Nanoscale materials raise questions where toxicity is concerned

By Chuck Berndt, Communications Vice President, IEST

The safety (toxicity) of nanoscale materials is largely an unknown. This is a significant knowledge void that should be considered and rectified. This includes exposure, dose, absorbency, absorbency rate, and what happens at the molecular/cellular level-namely, toxicity, mutagenicity, carcinogenicity, teratogenicity, metabolic anomalies, and so forth.

According to the National Toxicology Program (NTP), established by the Department of Health and Human Services’ Nanotechnology Safety Initiative, Nanotechnology is defined by the National Nanotechnology Initiative (NNI) as “‘the understanding and control of matter at dimensions of roughly 1 to 100 nanometers, where unique phenomena enable novel applications.’ These materials can, in theory, be engineered from nearly any chemical substance; semiconductor nanocrystals, organic dendrimers, and carbon fullerenes and carbon nanotubes are a few of the many examples. Nanoscale materials are already appearing in commerce as industrial and consumer products and as novel drug delivery formulations. Commercial applications and resultant opportunities for human exposure may differ substantially for ‘nanoscale’ compared with ‘bulk’ materials.”1,2

The NTP goes on to point out that “there is very little research focus on the potential toxicity of manufactured nanoscale materials,” suggesting the possibility that the very diverse properties of nanoscale materials indicate that their toxicological characteristics may be different from those materials with similar composition but larger dimensions.

What is toxicology?

The study of poisons is known as toxicology. In other words, toxicology is the study of the adverse effects of chemical, physical, or biological agents on living organisms and the ecosystem, including the prevention and amelioration of such adverse effects. It is the study of the adverse effects of chemicals on living organisms, including the study of symptoms, mechanisms, treatments, and detection of poisoning, especially the poisoning of people. The chief criterion regarding the toxicity of a chemical is the dose, i.e., the amount of exposure to the substance. Almost all substances can be toxic under the right conditions.

Many substances regarded as poisons are toxic only indirectly. An example is “wood alcohol,” or methanol, which is chemically converted to formaldehyde and formic acid in the liver. It is the formaldehyde and formic acid that cause the toxic effects of methanol exposure. Many drug molecules are made toxic in the liver; a good example is acetaminophen, especially in the presence of alcohol. The genetic variability of certain liver enzymes makes the toxicity of many compounds differ between one individual and the next. Because demands placed on one liver enzyme can induce activity in another, many molecules become toxic only in combination with others. A family of activities that engages many toxicologists includes identifying which liver enzymes convert a molecule into a poison, what are the toxic products of the conversion, and under what conditions and in which individuals this conversion takes place.

The term LD50 refers to the dose of a toxic substance that kills 50 percent of a test population (typically rats or other surrogates when the test concerns human toxicity). LD50 estimations in animals became obsolete in 1991 and are no longer required for regulatory submissions as a part of a pre-clinical development package.

Toxicity

Toxicity may be defined as (1) the quality or condition of being toxic; (2) the degree to which a substance is toxic; and (3) a measure of the degree to which something is toxic or poisonous. Toxicity can refer to the effect on a whole organism (such as a human, a bacterium, or a plant), or to a substructure (such as the liver). By extension, the word may be metaphorically used to describe toxic effects on larger and more complex groups, such as the family unit or “society at large.”

In the science of toxicology, the subject of such study is the effect of an external substance or condition and its deleterious effects on living things, i.e., organisms, organ systems, individual organs, tissues, cells, and subcellular units. A central concept of toxicology is that effects are dose dependent. Even water is toxic to a human in large enough doses, whereas for even a very toxic substance such as snake venom, there is a dose for which there is no toxic effect detectable.

There are generally three types of toxic entities: chemical, biological, and physical.

• Chemicals include both inorganic substances such as lead, hydrofluoric acid, and chlorine gas, as well as organic compounds such as ethyl alcohol, most medications, and poisons from living things.
• Biological toxicity can be more complicated to measure because the “threshold dose” may be a single organism, as theoretically a single virus, bacterium, or worm can reproduce to cause a serious infection. However, in a host with an intact immune system, the inherent toxicity of the organism is balanced by the host’s ability to fight back; the effective toxicity is then a combination of both parts of the relationship. A similar situation is also present with other types of toxic agents. In particular, toxicity of cancer-causing agents is problematic, since for many such substances it is not certain if there is a minimal effective dose or whether the risk is just too small to see; here, too, the possibility exists that a single cell transformed into a cancer cell is all it takes to develop the full effect. Mixtures of chemicals are more difficult to assess in terms of toxicity, such as gasoline, cigarette smoke, or industrial waste. Even more complex are situations with more than one type of toxic entity, such as the discharge from a malfunctioning sewage treatment plant, featuring both chemical and biological agents.
• Physically toxic entities include things not usually thought of as such by the lay person: direct blows; concussion; sound and vibration; heat and cold; non-ionizing electromagnetic radiation, such as infrared and visible light; ionizing non-particulate radiation, such as x-rays and gamma rays; and particulate radiation, such as alpha rays, beta rays, and cosmic rays.

Toxicity can be measured by the effects on the target (organism, organ, or tissue). Because individuals typically have different levels of response to the same dose of a toxin, a population-level measure of toxicity is often used that relates the probability of an outcome for a given individual in a population (e.g., the LD50). When such data does not exist, estimates are made by comparison to known similar toxic things or to similar exposures in similar organisms. Then ”safety factors“ must be built in to protect against the uncertainties of such comparisons in order to improve protection against these unknowns.

Factors influencing toxicity

Toxicity of a substance can be affected by many different factors, such as the pathway of administration (is the toxin applied to the skin, ingested, inhaled, injected), the time of exposure (a brief encounter or long term), the number of exposures (a single dose or multiple doses over time), the physical form of the toxin (solid, liquid, gas), the genetic makeup of an individual, an individual’s overall health, and many others. Several of the terms used to describe these factors have been included here.

• Acute exposure: a single exposure to a toxic substance that may result in severe biological harm or death; acute exposures are usually characterized as lasting no longer than a day
• Chronic exposure: continuous exposure to a toxin over an extended period of time, often measured in months or years

What is needed to address these concerns?

In recognition of this knowledge void, the NTP has formed an initiative to address the potential human health hazards associated with the fabrication and use of nanoscale materials. The research program was founded with the aim of investigating and evaluating the “toxicological properties of major nanoscale materials classes which represent a cross-section of composition, size, surface coatings, and physicochemical properties, and use these as model systems to investigate fundamental questions concerning if and how nanoscale materials can interact with biological systems.”2

The President’s Council of Advisors on Science and Technology submitted its assessment and recommendations on nanotechnology toxicology research via the National Nanotechnology Advisory Panel (NNAP) in 2005: “The National Nanotechnology Initiative (NNI) is funding research within several agencies to develop a broad understanding of the environmental and health effects of nanotechnology, in particular those nanomaterials that show the most promise for commercial use. The NNAP draws special attention to the ongoing research by the [NTP] to determine the toxicity of specific nanomaterials, and by the National Institute for Occupational Safety and Health to ensure worker safety.”3

The document goes on to delineate the planned budget allocations for research and development into the potential health and environmental risks of nanotechnology, as well as detail other government and organizational efforts engaged in researching the use of nanoparticles. For example, NNAP enlisted the Science and Technology Policy Institute to conduct a survey of National Institutes of Health (NIH)-funded nanotechnology research projects. To move forward with enlarging the body of knowledge necessary to set standards and develop guidelines and regulations related to nanotechnology manufacture, the NNAP established the Nanotechnology Environmental and Health Implications Working Group under the NSET Subcommittee, explaining that “[the] working group has enabled exchange of information among research and regulatory agencies and has brought together a group that can both identify the research needed in support of regulatory decision-making and implement those priorities into the R&D program.”3

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Charles W. Berndt is the principal in C. W. Berndt Associates (Highland Park, IL), which provides advisory services associated with human-sourced contamination control. He spent eight years as group manager of the Araclean Division of ARA/Aratex Services (now known as ARAMARK Cleanroom Services). He serves on the Editorial Advisory Board of CleanRooms magazine, chairs the Editorial Board of the peer-reviewed Journal of the IEST, is communications vice president of IEST, and serves on IEST’s Executive Board. He chaired Working Group CC003 during the development of IEST-RP-003.3.

About IEST

IEST is an international technical society of engineers, scientists, and educators that serves its members and the industries they represent (simulating, testing, controlling, and teaching the environments of earth and space) through education and the development of recommended practices and standards. IEST is the Secretariat of ISO/TC 209, Cleanrooms and associated controlled environments, charged with writing a family of international cleanroom standards. IEST is also an ANSI-accredited standards-development organization. For more information, contact IEST at [email protected] or visit the IEST web site at www.iest.org.

References

1. http://ntp.niehs.nih.gov/index.cfm?objectid=720163E9-BDB7-CEBA-FB0157221EB4375F.
2. For questions or additional information, contact: Dr. Nigel Walker, NIEHS/NIH, P.O. Box 12233, MD EC-34, 79 T.W. Alexander Dr., Research Triangle Park, NC 27709.
3. The National Nanotechnology Initiative at Five Years: Assessment and Recommendations of the National Nanotechnology Advisory Panel (NNAP), Chapter 3, Sec. 1, Environmental, Health, and Safety, submitted by the President’s Council of Advisors on Science and Technology, May 2005.