The scientific basis for the regulation of nanoparticles: challenging Paracelsus and Pare.

• Author: Goldstein, Bernard D.

1. INTRODUCTION II. NANOTECHNOLOGY AS A SEMANTIC CHALLENGE TO SCIENCE-BASED REGULATION III. THE TOXICOLOGICAL BASIS FOR THE REGULATION OF CHEMICAL AND PHYSICAL AGENTS A. Paracelsus: The Dose Makes the Poison B. Pare's "Law": The Specificity of Effects C. Humans are Animals D. Mode of Action E. Predictability and Surprise IV. EXISTING OR PROPOSED REGULATORY APPROACHES IN SITUATIONS POTENTIALLY NOT RECOGNIZABLE BY PARACELSUS OR PARE A. Radiation B. Homeopathy: The Control of Low Dose Medication C. Hormesis V. REGULATION BASED ON INADEQUATE SCIENCE: THE PRECAUTIONARY PRINCIPLE VI. THE NEED FOR NEW SCIENCE A. Toxicology B. Exposure Assessment VII. PUBLIC HEALTH AND ENVIRONMENTAL SURVEILLANCE VIII. SUMMARY INTRODUCTION

In this article I consider the challenges posed by nanotechnology to regulations based on the standard "laws" of toxicology. These "laws", applicable to chemical and physical agents, are: (1) the dose makes the poison; (2) the specificity of effects; and (3) humans are animals. Although these "laws" are somewhat pertinent to nanoparticles, my conclusion is that the properties of nanoparticles can be sufficiently different from other chemical and physical agents so that standard regulatory approaches based upon the three "laws" of toxicology may not be protective of public health or the environment. For the most part I will restrict my comments to the scientific basis for regulation of nanotechnology aimed at protecting human health. (1)

After discussing some of the semantic problems posed by defining a field solely on a physical attribute, I will briefly describe the "laws" of toxicology underlying safety assessment and how nanotechnology provides problems for their routine use for developing regulatory controls--particularly for dose-response assessment. These challenges to protective regulation of nanoparticles are further addressed through the consideration of three other types of agents for which it is known or alleged that the biological response to the dose of the chemical does not fit common dose response characteristics: radionuclides, homeopathic drugs, and agents said to have hormetic properties. Also considered are the challenges posed by nanoparticles to exposure assessment, a central process in regulatory risk assessment and in the public health approach to environmental protection. I conclude that the existing and planned investments in understanding the scientific basis for appropriately regulating nanotechnology are not sufficiently robust to protect the public--or to protect the industry.

This article will not detail the growing literature on the toxicity of nanoparticles. The key point for this article is that there is ample literature to support the contention that, under the appropriate exposure conditions, nanoparticles can cause adverse consequences. (2)

II.

NANOTECHNOLOGY AS A SEMANTIC CHALLENGE TO SCIENCE-BASED REGULATION

The term nanotechnology is useful because it describes a field of endeavor that is linked by novel technical approaches to the generation and use of the special qualities of very fine particles. It is sufficiently distinct from usual incremental advances in research and development to be separable on a company balance sheet, or as a component of a national R&D strategy. Inevitably, any success in one specific nanotechnology will be generalized to all, as will any failures.

Nanotechnology describes a process. This process produces a variety of very different agents with markedly different chemical and biological properties, although at some stage sharing the physical characteristic of size within the nano range. Although knowledge that this small size is involved provides useful guidance to toxicological scientists seeking to provide the basis for regulatory regimes, it is not as helpful as a characterization that is based on use. For example, classification of a compound as a solvent, or as a pesticide, provides far more information about the likelihood for human and environmental exposure and toxicity. (3)

In essence, the term nanotechnology represents a bottleneck based solely on size. But once an agent is through this bottleneck, its effects can go in many different directions--though potential effects can be grouped together based on predicted mechanisms of action, as well as exposure routes and organ specific effects. (4) Semantic generalization across very diverse agents with a wide range of properties, both harmful and helpful, is common. (5) A major threat to all in the nanotechnology field is the possibility that adverse consequences demonstrated to occur from one nanoproduct will apply to all nanotechnology products in the minds of regulators and the public. This effect may detrimentally affect all subsequent regulation. (6) This appears to have occurred with GMO products, particularly foodstuffs that have received the generic label of "Frankenfoods." (7)

III.

THE TOXICOLOGICAL BASIS FOR THE REGULATION OF CHEMICAL AND PHYSICAL AGENTS (8)

Central to the interest in nanotechnology is that the properties of nanoparticles are often unique or at least far more effective than the same chemical molecules that are not nanostructures. This uniqueness also indicates the challenge to routine safety assessment of nanocompounds and nanoproducts.

It is helpful to explore why nanocompounds are similar to or different from other agents subject to regulation by considering the properties of nanocompounds through the lens provided by the three "laws" of toxicology. Of note is that nanoparticles can have two separate attributes in relation to the same chemical in its larger size: (1) nanoparticles are more effective in performing what would be done by the same chemical if not formulated in a nanosize; and (2) they can have completely different properties than would be observed when in a larger size. The first attribute challenges the first "law" of toxicology, the dose makes the poison. The second attribute relates to the second "law" of toxicology, the specificity of effects.

1. Paracelsus: The Dose Makes the Poison

   Paracelsus, a fifteenth century scientist and physician, is credited with the formulation that all chemicals are toxic, it is only a question of dose. For nanoparticles, the dose is as or more likely to be related to surface area or surface properties, such as charge, than it is to weight. For any given solid chemical's weight, the finer the particle size, the greater the surface area. This can lead to paradoxical dose response curves based on the weight of the chemical if particle size is not considered. A small amount of chemical formulated in nanoparticles can be more toxic, or more effective in its use, than a larger amount of the same chemical formulated in larger chemical particles. (9) For many specific nanoparticles, the physical phenomena related to a larger surface area are responsible for its intrinsic properties and effects. In essence, nanotechnology can provide an exception to the "dose makes the poison."

2. Pare's "Law": The Specificity of Effects (10)

   The second law of toxicology, that chemicals have specific effects, is analogous to the legal concept of general causation: can a chemical or physical agent produce a specific effect?

   Modern approaches to determining specificity often depend upon focusing on the total weight of evidence, such as the expert panel processes used by the International Agency for Research on Cancer (IARC) or the U.S. National Toxicology Program (NTP) in assessing whether a chemical is a carcinogen. If nanosizing leads to novel properties that cannot be discerned with standard toxicological testing, then Pare's law is significantly challenged.

3. Humans are Animals

   Central to the science of toxicology is an understanding of the relevance to humans of testing in laboratory animals. The respiratory tract is at particular risk of adverse effects through inhalation of nanoparticles, and there have been numerous studies demonstrating the toxicity of specific nanoparticles to the airways and lung. (11) While important information about the potential respiratory toxicity of nanoparticles can be obtained from in vitro studies, inhalation studies in laboratory animals are particularly important as the properties of the respiratory tract may alter the physical characteristics of nanoparticles during inhalation. For example, the 100% humidity of the respiratory tract may cause agglomeration of certain types of nanoparticles, a physical process akin to particles of table salt becoming too large to fit through the holes of a salt shaker in humid weather.

4. Mode of Action

   A central focus of the science of toxicology is to identify the underlying processes by which external agents cause adverse effects. Extensive advances in recent years have built upon the expanding knowledge base in the biological sciences. This has facilitated one of the very positive changes in EPA science-based regulatory approaches, namely, the inclusion of information about an agent's mechanism of action or mode of action. (12) The use of such information in decision-making about the weight of evidence concerning a chemical or physical agent has also occurred in deliberations about cancer-causing agents by IARC and by the U.S. National Toxicology Program. (13) There has been much recent interest in making use of the advances in molecular biology and information technology to develop better in vitro screening methods for predicting toxicological effects. (14) However, nanoparticles pose additional problems to determining mode of action through in vitro testing because of uncertainty about the size dimensions of the nanoparticle in the test system as compared to in vivo.

5. Predictability and Surprise

   As a preventive science, toxicology depends upon providing the tools to predict and avoid the adverse-effects of a chemical or physical agent. Simply put, an adverse effect caused by a chemical or physical agent represents the failure of...