In an opinion piece titled "Chemical regulators have overreached" in the August 27, 2009 issue of Nature, two prominent animal welfare advocates claim that vastly larger numbers of chemicals will have to be tested under the European Union's REACH regulation than previously estimated, and hence that 20 times more laboratory animals will be sacrificed.  They call for a moratorium on some animal tests.  Well, a closer look reveals that it's the opiners themselves that have greatly overreached.

[Update 8/28:  The European Chemicals Agency (ECHA) has just issued this press release also disputing the findings of this new study.]

The authors of the Nature opinion piece are Thomas Hartung and Costanza Rovida.  Hartung is the director of the Center for Alternatives to Animal Testing (CAAT), while Rovida is identified as a private consultant, but was formerly affiliated with the European Centre for the Validation of Alternative Methods (ECVAM), as was Hartung. 

The Nature piece cites a longer, 22-page report by the same authors released by the Trans-Atlantic Think Tank for Toxicology (t4).  t4 is a creation of CAAT.

The report is laid out to look like a peer-reviewed journal article but is self-published (more later on what the authors claim to be the expert review conducted of the report).  [Note added 8/27: The report is to be published in a journal called ALTEX.  According to its website, ALTEX is "the official journal of CAAT ... and t4, the transatlantic think tank of toxicology."  According to an article appearing in today's BNA Daily Environment Report (p. A-4):  "The study was prepared with funding from the Transatlantic Think Tank for Toxicology, which works with [CAAT]."  Hence my characterization of the report as "self-published" is quite appropriate.]

This study has used numerous demonstrably false or highly questionable assumptions, one piled on another, to grossly inflate the number of chemicals requiring testing under REACH, and the number of animals involved.

Both the opinion piece and the accompanying report reflect a fundamental misunderstanding of the basics of REACH and an apparent willingness to inflate every number in long chains of calculations to yield the largest possible estimates for the number of animals to be sacrificed under REACH. 

In this post, I will address in detail some of the more egregious claims.  They include:

• Vastly overstating the number of chemicals in commerce, to be registered and required to tested under REACH.
• Vastly overstating the number of high-production-volume chemicals in the EU.
• Overstating the number of animals required for at least certain tests.
• Claiming expert review of its report, when 7 of the 8 reviewers are either close colleagues of the authors or representatives of the chemical industry.  Not a single representative of the European Commission or the European Chemicals Agency reviewed the report.

Prepare for a fairly deep dive, with lots of numbers, because that's what the authors have based their claims on.

Some context

But first, some context.  During the nearly decade-long debate over the final text of REACH, animal welfare advocates extracted major concessions from the EU.  In addition to peppering REACH with statements to the effect that animal testing would be done only as a "last resort," the changes forced by animal welfare advocates included elimination of all animal testing for existing chemicals produced below 10 tons per year per manufacturer, and a requirement that only testing proposals, not test data, be submitted at the time of registration for any tests involving laboratory animals. 

Most notably, an entire Title of REACH is devoted to "Data Sharing and Avoidance of Unnecessary Testing," setting in motion the mandatory formation of so-called Substance Information Exchange Forums (SIEFs) among makers and users of a chemical that have become the latest poster child for the chemical industry's ongoing gripes about REACH.

Let me be clear:  I personally, and EDF organizationally, strongly support taking all possible measures consistent with good science and sound chemicals safety policy to reduce unnecessary animal testing.  That includes unearthing and utilizing all available data, allowing and facilitating the appropriate use of alternatives to animal testing, including in vitro methods, read-across within chemical categories, and estimation models based on structure-activity relationships (SARs).  It also means aggressively developing more alternatives, including high-throughput screening methods and computational toxicology – approaches that form the core of the long-term vision embodied in the National Academy of Sciences' seminal report Toxicity Testing in the 21^st Century.

But we also need to address the fact that tens of thousands of chemicals are in active use today that have never been sufficiently tested or assessed for safety, due to policies put in place decades ago that simply presumed them to be safe.  That is a very deep hole to dig ourselves out of.

But it's not nearly as deep as Hartung and Rovida would have us believe.  Let's examine some of their claims:

Claim #1:  "More than 100,000 synthetic chemicals are used in consumer products."

That's the very first sentence in the Nature opinion piece, and it's flat wrong.  This number is derived from the number of chemicals listed in the EU's inventory of all chemicals that were in commerce in the EU at the time the inventory was developed in 1981.  It is not an accurate count of chemicals currently in commerce.

In the US, about 84,000 chemicals are listed on the cumulative TSCA Inventory, first set in 1979, but again not all of those are currently in commerce.  EPA's latest count of those manufactured or imported above 25,000 pounds/year is less than 7,000 chemicals.  While that is clearly an underestimate as there are many chemicals below this threshold, and the reporting system has a number of exemptions, nowhere near 84,000 chemicals are in active commerce in the U.S.  Given the global nature of the chemicals market, it seems highly unlikely that the situation is radically different in the EU.

Claim #2.  "Our report … is based on the pre-registration of chemicals [under REACH]."

The authors' primary analysis is based on the gross number of substances that were pre-registered under REACH last year.  However, as the European Chemicals Agency (ECHA), which administers and oversees REACH, has made clear, pre-registration is not an accurate representation of the number of chemicals to be registered under REACH. 

ECHA's press release from March of this year states:

• "ECHA does not expect all of these [preregistered] substances to be registered."
• "In ECHA’s opinion the list contains many preparations and substances that did not require registration."

ECHA has already found that the list of pre-registered substances contains many substances (as well as items such as articles) that are duplicates or are entirely exempt from or inapplicable under REACH and will not need to be registered at all.  Pre-registrations were filed not only by chemical makers and importers, but by downstream users, as well as contract testing labs, consultants and others, mining for business opportunities.

Bizarrely, Hartung and Rovida acknowledge "a large abuse of preregistration" as well as significant duplicative entries.  Yet they proceed unfazed to base much of their analysis on the inflated pre-registration numbers.

Claim #3.  "The latest published list of REACH chemicals contains 143,835 substances that are supposed to be fully registered, each requiring a chemical safety report."

     AND

There are a total of "140,008 substances that may require extensive testing for registration."

These sentences contain several significant errors.  First, they reflect the gross number of pre-registered substances.  It is true that ECHA's pre-registration list contains more than 140,000 entries.  But as noted above, that number is highly inflated and the number of substances to be registered under REACH is expected by ECHA to be far lower. 

In a statement sent to Nature by ECHA in response to Hartung and Rovida's study (referred to in NatureNews here), ECHA reiterates that, based on its review of the pre-registration lists, it still believes its original estimates for the number of unique substances to be registered under REACH (about 30,000) is quite close to accurate.

Second, only those registered substances above 10 tonnes/year are required to have chemical safety reports (CSRs).  The EU estimates that the large majority (about two-thirds) of all registered substances will fall under this threshold and not require CSRs.  For these chemicals, no animal testing is to be required under REACH.

Claim #4.  We estimate "68,000 chemicals falling under REACH, and this is the lower (optimistic) estimate in our study."

The authors characterize the estimate they derived from pre-registration lists as "worst-case," yet they use it as the primary basis for their analysis.

But even their "best case" number of 68,000 chemicals is also highly inflated.  Its derivation is frankly, laughable:

• They start with the EU's own estimate that about 30,000 chemicals will be registered under REACH.  That number was derived by data collected by the EU in the mid-1990s, compelling the authors to seek to "update" it.
• First they note that chemical production as measured by sales volume has increased substantially in the EU, nearly doubling between the mid-1990s and today.  I have no reason to doubt this.
• Second, they point out that the EU itself has grown by accepting into its ranks a number of new countries.  They put that growth at about 20%.  Again, all fine.
• But then, astoundingly, they assume that the number of chemicals produced in the EU has increased in direct proportion to these growth factors.  That leads them to multiply the 30,000 EU estimate by about 2 and then again by about 1.2, to yield the 68,000.

The notion that recent growth in the sales and volumes of chemicals in the EU was derived entirely by introduction of new chemicals, and not primarily by increases in production of existing chemicals, is contradicted by all empirical evidence – including the statistics cited by the authors themselves in the very first paragraph of the Nature opinion piece. 

They point out that "existing 'old' chemicals represent about 97% of those in use today and 99% of the production volume."  I'll let you do the math to conclude that there is simply no way that 38,000 new REACH-eligible chemicals have been introduced in the EU since the mid-1990s.  OK, I'll do the math:  That would mean, among other things, that the "old" chemicals would account for well under half of those in use today, not 97%!

Indeed, the actual number of new chemicals registered in the EU since 1981 (which is cited by the authors elsewhere but ignored here!) is about 4,400.

Claim #5.  After going through more arcane calculations, the authors finally arrive at the following numbers of chemicals that they claim will require extensive animal testing:

• 47,858 chemicals marketed above 1000 tonnes/year, to which a 2010 registration deadline applies
• 53,040 chemicals marketed above 100 tonnes/year, to which a 2013 registration deadline applies

The former of these numbers represents what the EU calls high-production-volume (HPV) chemicals.  The authors claim there are nearly 48,000 such HPV chemicals.  The EU estimates there are only a few thousand.  Who's right?

The Organization for Economic Cooperation and Development (OECD) maintains a list of HPV chemicals produced in its 33 member countries.  OECD includes not only all of the EU, but also the U.S., Japan, Australia, Canada, Korea and all of the rest of the developed world.

How many HPV chemicals does the OECD list?  About 5,000.

So yet again, Hartung and Rovida grossly overstate reality:  They are off by at least an order of magnitude.

Claim #6.  "The two-generation study for reproductive toxicity … consumes an average of 3,200 rats per chemical."

The authors zero in on this particular test as a primary culprit, calling for a moratorium on such testing under REACH.  Let's look at the claim.

The authors claim this "average" number was calculated in a paper by Höfer et al (2004).  That paper, however, merely asserts the number and provides no calculation.  It does, however, characterize the number as a "maximum" number, and includes it in a table of "theoretical extrapolation of a maximum number of animals to be used."

The authors allude to a second paper by Cooper et al. (2006) that estimates only 2,600 rats per test, but doggedly stick with the higher number for all of their calculations.  Even that number seems high to experts we have contacted.  The Cooper et al. estimate assumed an average of 15 offspring per mated pair of rats; Hartung and Rovida themselves cited data that the average litter size for rats is only 8.2 offspring, while others put it at around 10.  Yet the authors appear unaware of and certainly never flag this major discrepancy.

There are, of course, many reasons why understanding a chemical's effects on reproduction is critical, and there is a large number of chemicals for which we are already finding such effects.  ECHA's statement summarizes the need for this test as follows:

     "The two generation study is the only study where functional fertility (including mating, fertility, number of implantations and litter size) is investigated in parental animals exposed during vulnerable life stages from conception, in utero up to puberty. Such an exposure design may be of special importance, e.g., for endocrine disrupting chemicals. This is not covered by any other reproductive study, including one-generation study protocols, as long as mating of the F1 generation [offspring of the exposed parents] is not performed."

Claim #7.  "The plausibility of our assumptions and calculations was checked by eight experts from industry, academia and regulatory authorities."

This paper has not been peer-reviewed in any normal sense of the term. 

A footnote on the first page identifies two reviewers.  One is the current Chair of the Board and former director of CAAT, the organization Hartung now directs.  The other is a colleague of Hartung's at the University of Konstanz in Germany, where Hartung has a joint appointment.

Six other expert reviewers are cited in the Acknowledgement section of the paper.  Five of the six work for the chemical industry or its trade associations:  ECETOC (a trade association "financed by its membership, which comprises 50 of the leading companies with interests in the manufacture and use of chemicals"), Dupont, Shell, Exxon-Mobil and BASF.  CAAT's advisory board is also well-stocked with industry representatives.

This is no accident:  There is, shall we say, a strongly shared interest between the chemical industry and animal welfare advocates in undercutting chemical testing programs.  This isn't the first instance of such close cooperation, and I very much doubt it will be the last.

A single reviewer was drawn from government (a German federal agency). 

The paper received no review whatsoever from anyone from the European Commission or ECHA.  Perhaps had that occurred, some of the huge errors might have been caught before publication.

Conclusion

As noted at the start, this study has used numerous demonstrably false or highly questionable assumptions, one piled on another, to grossly inflate the number of chemicals requiring testing under REACH, and the number of animals involved.

Why?  One need only look at the last concluding sentence of the author's study for what I think is at least part of the answer:

     "It is be­yond dispute that the primary aim of REACH is protecting hu­man health and the environment from unwanted consequences of exposure to chemicals.  The challenge will be to do it sensibly within the context of REACH while using all the information and experience we have and recognizing that most chemicals have been produced and used safely for many years without ex­tensive testing on animals.  (emphasis added)

That naïve assumption – that what we haven't tested can't hurt us – is what got us into this mess in the first place.  I cited many sources of information that demolish that argument  in the Introduction to my 2007 report, Not That Innocent.

There is a near-total absence in either the Nature piece or the accompanying study of mention of concern for the need to protect human health from the effects of toxic chemicals.  More striking, given the animal welfare orientation of the authors, is their utter failure to recognize or acknowledge that gaining a better understanding of chemical hazards is essential to protecting animals in the wild from toxic chemicals. 

Our knowledge of the endocrine-disrupting effects of chemicals originated with studies of animals in the wild.  DDT's devastating effects first came to light through witnessing the dramatic declines in reproductive success of ospreys and eagles in the wild.  Growing evidence indicates that the widespread and increasing deformations and gender-bending effects seen in wild fish and amphibians are the result of chemical exposures.  We now know that wildlife in the remotest parts of the Earth carry dangerous levels of persistent substances in their bodies.

All of these impacts of untested and under-assessed chemicals affect untold billions or trillions of animals in the wild.

Doesn't that matter?

[My EDF colleague and toxicologist, Dr. Cal Baier-Anderson, helped with some aspects of the content of this post.]

It's been nearly a year since EPA launched its voluntary Nanoscale Materials Stewardship Program (NMSP) – and over three years since EPA was urged, by a diverse group of stakeholders, to do so only in conjunction with the development of mandatory reporting rules as a backstop and to limit the duration of the basic part of the program to at most six months.

EPA ignored that advice, and proceeded with an open-ended voluntary program and no development of backstop rules.  Now EPA has issued its first evaluation of the NMSP.  So what did EPA find?

Despite a major arm-twisting effort by EPA to get companies to sign up, only 29 have made submissions to EPA under the basic program, and only four have said they're willing to discuss the possibility of doing any testing under the in-depth program.

Perhaps not surprisingly, few of the submissions contain any health and environmental data – confirming that few if any nanomaterials have been sufficiently studied, despite their rapid commercialization.  Also in the category of "not surprising:"  Large amounts of the data that were submitted were claimed to be confidential business information – despite EPA's plea that companies disclose as much information as possible.

More surprising, but welcome, is EPA's forthright acknowledgment that the submissions cover only a small fraction of both:  a) those nanomaterials likely to be already commercially available, and b) the underlying chemical structures on which they are based.  EPA's report provides a rather extensive analysis that reveals the following:

• Fewer than 10% – 123 out of the more than 1,600 unique nanomaterials EPA estimates are already commercially available – were addressed in the basic program submissions.
• The submissions encompass only one-seventh (28 of 200) of the unique chemical structures on which nanomaterials in use or development are based.

[Update:  In my haste to get this post up, while I got the "fewer than 10%" and "only one-seventh" right, I mis-stated the underlying numbers: The first bullet above should read "123 out of the more than 1,800 ... ."  And the ratio in the second bullet should be 34 out of 238 unique existing chemicals.]

EPA also acknowledged it cannot determine whether participants submitted information on all or only a subset of nanomaterials they produce, and whether information submitted for a given nanomaterial was complete or selective.  EDF had predicted precisely this problem because of EPA's failure to include these metrics in the design of the Nanoscale Material Stewardship Program.

And given that only four companies have agreed to consider conducting any testing, EPA concluded that "most companies are not inclined to voluntarily test their nanoscale materials."

The good news is that, given the poor showing for the NMSP, EPA now says it is finally "considering how to best use testing and information gathering authorities under the Toxic Substances Control Act" to address the remaining gaps in information. 

Reading between the lines a bit, this is the first time EPA has been willing publicly to state that mandatory reporting and testing rules will be needed to provide the Agency with the information it needs to craft a regulatory approach to nanomaterials. 

Let's hope EPA is serious about refocusing its energies on these critical tasks.

In some nanotechnology circles, it is almost a mantra that, once released to the environment, nanoparticles will inevitably aggregate or agglomerate into larger masses and thereby lose their nanoscale-related properties and, by implication at least, any associated risks.

But can we count on nanoparticles released to the environment to self-regulate their own risk so conveniently?

For example, the National Nanotechnology Initiative prominently features on its website an article it commissioned, titled "Understanding Risk Assessment of Engineered Nanomaterials:  How can we know what is a risk and what is not?"  In a section designed to lead readers to question published studies that suggest nanomaterials might pose risks, the article says: "In solution or in air, it's quite difficult to keep nanomaterials separate, as they tend to clump in larger aggregates or agglomerates."  This is a point the author of this rather short article felt compelled to repeat twice more.

An FAQ issued by Germany's Federal Institute for Risk Assessment states that "nanoparticles tend to aggregate into larger unions which are generally larger than 100 nm. The toxic effects of nanoparticles linked to their small size and higher reactivity are then no longer relevant."

And a recent post on the blog of the nanotechnology practice group at Porter and Wright asserts that nanoparticles "have been shown to have fewer potential adverse health effects when they occur in cluster form (aggregates and/or agglomerates).  In the 'good news' department, scientists studying aerosol dispersion of nanoparticles have found they tend to cling together when dispersed into the environment." 

I won't even begin to try to lay out here how much more complex and unpredictable than this nanoparticle aggregation and environmental fate and transport are in the real-world.  Instead, let me just cite two excellent papers that do so:  see Maynard and Weisner et al.

But I do want to briefly discuss and cite some recent studies supporting three reasons why we can't count on nanoparticles released to the environment to self-regulate their own risk so conveniently: 

1.  Some nanomaterials can be stabilized as nanoscale particles in solution under environmental conditions.  A number of studies have found that carbon-based nanomaterials – despite their inherently very low water solubility – can be "solubilized," that is, can enter and remain in stable suspensions upon interaction with water or with other common, naturally occurring substances.  The latest study, authored by Salonen et al. and published in the journal Small, finds that C₇₀ fullerenes can form "stable, homogeneous suspensions" in water through interaction with ubiquitous phenolic acids that are present in and released from virtually all plant matter.  It appears that individual C₇₀ fullerenes first become coated with the phenolic acid, and then form small, loose clusters with diameters on the order of a few nanometers.  This study merited a "spotlight" on the Nanowerk website.

Earlier work has found similar behavior:  Fortner et al. identified the formation of stable suspensions of "nanocrystals" of C₆₀ fullerenes in water – nanoscale (25-500 nm diameter) aggregates they call "nano-C₆₀" that have entirely shed the extreme hydrophobicity of the individual fullerenes.  Hyung et al. found that multi-walled carbon nanotubes could be stabilized as individual particles through interaction with natural organic matter found in river waters; the natural material actually worked better than commonly used surfactants selected to serve that same solubilizing function.

2.  For performance reasons, nanoparticles are being actively engineered not to clump.  For most nanomaterial applications, optimal performance depends on minimizing any disordered clumping or even maximizing dispersal, so that the properties of individual nanoparticles or highly ordered nanostructures can fully exert themselves.  For this reason, researchers are working overtime to coat, cap, chemically modify or otherwise force nanoparticles not to aggregate or agglomerate.  See, for example, Yang et al.'s use of special capping agents to prevent aggregation of platinum nanoparticles, and Nadagouda and Varma's similar work with silver and palladium nanoparticles.  Similar efforts have been mounted to chemically modify ceramic nanoparticles to ensure dispersal.

So even to the extent that native or current forms of nanoparticles do readily clump or retain their hydrophobicity, any assumption that engineered nanomaterials entering commerce and the environment will inevitably do so is wholly unwarranted.

3.  Even agglomerated or clumped nanoparticles can be toxic.  The assumption that aggregated nanoparticles lose all of their nanoscale properties or become benign is also unwarranted.  Maynard and Kuempel have amply demonstrated that even large aggregates on individual nanoparticles typically retain many of their nanostructural features and properties.  But what about toxicity?

Fortner et al. found that their fullerene nanocrystals exhibited antimicrobial activity, suppressing bacterial growth and respiration.  In addition to confirming nano-C₆₀'s antibacterial activity, a recent paper by Lyon and Alvarez cited a number of studies demonstrating that the formation of these nanoscale aggregates in water yields a material with high toxicity to aquatic invertebrates, fish and the cells of higher organisms.  The aggregates have also been shown to enter and accumulate in those cells and to adhere to lipids.

Finally, Salonen et al. showed that their phenolic acid-coated C₇₀ clusters could readily translocate across the membranes of human cells in culture and enter the membrane surrounding the cell nucleus.  Moreover, they induced the contraction and ultimate death of those cells – ironically, apparently by aggregating into micro-sized particles through interaction with the cell membranes.

Once again, we find that nanomaterials' actual behavior confounds conventional wisdom and, when approaching their toxicology, forces us to question or abandon our assumptions and biases.

John Balbus, M.D., M.P.H., is Chief Health Scientist.

Some 216 delegates representing 26 countries converged on the largest city in China last week for the 7^th meeting of the International Standards Organization (ISO) Technical Committee (TC 229) on Nanotechnologies.

In China, the turtle symbolizes cosmic order, strength, endurance and wisdom.  In the US, the turtle has come to symbolize slow progress and not keeping up with the times.  Which representation better captures what's going on in ISO's TC 229?   Maybe a little of both.

ISO is an international voluntary standard-setting organization comprised of national delegations (each country has one vote) that are dominated by government and industry interests.  Most of ISO's work is devoted to harmonizing and standardizing industrial processes and products to facilitate commerce and global trade.  But a significant portion entails the development of environmental, health and safety (EHS) standards, like the ISO 14000 series.  For better or worse, these standards tend to emphasize implementing corporate management systems and procedures over achieving specific measureable results. 

There are three levels of documents that come out of ISO.  The first is a technical report, which does not carry the force of a standard or require broad consensus, making it the easiest to adopt.  Next is a technical specification, which again is short of a standard but represents a stronger consensus of the countries participating.  Getting a full standard passed is the hardest and usually takes years.

Countries are starting to put forward a number of documents addressing EHS for nanotechnology.  But given the early state of the science, most of these documents are technical reports or technical specifications.  The expectation is that it will take a few years for the science and practice to evolve to the point where developing full standards will be practical.  In the meantime, technical reports and technical specifications can provide useful guidance now, and potentially serve as the basis for standards development later. 

It's all pretty bureaucratic, but ISO is one of very few ways to influence corporate behavior on a global basis.

As I reported in my last post, the US delegation brought to ISO a proposal to use the EDF-DuPont Nano Risk Framework (NRF) as a basis for an ISO Technical Report.  The Shanghai meeting marked the first international discussion of this proposal.  Former EDF staffer (now consultant) Scott Walsh and I went to Shanghai as US experts on the project group for this document.

The Nanomaterial Risk Evaluation Framework (NMREF), as the ISO version is provisionally titled, was generally well-received by the international delegates.  While some concerns were raised about how OECD guidelines and the European Union's REACH Regulation might conflict with elements of the starting document, there was no opposition to some of the most important elements of the Framework, such as taking a lifecycle approach, information-driven decision-making, and emphasis on transparency.  And the mood for moving forward was very positive.

There are other projects underway within the EHS workgroup.  These range from detailed testing methods to general guidelines for workplace handling of nanomaterials.   In addition, the committee created a new group on nanotechnology and sustainability.  And the groups working on material specifications are including guidelines for incorporating EHS information in every specification.

Is ISO the global key to ensuring safe development of nanomaterials?  Probably not.  For starters, all ISO standards are voluntary — they don't carry the force of law.  Ensuring that all nanomaterials are carefully assessed and that all companies take the necessary precautions to limit uses and releases of potentially harmful materials will require sound regulations. 

But there are a couple of reasons to ride the turtle for now.  First, there are enormous gaps in regulatory frameworks in most if not all countries.  Until those gaps are filled, many companies will look to ISO documents for operational guidance.  And second, as countries around the world decide how to adapt or extend current regulations to the special case of nanomaterials, ISO will play a role in validating and disseminating concepts to be used in the development of regulations.

So while the turtle moves slowly, it has set out on its way, and we're doing what we can to make sure it gets steered in the right direction.

Can nanoparticles get into our drinking water and if so, what's the harm?

Nanoparticles are being used in cosmetics and other personal care products with increasing frequency.  Carbon fullerenes, also known as buckyballs, have recently been touted as imparting age-defying antioxidant benefits when added to skin cream.  And there are some studies that seem to support these claims.  But even if such claimed benefits turn out to be true, this is by no means the end of the story. 

Skin creams are eventually washed off and down the drain.  Once they enter a sewage treatment system, the fate of nanoparticles is largely unknown.  Depending on their physical and chemical properties, engineered nanoparticles may wind up in the sludge – the solids – or they could spill over into the wastewater discharge, and wind up in lakes, rivers and streams.  If the latter occurs, they could end up in our drinking water.

This is not wild speculation.  One of the most hotly debated issues in environmental science is the frequent detection of chemicals from pharmaceuticals and personal care products in our drinking water.

If fullerenes act as antioxidants, then what's the big deal if they get into our drinking water — wouldn't they be beneficial? The very properties that allow antioxidants to scavenge the reactive oxygen species (ROS) that can damage cells also allow these compounds to liberate them, by cycling between uptake and release.  Under certain circumstances, antioxidants are more likely to release ROS than to take them up.  More research is needed to understand under what conditions so-called antioxidants might be likely to contribute to rather than prevent cell damage.

A new study published in Environmental Health Perspectives evaluated the effect of a single oral dose of fullerenes and single-walled carbon nanotubes (SWCNTs) on the extent of oxidative damage to DNA in the liver, colon and lungs of rats.  The authors were duplicating a study that demonstrated oxidative DNA damage in these organs following a single oral dose of the constituents in diesel exhaust.  DNA damage is important, because it is often a precursor to cancer.

In the new study, rats fed either fullerenes or SWCNTs exhibited increased levels of DNA damage in the liver and lungs, sometimes even at quite a low dose.  Neither nanoparticle had a significant effect on the colon at the doses tested, however.

So what does all this mean?  In my view, since we already know that chemicals in personal care products can wind up in drinking water, we should take more of a look-before-we-leap approach to evaluating new chemicals, including engineered nanomaterials, for use in these products.  This need also extends, of course, to the thousands of ingredients already present in personal care products that have not been adequately tested for safety.

Among the questions we need answered up front:  what is the expected fate and transport of such nanoparticles in the environment, who or what might be exposed during this process (including fish, bacteria, and any other critters), and if they wind up in our drinking water, what are the potential health effects?  The study discussed in this post is but one tiny piece of this puzzle.  (Of course, oral exposure to nanoparticles may occur through routes other than drinking water contamination, such as through direct ingestion of nanomaterials in foods or via the mucociliary escalator that removes inhaled particles from the lung to the digestive tract.)

Clearly we need regulators to be asking more of these questions – and requiring companies to provide the answers.  As my colleague Richard Denison pointed out in two of his recent posts, however, this doesn't appear to be happening with new chemical notifications being processed by EPA.  Instead, EPA seems to regard an absence of data as grounds for concluding an absence of risk.  And EPA gives the potential impacts at the downstream end of nanomaterials' lifecycles very short shrift.

Since my first post concerning EPA's Consent Order, I've been reflecting further on the management conditions it imposes – or, more accurately, on what conditions it doesn't impose.  The Order's only such conditions address potential worker exposure.  What about the rest of the nanomaterial's lifecycle?

The need to consider the full lifecycle and the full range of potential release and exposure pathways is a basic tenet of sound and responsible management of nanotechnology.  That's the backbone of the EDF-DuPont Nano Risk Framework, and it's also a key principle in EPA's own Nanotechnology White Paper and Nanotechnology Research Strategy.

Yet the Consent Order lacks conditions to address any potential releases or exposures beyond requiring gloves and other personal protective equipment for workers handling the nanomaterial.

Remember, the Consent Order notes that no test data were included in the producer's premanufacture notification (PMN).  On what basis, then, has EPA concluded that no other potential risks exist?  What about potential releases:

• from the manufacturing facility to the ambient air or water?
• from disposal or other management of wastes?
• from downstream transport, storage or processing?
• from post-use management (e.g., aging, weathering, repair, recycling) and disposal of products (electronics, polymer composites) containing the nanomaterial?

Nothing in the Consent Order addresses these questions – not, for example, a requirement to test products for potential releases, not even provisions to require reporting of waste management information or measurement or monitoring of releases.

Now, it may be that EPA has somehow managed to fully evaluate these and related questions and has determined that all of these risks are – and will remain, no matter what quantity of the nanomaterial is produced and used in the future – negligible.  If so, it should disclose how and on what basis it did so. 

EPA's failure to make public the decision framework it uses to evaluate new chemical submissions for nanomaterials – something we and other stakeholders have been requesting for some time – is a major impediment to building public trust in its process.

EPA's only bite at the apple

Some might argue that all this is premature and that EPA should wait until manufacture and use of this nanomaterial has ramped up even to consider such questions.  But here's the problem with that:  Under TSCA, the PMN review and conditions imposed through the Consent Order are essentially EPA's only bite at the apple.

Once Swan Chemical commences manufacture of its multiwalled carbon nanotubes (MWCNTs), they will be listed on the TSCA Inventory and will no longer be a "new" chemical.  At that point, anyone may manufacture and use the substance without even having to notify EPA.  And no matter what the quantity of the nanomaterial being produced and used, no further review by EPA would be triggered.

It should be noted that EPA is likely developing a Significant New Use Rule (SNUR) to accompany this Consent Order, and there are hints of that in the Order itself.  But all that a SNUR will do is to extend the same conditions that apply to the submitter of the PMN to other producers; it would require them to notify EPA only if they don't comply with these conditions.

Should a concern later develop about some other type of release or exposure not addressed by the Order and SNUR, EPA's only recourse would be to seek to use its authority under TSCA Section 6 to regulate the MWCNTs as an "existing" chemical – something EPA was unable to do, ironically, even for asbestos.  Yet that would be the only way that EPA could impose further conditions on production, processing, use, distribution or disposal of this nanomaterial.

Absent reform of TSCA to provide EPA with greater authority to regulate "existing" chemicals, EPA's new chemical review is, practically speaking, the only chance to ensure that potential risks across a new substance's full lifecycle are addressed.  An examination of EPA's Consent Order suggests that this opportunity has been lost for this nanomaterial.

[Part II of this post is available here.] 

Word hit the street today that EPA intends to make public a "sanitized" version of a Consent Order it has negotiated with a producer of multiwalled carbon nanotubes (MWCNTs).  [A link will be provided once available.]  We obtained a copy of the Order, which has redacted all information claimed confidential by the company involved.  What can we learn from this well-scrubbed Order?

The Order was triggered by EPA's review of a premanufacturing notification (PMN) – which, of course, is only required of companies producing the subset of nanomaterials EPA has decided to regard as "new."  This is the first public glimpse, albeit limited, into both EPA's thinking and its regulatory approach to "new" nanomaterials. 

EPA redacted the name of the company that has agreed to this Order – even though a simple Google search revealed that it almost certainly is Swan Chemical, Inc., of Lyndhurst, NJ.  That's because the company recently issued a press release announcing the Order.

So what does the Order call for?  The company is to:

• conduct a 90-day inhalation toxicity test in rats;
• supply EPA with a 1-gram sample of its MWCNTs and its Material Safety Data Sheet;
• submit certain characterization data within 6 months after commencing full manufacture;
• require its workers to wear protective gloves and clothing shown to be impermeable and NIOSH-approved respirators;
• use the substance only for a particular use, claimed confidential but generically identified as a "property modifier" in electronics and polymer composites; and
• provide the nanomaterial only to entities that agree to the same use restrictions and worker protection conditions.

Given recent evidence that MWCNTs can behave biologically rather like asbestos, such measures are more than called for.

But what's equally interesting are the details, including those that are missing from the sanitized Order because they were deemed confidential:

• The inhalation toxicity study doesn't need to be submitted before manufacture commences, but rather 14 weeks before either:  a) manufacture reaches a level of [BLEEP] kilograms, or a period of [BLEEP] years and [BLEEP] months after manufacture passes, whichever comes first. 
       From this, it's not at all clear:  a) why such details are secrets, and b) just how long it will be before the study is submitted.
• Adding to this mystery, the clock doesn't even start clicking on the time limit until two years after the Order is signed.
• The Order notes that no – zero, none, nada – test data were submitted with the company's PMN.
       This is actually not unusual for PMNs that come in under the Toxic Substances Control Act (TSCA), since EPA cannot require development and submission of such data up front, even for conventional chemicals. 
• Despite this lack of data, the Order states that EPA has determined that no significant environmental effects are expected.  Given how little environmental data exist on nanomaterials in general, let alone this particular MWCNT, it's hard to imagine how EPA reached this conclusion.
• The Order does state that "EPA is unable to determine the potential for human health effects" from exposure to this nanomaterial, and hence that it "may present an unreasonable risk of injury to human health."
       Presumably this is because of those recent findings that MWCNTs may act like asbestos.

So, to summarize these last two points:  Only if EPA already has evidence of a potential effect can it conclude that it is unable to determine whether there is an effect and call for testing.  If EPA doesn't have evidence of a potential effect – even if it has no data at all – it's ready to conclude that no significant effects are expected.  Welcome to life under TSCA!

Other very interesting tidbits:

The Order encourages the company to sign up for the in-depth phase of EPA's voluntary Nanoscale Materials Stewardship Program (NMSP), stating that if it does, EPA may waive the Order's requirement to conduct an inhalation toxicity test.  We can only wish that EPA gets something more than a non-binding commitment from the company to do some testing before vacating the Order!

Assuming the Order stays in place, if EPA finds the results of the required study to be "equivocal," the company can expand production beyond the production limit.  (I won't even discuss the perverse incentive this provision could create.)  Only if the company wants to get out from under the Order's other requirements (the use restriction or the worker protection provisions) need it reconduct the study.

What if the test results are invalid?

The Order appears to state that, if EPA finds the test data to be invalid, the company cannot expand production.  But there's a catch:  If there's not enough time to reconduct the study and submit it 14 weeks before exceeding the production limit, then the company can go ahead and exceed the limit as long as it submits the study "within a reasonable period of time."  The company can also exceed the production limit if it challenges EPA's determination that the data are invalid in writing.

If the company decides the test data are invalid before submitting them to EPA, as long as it informs EPA of this determination, EPA can still decide to allow expanded production.  As before, if EPA does decide to require the company to reconduct the study, but there's not enough time to reconduct and submit it 14 weeks before exceeding the production limit, then the company can go ahead and exceed the limit as long as it submits the study "within a reasonable period of time."

What if the test results show significant risk?

The Order states that if EPA determines that the data are valid and unequivocal and indicate the nanomaterial "will or may present an unreasonable risk," EPA may but is not required to notify the company, and may but is not required to impose additional conditions.  If EPA does issue such a notice, the company must either comply with the new conditions or cease production, use and distribution.  But again there's a catch:  If the company challenges EPA's determination in writing, it can continue these activities while the dispute is resolved.

All these allowances for the very type of nanomaterial that is #1 on just about everyone's concern list.

[UPDATE:  It should be noted that the above allowances are actually fairly standard practice for new chemical consent orders and are not limited to those issued for nanomaterials; indeed, EPA has developed "boilerplates" for its consent orders that contain very similar language.]

I have been among those calling on EPA for greater transparency in how it assesses new nanomaterials.  This is a step in the right direction in that regard.  But I have to say that getting this glimpse at EPA's inner workings doesn't exactly bolster my confidence in what they're doing.

John Balbus, M.D., M.P.H., is Chief Health Scientist.

At its most recent meeting a few weeks ago, the US Technical Advisory Group (TAG) to the International Standards Organization (ISO) Technical Committee on Nanotechnologies approved a motion to have ISO develop a Technical Report based on the EDF-Dupont Nano Risk Framework (NRF). Or to put it another way in acronym-laden Washington-speak, the US TAG to the ANSI-accredited ISO TC229 approved a TR based on the EDF-DD NRF. 

The motion to submit the NRF as the basis for this ISO technical report did not come from either EDF or Dupont. Other members of the TAG took this on and helped adapt the NRF for submission to the ISO. The vote was unanimous: All 21 members were in favor of moving the NRF forward in this way.

Surprising? In some ways yes, some ways no. A technical report is not a standard, and so countries and companies will not be bound to apply the report fully to their practices as they would an ISO standard. Nonetheless, representatives of a number of US industries are supporting the information-based approach to nanotechnology risk management incorporated in the NRF. And those of us concerned about the health effects of nanomaterials can support that.

The next step will be convening the TAG in Shanghai in November to review the document and start taking comments from the other country delegations. EDF will be there to try to ensure that the principles and science-based prudent approaches of the NRF are supported and are retained in the official ISO guidance.

The proliferation of nanoscale materials in consumer products is impressive:  nano titanium dioxide and zinc oxide in sunscreen, buckyballs in face creams, and nanosilver in socks are but a few examples of what is currently available for purchase.  But they make me wonder:  what happens when the nanomaterials in or released from these products are washed down the drain?  

A recent study published in Environmental Science & Technology (ES & T) demonstrates that nanoscale silver, added to socks to reduce the growth of odor-causing bacteria, readily washes out into wash water.  Testing of the wash water demonstrates that some of the silver is present in nanoparticle form, although dissolved silver ions are also present.  And of course, at the end of the day, nanoparticles present in personal care products, such as nanoscale zinc oxide and titanium dioxide in sunscreen and carbon fullerenes in face creams, will also be washed down the drain in the sink, shower, or tub. 

For most communities, the wastewater treatment plant is the next downstream recipient of these down-the-drain nanoparticles.  The impact that wastewater treatment has on nanomaterials, or conversely, the impact that nanomaterials have on wastewater treatment, is largely unknown. 

According to Cynthia Finley, Ph.D., Director for Regulatory Affairs at the National Association of Clean Water Agencies, “Our first concern is that nanoparticles could interfere with the wastewater treatment process and undermine our ability to meet our obligations under the Clean Water Act.”

“Our second concern is that the nanomaterials will make it through the wastewater treatment process and be discharged into receiving waters.  Although currently there is no requirement for us to treat nanomaterials, we take our responsibilities seriously, and are mindful of the potential impacts of unregulated chemicals.  Right now we don’t know how to treat nanomaterials in wastewater, so research will be very important in determining the appropriate response of wastewater treatment agencies.”

Depending on their characteristics, nanoparticles could wind up in the sludge (the solid materials removed from wastewater in the course of its treatment) or could be discharged with the treated wastewater.  The disposition of nanoparticles following wastewater treatment will determine their subsequent fate and transport pathways; if nanoparticles primarily find their way into sewage sludge, then impact studies will need to focus on potential releases following land application and incineration, the main means by which we manage such sludge.  If, however, nanoparticles primarily flow out in the discharge water, impact studies must consider their potential effects on aquatic organisms and ecosystems.

Another new paper published in ES & T describes a computer model that seeks to predict the movement of three types of nanoparticles – nano silver, nano titanium dioxide, and carbon nanotubes – throughout the materials’ life cycles.  If validated for nanomaterials, models such as these can be useful, because they help us predict where nanoparticles may go, and hence where we might want to search for possible adverse impacts. 

Of course, given how little data are actually available, modeling studies like these are constructed on a mountain of assumptions, or even best guesses.  In this study, the authors assume that 60% of nano titanium dioxide produced is used in cosmetics and sunscreens, and that 95% of this material winds up in wastewater treatment plants.  In contrast, the authors assume that carbon nanotubes are more likely to be used as additives to solid materials, such as plastics or other composites, and therefore they are more likely to be disposed of with solid waste.  Because the uses of nano silver are currently much more diverse, the authors assume some would end up in wastewaters, some would be released to air and some would be disposed of as solid waste.

As more real data are acquired, models need to be adjusted and or updated.  For example, the model I just described assumes that dissolved silver, rather than silver nanoparticles, will be the dominant form of silver released into wastewaters.  Based on the results of the sock study, however, we now have good reason to expect that silver still in the form of nanoparticles will be released into wastewaters – something any good model would need to account for.   

All this is to say that we are a long way from understanding the environmental fate and transport of down-the-drain nanomaterials.  The development of models, as imperfect as they may be, can still help to guide research by allowing us to make predictions that we can then empirically test.  Through such bootstrapping, we can hopefully move toward developing better guidance and standards that wastewater treatment system operators will need to protect the environment and public health.  

But better models and more research don’t ensure safety.  Our concerns regarding down-the-drain nanomaterial releases are yet another reason we urge that nanomaterials not be used in dispersive applications until their potential effects to human health and the environment are fully understood and mitigated.

Update:  Jen Jackson of the East Bay Municipal Utilities District wasn't able to get back to me with her thoughts until after I published this post.  Here's what she says:

“There is growing concern among wastewater agencies about the proliferation of products containing nanomaterials, such as nanosilver and nanocopper.  Nanomaterials may behave differently than larger molecules when they reach wastewater treatment plants.  We don’t know whether some nanomaterials may impair the wastewater treatment process, or sail through treatment plants into local waterways.  Unfortunately, research on the impact of nanoparticles to the wastewater treatment process has not kept pace with the number of uses and applications of nanomaterials."

Yesterday the U.S. House of Representatives overwhelmingly passed the National Nanotechnology Initiative Amendments Act of 2008 (H.R. 5940), by a vote of 407-6.  Among other changes, the bill calls for a number of much-needed improvements in how the NNI addresses health and environmental concerns associated with nanotechnology.  See EDF’s news release issued today.