As noted in prior posts, nanoparticles appear to offer significant promise in many fields of endeavor (e.g., their application to thin-film solar cells to yield much higher efficiencies). Frequently such new technologies generate much hype along with the promise of breakthroughs in a wide variety of fields. See, for example, in medicine [http://www.economist.com/science/displaystory.cfm?story_id=12551598], manufacturing [http://www.economist.com/science/tq/displaystory.cfm?story_id=10202708], and computer data storage [http://www.economist.com/science/displaystory.cfm?story_id=E1_RJNNVNG]. But, regulators are beginning to express concern about the potential for exaggeration [see, for example, http://www.economist.com/science/displaystory.cfm?story_id=11043927, in which EPA questions certain antimicrobial claims made for nanoparticles], as well as for adverse environmental and health impacts from the new technology. Thus, EPA is beginning to look at the regulatory tools it has available to address these issues. In January 2008 EPA released its view of whether nanomaterials should be treated as "new" or "existing" chemical substances under the Toxic Substances Control Act. [See http://epa.gov/oppt/nano/nmsp-inventorypaper2008.pdf.] As summarized in the EPA analysis: "Thus, in determining whether a chemical substance is a new chemical for purposes of TSCA Section 5, or instead is an existing chemical, EPA determines whether the chemical substance has the same molecular identity as a substance already on the Inventory. A chemical substance with a molecular identity that is not identical to any chemical substance on the TSCA Inventory is considered to be a new chemical substance (i.e. not on the Inventory); a chemical substance that has the same molecular identity as a substance listed on the Inventory is considered to be an existing chemical substance." Demonstrating that it is likely to view virtually all nanomolecules as new chemicals (without saying so explicitly), EPA noted: "EPA views molecular identity as being based on such structural and compositional features as the types and number of atoms in the molecule, the types and number of chemical bonds, the connectivity of the atoms in the molecule, and the spatial arrangement of the atoms within the molecule. EPA considers chemical substances that differ in any of these structural and compositional features to have different molecular identities." Toward that end, EPA has given notice that it considers most carbon nanotubes to be "new chemicals" under TSCA, and the regulatory requirements applicable thereto. [See http://edocket.access.gpo.gov/2008/pdf/E8-26026.pdf.] It should not be surprising that EPA has taken this position because at the nano-level, the physical, chemical, and biological characteristics of atoms is often significantly different than it is for larger agglomerations of these atoms. [See, for example, a discussion of the quantum properties of gold nanoparticles compared to larger gold molecules at http://cnmt.kist.re.kr/data/newsletter/file/gold%20nanoparticles.pdf.] Thus, under TSCA, manufacturers and importers of new TSCA chemicals must submit a pre-manufacture notice (PMN) before commencing manufacture or import. After the review period passes, the manufacturer or importer submits a Notice of Commencement, and EPA places the chemical on the TSCA Inventory. Once in the Inventory, the chemical is deemed an “existing" chemical. EPA has received numerous PMN''s for nanoscale materials, and has taken steps to limit exposure, including (a) limiting uses of the materials, (b) requiring personal protective equipment (e.g., impervious gloves and NIOSH-approved respirators), and (c) constraining environmental releases. EPA has other tools available to it. For example, EPA has issued a "significant new use rule" (SNUR) for siloxane modified silica nanoparticles and siloxane modified alumina nanoparticles. [See http://edocket.access.gpo.gov/2008/pdf/E8-26409.pdf.] Issuing a SNUR allows EPA to require additional test data, enhance record-keeping requirements, and/or conduct a risk assessment based on new data. To the extent that a manufacturer or importer intends to use the substance for the significant new use described in the SNUR, the manufacturer or importer must notify EPA at least 90 days prior to commencing that activity. With respect to these silica and alumina particles, EPA has expressed concern regarding adverse effects on the lungs and potential systemic effects from dermal exposures. EPA recommends a 90-day inhalation toxicity test for each substance, and has noted that any use beyond the use of these substances as additives, as described in the PMN, could result in serious health effects. But, is TSCA the appropriate tool for addressing nanosubstances, or does a new regulatory apparatus need to be developed? Do the unique quantum properties of nanosubstances require a more comprehensive toxicity screening before these materials are used? Recently published research demonstrates the wide range of adverse effects that need to be considered when examining nanosubstances for their potential to cause harm. Researchers looked at quantum dots (QDs) [see http://en.wikipedia.org/wiki/Quantum_dots]. Nanosized QDs have specific properties-tunable emission wavelength, broadband absorption spectrum, and photostability-that make them ideal diagnostic probes for long-term in vivo and in vitro (multicolor) imaging. However, the toxicological information on QDs is limited. The researchers investigated the acute in vivo toxicity, including systemic and pulmonary inflammation, tissue distribution, and prothrombotic effects, of commercially available cadmium selenide/zinc sulfide (CdSe/ZnS) QDs; they also paid attention to surface charge, which past research suggested was an important factor in evaluating toxicology of nanomaterials. The investigative method involved injecting various quantities of materials in mice. "Because this is the first in-depth study specifically designed to test the in vivo toxicity of QDs, our purpose was to assess acute effects and to provide a dose-response relationship, together with an assessment of the tissue distribution, to identify the important target organs. Because vascular thrombi were produced in the lung, we investigated whether this thrombosis was due to either platelet activation or activation of coagulation. We examined platelet activation by assessing the effects of administering QDs on levels of P-selectin on circulating platelets (using flow cytometry) and by measuring platelet aggregation upon in vitro incubation of murine and human PRP with QDs. The role of coagulation was assessed by examining the effects of pretreatment with the anticoagulant heparin." The results were summarized as follows: "At high doses, the QDs caused pulmonary vascular thrombosis [a blood clot in a vein in the lungs; see http://en.wikipedia.org/wiki/Vascular_thrombosis], with carboxyl-QDs being more potent in inducing this effect than amine-QDs. Because fibrin fibers [a protein involved in blood clotting; see http://en.wikipedia.org/wiki/Fibrin] were present in the thrombi and because pretreatment with heparin [an anticoagulant; see http://en.wikipedia.org/wiki/Heparin] abolished the thrombotic effects, we speculate that negatively charged QDs activate the coagulation cascade via contact activation. We saw an effect of surface charge in all the parameters tested. Lower doses of 14.4 pmol or 1.44 pmol did not elicit acute adverse effects. This is the first comprehensive evaluation of the hazard of injected QDs and emphasizes that surface charge is an important parameter in assessing nanotoxicity." In summary, then, the QDs caused clots to form in the veins of the lungs, a highly dangerous effect [in humans, such situations can be fatal; see http://www.merck.com/mmhe/sec03/ch036/ch036b.html?qt=pulmonary%20vascular%20thrombosis&alt=sh]; the initiation of the clotting mechanism appears to be associated with the surface charge of the QD [that is, the electrical charge at the interface between the QD and the surrounding environment (which in this case was the contents of the body); see http://en.wikipedia.org/wiki/Surface_charge]. The study can be found at http://www.ehponline.org/members/2008/11566/11566.html. This type of research highlights that for many nanomaterials our knowledge of their behavior within mammalian physiology is limited, and that many effects are driven by unanticipated factors (in this case, surface charge). Research of this type suggests that caution is a prudent guideline until a better understanding of behavior and effects of nanosubstances within biological systems is had.