Safe-by-Design part I: Proposal for nanospecific human health safety aspects needed along the innovation process

Safe-by-Design aims to reduce uncertainties and/or increase the human health and environmental safety from already early in the innovation process onwards and will thereby contribute to increased innovation efficiency, economic viability, interdisciplinary collaboration, consumers trust and improve sustainability. Since most innovators or designers are neither toxicologists nor risk assessors, considering human health safety aspects within their innovation process may be challenging. This paper provides sets of questions that can help innovators to assess nanospecific human health safety aspects of their product or material along the various stages of the innovation process. Addressing these questions will facilitate innovators to identify which type of information may support decisions on how to address potential human health risks in the innovation process. The identified information on the human health safety aspects can help innovators to decide if further investments in the product or material are beneficial. It may allow them to rank, prioritize and choose safer alternatives early in the innovation process. This may enable innovators to better anticipate on potential safety issues in an early stage, preventing these safety issues to become an innovation killer in a later stage of the innovation process. This approach to identify potential nanospecific human health risks should be considered as complementary to current regulations. The applicability of this approach was evaluated using a few industrial case studies. To determine if the approach is applicable to the innovation of a broader group of nanomaterials and nano-enabled products, more experience within various industrial sectors is needed

Interpretation and implications of the European Commission's definition on nanomaterials

In October 2011, the European Commission published the Recommendation on the Definition of Nanomaterial. RIVM considers this definition to be a good basis for further discussion that should focus on two aspects of the definition: the proposed size limits for nanoparticles (1 to 100 nanometres); and the requirement that at least 50 % of the number of particles should be in this size range. According to RIVM, further scientific research would contribute to better understanding the implications of these threshold values. In addition, reliable and standardised measurement techniques are needed to determine particle number and size distributions. The European Commission will review the definition in 2014 in the light of experience and developments in science and technology. Understanding potential risks important: In recent years, an increasing number of applications and products containing or using nanomaterials have become available. However, the small size of the particles in nanomaterials gives these materials different properties relative to materials with larger sizes. A univocal definition of the term 'nanomaterial' is essential in EU legislation and regulations, particularly with regard to the management of potential risks of nanomaterials to humans and the environment. Once the definition of a nanomaterial has been established, it has to be incorporated in the appropriate legislative frameworks. Subsequently, further amendments may be required with regard to specific provisions for certain types of nanomaterials to ensure safe use. Particles outside the definition are not automatically safe: RIVM agrees with the Commission's principle that a nanomaterial should not automatically be considered as hazardous. Conversely, materials not covered by the definition should not automatically be considered as safe. Such materials may pose a nano-sized related risk, if a substantial number of the particles is in the nano-size range, depending on the degree of human and environmental exposure

Mouse models for xeroderma pigmentosum group A and group C show divergent cancer phenotypes

The accumulation of DNA damage is a slow but hazardous phenomenon that may lead to cell death, accelerated aging, and cancer. One of the most versatile defense mechanisms against the accumulation of DNA damage is nucleotide excision repair, in which, among others, the Xeroderma pigmentosum group C (XPC) and group A (XPA) proteins are involved. To elucidate differences in the functions of these two proteins, comprehensive survival studies with Xpa-/-, Xpc-/-and wild-type control female mice in a pure C57BL/6J background were done. The median survival of Xpc-/-mice showed a significant decrease, whereas the median survival of Xpa-/-mice did not. Strikingly, Xpa-/-and Xpc-/-mice also showed a phenotypical difference in terms of tumor spectrum. Xpc-/-mice displayed a significant increase in lung tumors and a trend toward increased liver tumors compared with Xpa-deficient or wild-type mice. Xpa-/-mice showed a significant elevation in liver tumors. Additionally, Xpc-deficient mice exhibited a strong increase in mutant frequency in lung compared with Xpa-/-mice, whereas in both models mutant frequency is increased in liver. Our in vitro data displayed an elevated sensitivity to oxygen in Xpc-/-in mouse embryonic fibroblasts (MEF) when compared with Xpa-/-and wild-type fibroblasts. We believe that XPC plays a role in the removal of oxidative DNA damage and that, therefore, Xpc-/-mice display a significant increase in lung tumors and a significant elevation in mutant frequency in lung, and Xpc-deficient MEFs show greater sensitivity to oxygen when compared with Xpa-/-and wild-type mice

Impaired genome maintenance suppresses the growth hormone--insulin-like growth factor 1 axis in mice with Cockayne syndrome.

Cockayne syndrome (CS) is a photosensitive, DNA repair disorder associated with progeria that is caused by a defect in the transcription-coupled repair subpathway of nucleotide excision repair (NER). Here, complete inactivation of NER in Csb(m/m)/Xpa(-/-) mutants causes a phenotype that reliably mimics the human progeroid CS syndrome. Newborn Csb(m/m)/Xpa(-/-) mice display attenuated growth, progressive neurological dysfunction, retinal degeneration, cachexia, kyphosis, and die before weaning. Mouse liver transcriptome analysis and several physiological endpoints revealed systemic suppression of the growth hormone/insulin-like growth factor 1 (GH/IGF1) somatotroph axis and oxidative metabolism, increased antioxidant responses, and hypoglycemia together with hepatic glycogen and fat accumulation. Broad genome-wide parallels between Csb(m/m)/Xpa(-/-) and naturally aged mouse liver transcriptomes suggested that these changes are intrinsic to natural ageing and the DNA repair-deficient mice. Importantly, wild-type mice exposed to a low dose of chronic genotoxic stress recapitulated this response, thereby pointing to a novel link between genome instability and the age-related decline of the somatotroph axis