundworm, and zebrafish might be able to serve as developmental toxicological models for human biological systems. Use of such organisms might allow for rapid and inexpensive testing of large numbers of chemicals for their potential to cause developmental toxicity; presently, there are little or no developmental toxicity data available for the majority of natural and manufactured chemicals in use. This new approach to developmental toxicology and risk assessment will require simultaneous research on several fronts by experts from multiple scientific disciplines, including developmental toxicologists, developmental biologists, geneticists, epidemiologists, and biostatisticians.

The EPA commissioned The National Academies to provide advice on the vexing question of whether and, if so, under what circumstances EPA should accept and consider intentional human dosing studies conducted by companies or other sources outside the agency (so-called third parties) to gather evidence relating to the risks of a chemical or the conditions under which exposure to it could be judged safe. This report recommends that such studies be conducted and used for regulatory purposes only if all of several strict conditions are met, including the following: The study is necessary and scientifically valid, meaning that it addresses an important regulatory question that can't be answered with animal studies or nondosing human studies; The societal benefits of the study outweigh any anticipated risks to participants. At no time, even when benefits beyond improved regulation exist, can a human dosing study be justified that is anticipated to cause lasting harm to study participants; and All recognized ethical standards and procedures for protecting the interests of study participants are observed. In addition, EPA should establish a Human Studies Review Board (HSRB) to evaluate all human dosing studiesâ€"both at the beginning and upon completion of the experimentsâ€"if they are carried out with the intent of affecting the agency's policy-making.