RENERENEWWABLEABLE RESOURRESOURCESCES JOURNALJOURNAL

®

VOLUME 23 NUMBER 4 WINTER 2005

CONTENTS

News and Announcements ...... 3 Articles: “Emerging” Chemicals as Pollutants in the Environment: a 21st Century Perspective...... 6 Christian G. Daughton Meetings, Workshops & Symposia...... 24 International News...... 29

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Winter 2005 renewable Resources Journal 1 ABOUT RNRF

Purposes Programs

The Renewable Natural Resources Foundation (RNRF) RNRF conducts national meetings, congressional forums, was incorporated in Washington, D.C., in 1972, as a non- public-policy round tables and briefings, and international profit, public, tax-exempt, operating foundation. It was es- outreach activities. It also conducts an annual awards pro- tablished to: gram to recognize outstanding per- sonal, project and journalistic achieve- MEMBER • Advance sciences and public edu- ORGANIZATIONS ments. More information about cation in renewable natural re- RNRF’s programs is available at sources; American www.rnrf.org. • Promote the application of sound Fisheries Society Renewable Resources Journal, first scientific practices in managing American published in 1982, promotes commu- and conserving renewable natural Geophysical Union nication among RNRF’s represented resources; disciplines. The journal is provided to • Foster coordination and coopera- American the governing bodies of RNRF mem- tion among professional, scientific Meteorological Society ber organizations, members of the U.S. and educational organizations hav- American Society of Congress and committee staffs with ju- ing leadership responsibilities for Civil Engineers risdiction over natural resources, fed- renewable natural resources; eral agencies, and universities. Tables and American Society of of contents of all volumes of the jour- • Develop a Renewable Natural Re- Landscape Architects nal are available at RNRF’s web site. sources Center. American Water Resources Association Center Development The foundation represents a unique, united endeavor by outdoor scientists Estuarine The Renewable Natural Resources to cooperate in assessing our renew- Research Federation Center is being developed as an office able resources requirements and formu- International Society and environmental center for RNRF’s lating public policy alternatives. of Arboriculture members and other nonprofit organi- zations. The Center is located on a 35- Membership Society for acre site in Bethesda, Maryland, where Range Management lawns and forested buffers provide an RNRF’s members are professional, Society of Environmental exceptional work environment. The site scientific and educational organiza- Toxicology and Chemistry is the former family estate of Dr. Gil- tions interested in sustaining the bert H. Grosvenor, of the National Geo- world’s renewable natural resources. Society of graphic Society. The foundation is governed by a board Wood Science and Technology The master site plan for the Center of directors comprised of a represen- Soil and Water contemplates additional construction— tative from each member organization. Conservation Society including a 16,500 square foot confer- The directors also may elect “public ence and common-services facility. interest members” of the board. Board Universities Council Organizations may either lease or pur- members are listed on the back cover on Water Resources chase their offices. The Center cur- of the journal. Individuals may become The Wildlife Society rently has approximately 52,500 square Associates for an annual contribution feet of office space. of $50 or more.

2 renewable Resources Journal Winter 2005 “Emerging” Chemicals as Pollutants in the Environment: a 21st Century Perspective

Christian G. Daughton

Editor's Note—Pesticides, pharma- RNRF’s upcoming Congress on Assess- taminants are regulated under interna- ceuticals, industrial chemicals, ing and Mitigating Environmental Im- tional, federal, and state programs, nanoparticles, and personal care prod- pacts of Emerging Contaminants, these represent but a minuscule frac- ucts are being detected increasingly scheduled for December 1-2, 2005, in tion of the universe of chemicals that throughout the environment. These sub- Washington, D.C. occur in the environment as a result of stances are being detected in tissues both natural processes and human ac- of humans, terrestrial animals, amphib- Abstract tivities. This array of chemical pollut- ians, and fish. We believe that a basic ants (or occupational hazards) might understanding of existing and poten- Defying comprehension is the com- at first seem large, but it pales com- tial threats posed by these substances plexity of the chemical sea that sur- pared with the universe of known has become prerequisite knowledge for rounds, sustains, and constitutes all life. chemicals, and would become insig- natural resources managers, profes- From this sea, never-ending challenges nificant if compared with those chemi- sionals in related disciplines, and those are faced by organisms striving to de- cals yet-to-be identified, waiting to be in government whose decisions affect fend against those multitudes of chemi- synthesized, and that are just now monitoring and regulatory activities. cals that cause cellular stress or harm. “emerging.” A key assumption is im- Thus, we have dedicated this issue of Biological mechanisms have evolved plicit in the limited and selective lists the Renewable Resources Journal to an for maintaining organism homeostasis or menus of chemicals targeted by expansive overview of the extent and during contact with these harmful sub- regulations—namely that these are in- nature of challenges we face. The next stances. Most of these chemical stres- deed the chemicals responsible for the issue of our journal will extend the ex- sors have long existed or are produced most significant share of risk to eco- amination by presenting findings and by myriads of human activities. How- logical integrity, economic impair- recommendations stemming from ever, for those chemicals that are rela- ment, and human health. Given the tively new to the world, the mecha- myriads of other chemicals that are nisms for homeostasis maintenance are ignored or escape notice by regulatory Daughton is chief, Environmental not necessarily adequate. Chemicals processes, a multitude of questions can Chemistry Branch, U.S. Environmen- for which organisms have had the least be posed regarding society’s relation- tal Protection Agency. This article has time to adapt are those that only re- ship with chemical pollutants, particu- been subjected to peer review. The cently have emerged as environmental larly with respect to whether a more United States Environmental Protec- contaminants. holistic understanding of risk might be tion Agency through its Office of Re- Essentially limitless combinations of required. With the immense size of the search and Development funded and a very small set of atomic elements can chemical universe, this is a daunting managed the research described here. yield a seemingly infinite number of challenge. How would we know when It has been subjected to the agency’s unique chemicals—a universe known we have narrowed the chemical uni- administrative review and approved for as “chemical space.” Although thou- verse to the most significant hazards publication as an EPA document. sands of chemical pollutants or con- worthy of our attention? Not necessar-

6 renewable Resources Journal Winter 2005 ily will the continued emergence of and its ramifications. More emphasis elucidated but which have long been new pollutants pose the biggest chal- needs to be placed on non-regulated present. There are a number of differ- lenge. A larger unknown might be the pollutants, especially those considered ent perspectives from which to view the occurrence of myriads of chemicals to be “emerging.” Over the last few many dimensions of “emerging” that remain hidden from our view. Per- years, the appellation “emerging” has (Daughton, comp. 2005a). One ex- haps more daunting will be gaining a been applied to chemical pollutants ample is that of PPCPs (pharmaceuti- better understanding of the unantici- with such frequency that its meaning cals and personal care products; see pated ways in which these substances is becoming confused. In reality, those Daughton, comp. 2005b), which in- can interact with the environment and pollutants that are truly “emerging” clude many substances that long have the creation of a new paradigm for their (for example, those that have just been present in the environment but management or stewardship. Adding gained entry to the environment be- whose presence and significance only yet additional challenge is the emerg- cause they are new to commerce) are now are beginning to be elucidated. ing realization that society is averse to sometimes confused with those whose “Emerging” also sometimes is intended exposure to certain chemicals, even in environmental presence just has been not to refer to the pollutant itself, but the absence of any hazard, simply be- cause these chemicals occur where they Table 1. Some Groupings of Chemical Pollutants. are not expected or desired—the chemical equivalent of “weeds.” Confusion results from their intersections and acronyms. Outlined in this paper is a sampling G:rouping Grouped According to of some of the many alternative per- spectives regarding chemical pollutants (especially those that are new to our EDC (Endocrine Disrupting Chemical) toxicological mode of action or attention—the so-called “emerging” endpoint pollutants) and their ramifications for CMR (Carcinogenic, Mutagenic, toxic biological systems and society’s val- to Reproduction) ues. A primary objective in presenting PBT (Persistent, Bioaccumulative environmental properties these alternative views of chemical pol- Toxic) (e.g., ease of degradation or fat lution is the hope of catalyzing dialog solubility) and debate regarding new approaches vPvB (very Persistent, very for its management, not to make rec- Bioaccumulative) ommendations for implementing solu- tions. POP (Persistent Organic Pollutant)

Introduction PPCPs (pharmaceuticals type of intended usage and personal care products) Tremendous investments continue to be made in the prevention, control, and “priority pollutants,” legislative enactment mitigation of environmental pollution and other regulated pollutants (e.g., CERCLA) by chemicals. Nevertheless, how can we be sure that these are the most im- xenobiotics, exotics foreign versus endogenous portant chemicals with respect to pro- tecting humans and the ecology? Do we sufficiently understand the pro- toxicants, toxins, toxics overall toxicity (note: “toxins” are a cesses that dictate exposure to these special subset that are proteins; pollutants and its aftermath? Is the in- “toxics” is jargon for “toxicants”) troduction of new chemicals to com- “emerging” contaminants/pollutants novelty, fad, timeliness, or new merce outrunning our ability to fully concern assess their significance in the environ- ment or to human health? HPV (high production volume quantity (manufactured/imported in This article is intended to foster dis- chemicals) U.S. in annual amounts >1 million cussion aimed at establishing a more pounds) holistic view of xenobiotic exposure

Winter 2005 renewable Resources Journal 7 rather to a newly hypothesized concern out the course of life on Earth. Some process, which takes place under con- regarding an old pollutant. For ex- are inherently harmful, some are essen- tinually changing conditions. Expo- ample, pollutants that long have occu- tial for sustaining life, and others share sure, for example, can range from pied our attention can gain new noto- both characteristics depending on their short-term contact with a small, select riety with the revelation of new aspects concentrations or when exposure oc- group of chemical stressors (“toxi- of their occurrence, fate, or effects; the curs during the course of an organism’s cants”) at relatively high concentra- production of acrylamide during the development or natural rhythms. Ex- tions (acute exposure), to extended cooking of certain foods is but one ex- posure, however, is not sufficient for durations of exposure with lower con- ample. toxicity. All organisms have evolved a centrations (chronic) of multitudes of A source of on-going confusion is complex repertoire of defense mecha- chemicals in extraordinarily complex the proliferation of acronyms for the nisms for coping with exposure to those mixtures. Effects can range from overt, different categorizations of chemical chemicals foreign to their normal ex- where adverse consequences are elic- pollutants. Various groupings of chemi- istence (xenobiotics). Living systems ited quickly (e.g., from a lethal dose), cal pollutants (see Table 1) have have developed protective, defensive, to subtle, where effects are not readily evolved, and each looks at chemicals or adaptive mechanisms for minimiz- apparent or easily measured (e.g., from a different perspective. Each ing exposure or even the toxicity of slight but gradual shifts in mental group tends to contain some but not many of the otherwise harmful, natu- health and behavior). Some stressors most of the chemicals from other rally occurring chemicals. For those can elicit delayed effects that become groups; each group slices the chemi- “new” chemicals that only recently apparent only weeks, months, or years cal universe pie in a different dimen- have emerged, however, and to which after an initial exposure (delayed on- sion. In this sense, members of “emerg- biological systems never have been set toxicity). The relative concentra- ing” pollutants can each belong to oth- exposed, these defensive mechanisms tions of stressors can change continu- ers of these groups. sometimes can be inadequate. ally. Likewise, the types and vulner- The discussion that follows will Chemicals Are Chemicals, But abilities of biological receptors that highlight some of the less appreciated They Are All Different. Whether from interact with the stressors also can aspects of chemical pollution (with nature or from industry, chemicals are change (as a function of the organism’s “emerging” pollutants as a common chemicals—both naturally occurring overall health status). Windows of par- thread) and place these in the context and anthropogenic. However, their ticular vulnerability can exist during of hazard and exposure, and whether characteristics and properties can dif- certain critical times, such as specific risk can be assessed more holistically. fer dramatically. The quantities in the development stages and biological environment and the toxicities of indi- rhythms. Chemicals of environmental The Chemical Universe vidual chemicals span an extraordinar- concern can have origins from both and Exposure 101 ily broad range. The types and quanti- purposeful human activities as well as ties of individual chemicals in a wide from nature. One of many examples An ever-expanding universe of array of environmental compartments includes the endogenous estrogenic and unique chemicals, untold numbers of (soil, sediment, water, air, biota) also androgenic steroidal hormones synthe- which have yet to be recognized or re- vary dramatically over time. Their sized and excreted by humans and other vealed, continually perfuse our envi- presence is not necessarily static, of- mammals, the plant-produced phtyo- ronment and contact living systems. ten varying temporally and spatially in estrogens consumed in our diet, and the Multitudes of chemicals originate both both absolute amounts and in relative anthropogenic, synthetic versions of from natural processes and from an- proportions. Concentrations of chemi- these naturally occurring chemicals thropogenic sources, including synthe- cals in any one sample can range from such as ethynylestradiol (synthetic ana- sis-by-design of new molecular enti- percent to parts-per-million to less than log of estradiol; an extremely potent ties and inadvertent formation of by- the yocto-molar range—a span exceed- active ingredient in reproduction regu- products from these syntheses or from ing 20 orders of magnitude. The inter- lators). the molecule’s destruction (incinera- actions of living systems with chemi- Legal or Illicit Chemicals—All in tion is an example). Sometimes, the cals (part of the study of “exposure”) the Pollutant Family. The environment chemicals produced by humans are the can result in myriads of biological re- does not discriminate between pollu- same as those produced in nature (this sponses or changes (“effects”), rang- tion from legal or illegal chemicals. has led to long-standing confusion over ing from adverse to benign to even ben- Whether the pollutant is chlordane, the meaning of “organic”). Many of eficial. Chemical exposure is an extra- codeine, or cocaine, whether methylm- these chemicals have existed through- ordinarily complex and dynamic ercury or methamphetamine, biologi-

8 renewable Resources Journal Winter 2005 cal receptors interact without regard to section in more detail to reveal poten- (nearly 9 million) were commercially the chemical’s legal standing or its tial oversimplifications of the various available, representing a 12 percent source. All can impart effects. Even so, tenets we long have held, and how we increase over the prior year. In contrast, the legal standing of chemicals seems might want to alter these to better ac- fewer than a quarter million (240,000) to affect the degree to which they are commodate reality. were inventoried or regulated by gov- studied. For example, while prescrip- Regulated Pollutants: Minor Ingre- ernment bodies worldwide (CAS, tion and over-the-counter pharmaceu- dients in a Small Slice from the Whole 2005b). ticals have gained much attention as Risk Pie? Since the 1970s, the impact “Chemical Space.” While the pollutants since the late 1990s, little of chemical pollution has focused al- known universe of organic chemicals effort has been devoted to uncovering most exclusively on lists (or menus) of might seem large, the universe of po- the environmental prevalence of illicit conventional pollutants, especially tential organic chemicals (those that drugs, such as cocaine or any of the those collectively referred to as “per- possibly could be synthesized and numerous amphetamines. The first re- sistent, bioaccumulative toxicants” those that already exist but which ports of illicit drugs occurring as trace (PBTs) or “persistent organic pollut- have not yet been identified) is un- pollutants in environmental waters re- ants” (POPs); see Table 1. This rela- imaginably immense. So-called cently were published by Jones-Lepp tively small number of primarily con- “chemical structure space” essentially et al. (2004) and Zuccato et al. (2005). is unexplored. If chemical space is de- Real or Fake—It’s All the Same. fined as comprising all possible struc- “Exotic” chemicals that are found in An ever-expanding tural configurations up to a certain the environment might seem, on first nominal molecular size, it is estimated examination, to originate from human universe of unique to contain between 1030 and 10200 activities. An accurate perspective, unique structures, depending on how however, also must recognize that some chemicals, untold the estimate is calculated and the up- of these chemicals have natural numbers of which per boundary for the molecular size sources. Microorganisms (bacteria, (Bohacek et al., 1996; Dobson, 2004). fungi, and algae) and plants are highly have yet to be The types of possible organic chemi- versed at synthesizing a bewildering cals essentially are limitless in their array of chemicals, most of which recognized or revealed, ever-expanding structural universe. The might at first seem to be foreign to liv- continually perfuse efforts of synthetic organic chemists, ing systems. Many possess extreme using advanced combinatorial chemis- acute and chronic toxicity. Indeed, our environment try and exploring new forms of matter many of these chemicals are involved such as nanomaterials and superatom in the unrelenting chemical warfare and and contact clusters, are only beginning to reveal signaling that occurs between organ- living systems. the complex dimensions of chemical isms. Natural abiotic processes (such space. The ramifications for risk asses- as sunlight and natural combustion sors and regulators indeed are pro- such as forest fires and lighting) also ventional, regulated pollutants, how- found. Historically, we only have stud- are capable of catalyzing the formation ever, represents but one piece of a much ied and regulated the tip of the chemi- of other xenobiotics. Some chemicals larger universe of potential pollut- cal space iceberg. (even certain persistent organochlo- ants—one of largely unknown scope. Looking Glass to Parallel Chemi- rines, including certain dioxins) can That biological systems can suffer ex- cal Worlds—Stereochemicals and originate from both natural and human posure to countless chemical stressors, Chirality. Strewn about in chemical activities. only a small number of which are regu- space are parallel chemical worlds, With this very brief and oversimpli- lated, poses many currently unanswer- where certain molecules (those with fied overview of the intersection of the able questions regarding risk. As of asymmetrical structures) exist in mul- universe comprising chemicals with the August 2005, over 26 million organic tiple forms whose mirror images are world of biological systems, a number and inorganic substances (excluding not superimposable. Known as chiral of questions can be posed with respect biosequences such as proteins and molecules, one of the simplest ex- to how this nexus can be managed to nucleotides) had been indexed by the amples is bromochlorofluoromethane, minimize risk to the environment and American Chemical Society’s Chemi- which contains a single carbon atom human health. We also can explore cal Abstracts Service in their CAS Reg- bonded to four different elements (hy- some of the many facets of this inter- istry (CAS, 2005a). One-third of these drogen, bromine, chlorine, and fluo-

Winter 2005 renewable Resources Journal 9 rine). Pairs of chiral molecules are one reason that the pharmaceutical and known portion of which may be new known as “enantiomers” or as “optical pesticide industries have been moving to organisms. isomers.” Chirality (“handedness”) toward the design of optically pure Whither the Bull’s Eye—Are We plays critical roles in the environmen- chemicals that cannot racemize among Aiming at the Correct Target? Two tal chemistry and toxicology of myri- enantiomers. A significant major ques- distinct approaches can be used by ana- ads of chemicals. A chemical compris- tion, however, is how a regulatory sys- lytical chemists to gage or probe the ing chiral forms can have properties of tem can best deal with stereochemical molecular make-up of an environmen- two or more distinct chemicals (de- mixtures, especially when it can be tal sample and hence reveal some of pending on its number of points of extremely difficult to distinguish be- its toxicological hazards. The preva- asymmetry), but each having the same tween them during environmental lent, most cost-effective approach uses composition and two-dimensional monitoring. “target” analysis, where the chemicals structure. Chiral chemicals composed Chemicals Unlike Themselves. For considered for measuring (known as of equal parts of their optical isomers those chemicals with optical isomers, “analytes”) are preselected from a stan- are known as racemates. Isomers of the seeming paradox exists where dardized “menu.” This is the approach more complex chiral molecules that chemically identical molecular struc- that necessarily drives the environmen- possess at least two stereogenic cen- tures can have wildly different chemi- tal monitoring dictated by regulatory ters can either be enantiomers or dias- cal or biological properties. Nanoscale priorities—where various chemicals tereomers (stereoisomers that are not chemicals (also called nanoscale par- are “listed.” The second approach is mirror images). Isomers of achiral ticles or materials) constitute another through non-target “characterization,” molecules possessing at least two potentially immense class of chemicals where the universe of chemicals that stereogenic centers are called meso iso- where an analogous conundrum exists; might compose a sample are all sub- mers (stereoisomers that are super- superatom clusters (whose atoms take ject to discovery by the analyst—the imposable). A ubiquitous pollutant on the properties of other elements) are analysis does not begin with predefined notorious for its complex stereochem- another example. Nanoscale materials notions as to what the search will en- istry is the flame retardant hexabromo- (which are much larger than most mol- compass or what it might reveal. This cyclodecane (HBCD), which com- ecules, but with one dimension smaller approach, which is used in “environ- prises six enantiomeric pairs and four than 100 nanometers) are distinguished mental forensics,” is much more time meso forms, a total of 16 steroisomers, by having chemical and biological consuming and costly. The latter ap- all having identical compositions but properties that differ profoundly from proach can uncover the presence of different chemical properties. those of their chemical constituents. many more chemicals than can targeted Many synthetic chemicals (e.g., cer- The size and shape of nanoscale mate- analysis, but even it eventually is sub- tain pesticides) are regulated as their rials (which, for example, dictates very ject to the gross limitations of even the racemates or isomeric mixtures. Of large surface-to-volume ratios, which most advanced analytical tools, which most significance, however, is that the in turn have enormous potential for still are incapable of revealing the environmental fate and toxicity of the catalyzing reactions) impart unique structures or even the presence of in- individual isomers can differ, some- properties. calculable numbers of chemicals in any times dramatically. For example, one Regulatory conundrums result from environmental or biological sample. isomer might by more readily degrad- the fact that although the constituent Even thorough chemical character- able, while the other persists. One chemicals already might be regulated, ization does not account for an un- might have much greater toxicity (or the nanomaterial does not resemble or known portion of organic chemicals. beneficial effect), while the other can act like its constituents. This problem These comprise those chemicals that have completely different effects (or is exacerbated further by the fact that cannot be detected or identified. Sig- none at all). The well-known drug tha- natural weathering processes could yet nificantly, these unidentified or uniden- lidomide is but one example, where one further alter these materials, produc- tifiable compounds almost always of its enantiomers has the designed ef- ing “structurally undefinable ubiqui- comprise an unknown fraction of all fect of sedation but the other is a po- tous xenobiotics” (SUDUX), which those present, so the toxicological sig- tent teratogen (causes fetal malforma- may not be measurable for monitoring nificance of their presence is rarely tions). Countless other examples would purposes. The potential is unknown for known. These unidentified chemicals show how the different forms of nanoscale pollutants resulting from are neglected, ignored, omitted, or stereochemicals can have different and nanomaterial weathering to create ex- overlooked because of any number of unpredictable ramifications with re- ponentially more xenobiotics, an un- limitations or idiosyncrasies of the spect to exposure and effects. This is many tools employed by the analyti-

10 renewable Resources Journal Winter 2005 cal chemist (see Figure 1 in Daughton, chemical contaminants at “trace” lev- tial chemical stressors, at lower and 2003a). The salient question is whether els can exceed those present at higher lower concentrations. Add this to the any significant risks for living systems levels. Largely stemming from this work of synthetic chemists designing are associated with the target analytes, ability to reveal ever more pollutants, new chemicals with abilities to impart with the non-targeted chemicals, or environmental analytical chemists of- new types of biological effects, some- both. Exactly where is the toxicologi- ten are perceived as problem makers— times at exquisitely low concentrations. cal target, and are we aiming for the not as problem solvers. It becomes in- The approaches used worldwide all bull’s eye? The proliferation of new creasingly difficult to assess risk and rely on assessing hazard on a chemi- anthropogenic chemicals coupled with to design regulatory programs for new cal-by-chemical basis (through various the continued discovery of new chemi- and moving targets. Where should “listing” processes). Some recent cals produced in nature will continue regulatory limits be placed? Does progress has been made toward con- to challenge analytical chemists and “zero” even exist? The chemicals of sidering “cumulative” and “aggregate” regulators alike. On the other side of potential concern comprise the broad regulation of certain groups or classes the coin, however, one can argue that spectrum of anthropogenic chemicals of chemicals. Examples of such a group those very few chemicals that we moni- (those purposefully synthesized and are those that share a well-defined tor in the environment, and to which indirectly produced by human activi- mechanism of action, or to which we we know organisms are exposed, also ties) as well as “natural products” are exposed from multiple routes or can be viewed as serving as surrogates (those created both by natural physi- origins, including the cholinesterase in- for the presence of untold numbers of cochemical or biological processes). hibiting organophosphorus and car- other chemicals possessing similar Using drinking water to illustrate, the bamate pesticides. physicochemical properties. By regu- gasoline oxygenate additive MTBE To illustrate the substantial (and per- lating one (e.g., via removal during (methyl-tert-butylether), tris (4-chloro- haps insurmountable) challenges to the waste treatment), untold others coin- phenyl)methanol, and halogenated dis- sustainability of a chemical-by-chemi- cidentally are controlled. infection by-products (DBPs) are three cal approach for regulating the occur- Analytical Chemists—The Regu- of countless examples of widespread rence of pollutants in the environment, lator’s Worst Friend? Analytical chem- anthropogenic contaminants. Arsenic consider the particularly diverse spec- istry plays a key role in expanding and and geosmin (the off-flavor bicyclic trum of ubiquitous pollutants that origi- refining our ever-changing perspective alcohol produced by certain algae and nate from the daily activities and ac- of the chemical sea in which we find fungi) are examples of naturally occur- tions of countless individuals—the ourselves. As the power of analytical ring contaminants. Some chemicals PPCPs. There are myriads of other an- chemistry increases, the types of chem- (e.g., DBPs and acrylamide) can origi- thropogenic chemicals whose occur- icals that can be detected and identi- nate from both natural and anthropo- rence in the environment originates fied increase, and the limits of concen- genic processes. Multitudes of ques- from the behavior and activities of con- tration at which they can be measured tions languish unanswered. Is a new sumers. Using PPCPs as an example, continually are lowered. By ever ex- paradigm required for more efficiently as of August 2005, more than 140,000 panding the horizon of the known and effectively assessing and protect- bioactive compounds were in various chemical universe, analytical chemists ing the world from whatever risks phases of drug research and develop- unwittingly add to the burden of re- might be posed by those stressors com- ment (Prous Science, 2005). The rapid sponsibility for risk assessors and regu- prising the chemical sea in which all evolution of the “omics” revolution lators. Lowering the limits of detection life forms must sustain their homeo- undoubtedly will feed an expansion of challenges our concepts of “purity,” stasis? new drug entities that already has been “zero,” and “safe,” which must then be Chemical-by-Chemical Regulation: underway (Daughton, 2003a). New revised. The extraordinarily wide range Thoroughfare or Dead-end for Pro- drug entities, many with mechanisms of concentrations at which chemicals tecting Ecological and Human of action never before encountered by can occur imposes seemingly insur- Health? An ultimate question is biological systems, can be expected to mountable hurdles for risk communi- whether the approaches that have enjoy continued introduction to com- cators. The lay public’s bewilderment evolved over the last half century for merce. All will have the potential to with the jargon required for express- regulating chemicals will be sustain- enter the environment merely as a re- ing these concentrations has fostered able. The challenge increases as ana- sult of their daily use (e.g., introduc- the perception that essentially all con- lytical chemists and toxicologists con- tion to surface and ground waters via centrations are the same—whether they tinue to redefine and expand the scope excretion, bathing, or disposal to sew- are minuscule or large. The number of of concern by discovering more poten- age systems).

Winter 2005 renewable Resources Journal 11 By following a road mapped out by found in just about any type of sample? in concentration by and accumulation a chemical-by-chemical approach, do What challenges will be faced by risk in lipids and fat; bioconcentration then we risk going in the wrong direction communicators, toxicologists, and risk leading to bioaccumulation via the or heading for a dead end? Will target- assessors. Will the way in which risk food chain); and (3) possess acute or lists (or menus) of pollutants blind us is perceived be altered dramatically, chronic toxicity in their own right. to more important pollutants, includ- will chemical exposure be more ac- While each of these factors is unques- ing truly emerging pollutants? Target cepted as a fact of life, or will risk per- tionably significant and has contributed chemical menus can never be suffi- ception become a major obstacle for to the notoriety of certain pollutants ciently large to satisfy our appetite to our increasingly technological world? (i.e., the “dirty dozen”), less appreci- minimize potential risk. By restricting ourselves to a single slice from the risk pie, are we getting the best toxicologi- cal value for our investment of re- sources in environmental monitoring? Ubiquity and Ubiety: Everything Can Be Found Everywhere. One might surmise that the number of chemicals that can be found in any environmen- tal sample increases as the detection limits achievable by chemists are re- duced. Perhaps exponentially more types of chemicals occur at incremen- tally (or exponentially) lower concen- trations. Those chemicals with distinct chemical structures that are detected (or are detectable) compose the minor- ity of the total number of unique chemicals present in any sample. In other words, most of a sample’s iden- tified contaminant molecules are asso- ciated with a minor part of the overall chemical diversity of a sample—the majority of the molecules in a sample belong to a minority of the unique Figure 1: Increasing Chemical Diversity at Lower Concentrations. The realm of chemical structures present. On the other hand, unknowns also expands at lower concentrations. the majority of the unique chemical structures present (i.e., the highest di- Alternative Perspectives ated is that they are not necessarily re- versity of chemical types) comprise a Regarding Chemical Pollution quired for a chemical to pose risks in minority of the total molecules present. the environment. These three factors The realm of chemical unknowns in- Persistence, Bioaccumulation, Tox- deserve further consideration with re- creases at lower concentrations (Fig- icity—the Only Talents for Hazardous spect to their restrictiveness in defin- ure 1) because modern analytical tech- Chemical Celebrities? Over the years, ing risk. nology cannot yet identify these count- a consensus view has emerged of three Reassessing “Persistence”—the less chemicals. factors that purportedly dictate the Weak Become Stronger. One of the At a certain range of infinitesimally highest propensity for adverse effects three hallmarks distinguishing those low concentrations, we may be ap- from exposure to chemical stressors. environmental pollutants that are the proaching the off-the-cuff truism: “Ev- Such stressors need to: (1) possess focus of regulatory actions is environ- erything can be found everywhere.” structural stability (which imparts en- mental persistence, which results from With this concept of chemical diaspora, vironmental persistence from long resistance of chemicals to structural the notion of “pristine” is relative. half-lives); (2) be lipophilic and alterations (e.g., the making and break- What then when molecules of vastly thereby more amenable to passively ing of covalent bonds) by biological or different types of chemicals can be crossing cellular membranes (resulting physicochemical transformation. Ex-

12 renewable Resources Journal Winter 2005 posure to chemicals that easily are tively carry (transport) chemically cussions regarding the possible envi- transformed was thought to be insig- similar endogenous chemicals impor- ronmental ramifications of nano- nificant. Possible outliers to this re- tant to the cell’s function. Others can materials are just emerging (e.g., quirement, however, are those un- gain indiscriminate, promiscuous intra- CBEN, 2005). known numbers of pollutants that are cellular access in the absence of high Hazards from “Non-toxic” Chemi- conveyed to open waters by sewage lipid-water partition coefficients by cals. Although generally recognized treatment plants and septic systems. other mechanisms. Some examples of that any chemical can pose a risk when The continual release of these pollut- these mechanisms are provided below. exposure occurs at a sufficiently high ants gives them a “pseudo-persistence” One example of an alternative route dose (“the dose makes the poison,” in any aquatic or marine environment, for bioaccumulation is illustrated by Paracelsus), certain chemicals pose regardless of their structural instabil- certain drugs that are transported ac- risks even when exposure is at levels ity. This alternative view was first for- tively, including ones that are hydro- where overt effects cannot be measured mulated with respect to PPCPs (see p. philic. In fact, one of the current strat- from exposure to the chemical in iso- 761 in Daughton, 2003a), many of egies under investigation for improved lation from other toxicants. These “in- which can have a continual environ- drug delivery is the design of drugs that direct” chemical stressors possess no mental presence, regardless of environ- capitalize on active transport (see inherent toxicity of their own at benign mental half-life, simply because their Daughton, 2003a). This property could exposure levels but they can potenti- degradation is offset by constant re- allow such chemicals, as water-soluble ate or amplify the toxicity of other plenishment. pollutants, to bioconcentrate, seem- chemical stressors. An example of this Reassessing Bioaccumulation and ingly in defiance of predictions based phenomenon involves the cellular Toxicity—“Me Too” Chemicals. on lipophilicity. A second example in- efflux pump systems, which are evo- Bioaccumulation is dictated largely by volves the small, subcellular scale of lutionary conserved across taxa and a chemical’s lipophilicity (fat solubil- nanoparticles, which can facilitate their which particularly are important for ity). Many pollutants, once ingested, promiscuous entry to intracellular do- aquatic organisms as a defensive rely on passive transport across the gut mains, thereby circumventing cellular mechanism against toxicant exposure. wall or across the dermis, facilitated defenses. The size and conformation These systems also are called multi- by lipid solubility. Lipophilic chemi- of these materials alone (rather than xenobiotic transporters, and confer re- cals gain access to intracellular do- their actual chemical composition) sistance for the organism to a wide ar- mains by passive diffusion within cel- holds the potential to adversely affect ray of ordinarily toxic substances lular lipids. This process serves to con- biological systems, such as via surface- (Daughton, 2001). These efflux pump tinually extract trace residues of these mediated effects (e.g., sorption and systems serve to physically remove chemicals from the environment until catalysis) or the ability to evade host xenobiotics that gain entry to a cell, as significant levels have bioconcentrated. defenses by freely penetrating or per- well as waste products generated dur- Subsequent consumption of this con- meating cellular membranes. Certain ing normal metabolism. They roughly taminated tissue by organisms in higher nanoparticles may have the potential are analogous to bilge pumps on ships. trophic levels of the food chain serves to indiscriminately concentrate within By preventing sufficient exposure, to further concentrate these chemicals, their porosities or on their surfaces a efflux systems allow an organism to leading to biomagnification. This is the wide spectrum of chemicals and maintain its homeostasis in an environ- classic way in which ubiquitous pol- thereby serve as Trojan horses for fer- ment surrounded by pollutants that lutants such as the organohalogens gain rying their chemical hitchhikers across might otherwise prove toxic. A wide significant presence in biological tis- biological membranes (facilitated number of chemicals, however, have sues and disperse worldwide. It also is transport), irrespective of cellular de- the ability to inhibit these efflux en- why seemingly insignificant, minute fensive barriers such as efflux pumps zyme systems (the best known ex- levels of these pollutants in the ambi- (cellular “bilge pumps”). Indeed, this amples are certain drugs), thereby al- ent environment can be important to ability is being pursued in the design lowing access to the cell by any extra- regulate. Less recognized, however, is of more effective approaches to drug cellular toxicants that previously had that certain hydrophilic chemicals delivery. Moreover, simply the sorption been excluded by the pumps. Toxicity (those that readily dissolve in water) of endogenous proteins to nano- testing currently has no way to account also have the potential to bio- particles within an organism could for these so-called “non-toxic hazards.” concentrate. Some of these chemicals theoretically elicit an immune response Another example of indirect toxi- can be transported actively via cellu- as a result of altering the native con- cants includes certain manufactured lar systems whose purpose it is to ac- formation of the exposed protein. Dis- nanoparticles. These substances can

Winter 2005 renewable Resources Journal 13 have extraordinarily large surface-to- sult of the exigency to focus on lists of (animal, plant, and microbial) and the size ratios. Even if not possessing tox- preselected analytes (“target-based” products from abiotic processes such icity of their own, their surface areas analysis). The use of water monitoring as sunlight and chemical-mediated re- nonetheless possess high potential for data based on “free” (dissolved) con- actions. Some parent chemicals can catalyzing reactions involving other centrations to predict total environmen- yield a multitude of so-called “break- chemicals. This single characteristic of tal loads of a particular pollutant has down” products or “degradates.” Just the nanoscale imparts nanomaterials the potential to yield misleading val- because the original “parent” chemi- with properties that differ dramatically ues that are biased low (perhaps even cal might be gone, does not mean that from those of their “macro” counter- by orders of magnitude). This is true its presence is no longer felt. Natural parts made from the exact same el- particularly for those pollutants that metabolism and engineered waste emental constituents. Whether the reside in alternative physicochemical treatment processes can create a products of these catalyzed reactions forms that serve as hidden reservoirs, plethora of transformation products, are toxic themselves, damaging free many of which can have bioactivity of radicals (oxidized chemicals with un- their own, sometimes greater than that paired electrons) frequently are pro- Rarely is any organism of the parent chemical. Carbamaze- duced as by-products. Nanoparticles, pine, for example, is an anticonvulsant in this sense, are examples of indirect exposed to but a single drug that occurs frequently in open toxicants, where exposure to the par- chemical stressor waters (from treated sewage), but its ent chemical alone is insufficient for metabolism yields a host of products adverse effects. at any time, in isolation that also can occur (Miao and Metcalfe, Living Systems Not Just Victims, but 2003). These types of transformed Also Creators, Perpetuators, and Vec- from all others. chemicals usually remain hidden from tors of Pollutants. Nearly all organ- Development of a all probing except by the curious ana- isms, ranging from microorganisms, lytical chemist. plants, and wildlife to humans, actively real-world With respect to obtaining a holistic and passively are involved in exposure view of risk, target-based environmen- to xenobiotics. While exposure holds understanding of tal monitoring necessarily yields a dis- the potential to elicit adverse conse- exposure involves torted, filtered view of environmental quences, these same organisms also can occurrence by purposefully and inad- create chemicals that serve as stressors organisms continually vertently neglecting an unknown (and for others, either purposefully (e.g., perhaps substantial) portion of uniden- natural products biosynthesized for interacting with tified constituents (see Daughton, establishing allelopathy—chemical mixtures of multiple or 2003a). In the final analysis, consider- warfare between plants) or inadvert- ation should be given to a quip, adapted ently (e.g., methylation of mercury). multitudes of stressors. from a purported Einstein quotation, Less appreciated, however, is that or- “Not everything that can be measured ganisms also can serve as vectors for is worth measuring, and not everything distributing pollutants worldwide. So- such as excreted metabolic conjugates worth measuring is measurable” called “biotransport” of lipid-soluble (which can be reconverted back to their (Daughton, 2003a). pollutants by migrating wildlife can parent forms) and residues tied up as Interfaces and Microenviron- occur, for example, via bird droppings ligands or reversible precipitates or ments—Where the Action Is. We tend (Blais et al., 2005). sorbed to suspended particulates or to examine the obvious places, such as Not Everything That Can Be Mea- sediments. In reality, a multitude of open bodies of water, for pollutants and sured Is Worth Measuring, and Not chemicals can be overlooked, ignored, how they behave in the environment. Everything Worth Measuring Is Mea- or omitted by environmental monitor- Nevertheless, the less obvious niches surable—Chemicals in Hiding. The ing for any number of reasons. also can prove significant. As one ex- data collected from water monitoring Maybe Gone but Not Forgotten. It ample, interfaces and their associated can be biased in two ways: i) limita- is not just the original (“parent”) heterogeneous microenvironments at tions in the actual analytical protocol chemical that may play a significant the junctures of dissimilar phases can or the measurement technology, and ii) role in the environment. Often of sig- act as cauldrons for complex interac- a consequence of ignoring large classes nificance are the transformation prod- tions and transformation of water pol- of potential chemical stressors as a re- ucts that result from its metabolism lutants. Interfacial phenomena are in-

14 renewable Resources Journal Winter 2005 sufficiently understood with respect to from the universe to which organisms Longer exposure durations can drive the removal or storage of xenobiotics can and do experience exposure. As we down the dose needed for the same ef- as well as the creation of new pollut- have seen, the chemicals composing fects. Completely different types of ants. Complex and poorly understood these high-profile categories are not biological effects can occur at differ- interface processes pose numerous representative of the full spectrum of ent exposure concentrations. Such a questions. As an example, consider the known chemical stressors or the mul- multitude of variables and possible in- low levels of dissolved antibiotics in titudes of transformation products. The teractions poses complex challenges environmental waters. Levels moni- multifactorial complexity faced by risk for predicting the trajectory of expo- tored in the dissolved aqueous environ- assessment includes the exposure fre- sure outcomes for an organism. These ment, which usually are orders of mag- quency and timing, exposure duration, factors are part of the overall consid- nitude below those required to select exposure complexity or “totality” (cu- eration of the “4Ts” of exposure, a for antibiotic resistance, may be irrel- mulative and aggregate exposure, syn- shorthand term that captures the com- evant if interface phenomena can serve ergism, and other multiple-stressor in- plete context of an organism’s cumu- to bring together much higher concen- teractions), prior exposure history (the lative exposure to chemical stressors. trations at solid surfaces where biofilms foundation for determining exposure The “4Ts” describe “toxicant totality develop. Could microenvironments and “trajectory”), or other factors includ- tolerance trajectory” and account for niches (such as interfaces occupied by ing delayed-onset toxicity or cross-gen- an organism’s complete exposure time biofilms) serve to maximize exposure erational effects. Given these limita- line (a trajectory traced in part by prior concentrations as well as resistance- tions, it is important that progress be multidimensional exposure history) gene selection and horizontal gene made toward more holistic assessments and the fact that a major objective of transfer (the movement of genes from that account for the wide range of po- all organisms is to maintain homeosta- one organism to another)? Upstream tential environmental pollutants and to sis in the face of continual perturba- sewage trunk lines are one example and pinpoint those pollutant scenarios with tion by stressors. Homeostasis can be biosolids (e.g., treated sewage sludge highest health-effects potential. maintained only within the tolerance disposed to land) are another where this The 4Ts and Homeostasis—the Poi- bounds for the organism’s regulatory could occur (Daughton, 2002). The son Is Made by More Than Just Its and biochemical defensive repertoire. water-air interface, where monomo- Dose. Rarely is any organism exposed Therefore, the paradigm of the 4Ts sets lecular films of lipophilic and amphi- to but a single chemical stressor at any the stage for the overall true risk as philic pollutants (also called amphi- time, in isolation from all others. De- reflected by the sum total of exposure pathic or amphiphatic; containing velopment of a real-world understand- to all toxicants (anthropogenic and structural features that are attracted to ing of exposure involves organisms naturally occurring) throughout the his- both lipid and water) can concentrate, continually interacting with mixtures torical multidimensional space and tra- add yet further complexity and a host of multiple or multitudes of stressors, jectory of all other exposure variables. of other questions. the composition of which continually A key aspect to this concept is the criti- can vary through time in terms of the cal state as determined by the 4Ts— Reassessing Exposure specific chemical constituents and their that state at which an additional single and Chemical Diaspora absolute and relative concentrations. A exposure event can result in an irrevers- further complication is that stressors for ible adverse effect, one that pushes the Holistic Exposure Assessment. The many organisms include not just organism beyond its ability to main- exposure environment to which envi- chemicals (the subject of this article), tain homeostasis. A cartoon illustration ronmental toxicologists traditionally but also physical (e.g., thermal), psy- of the 4Ts is shown in Figure 2 (page have focused their attention is limited chological (e.g., fear), and biological 16), with more information available to the “conventional” pollutants that (e.g., pathogenic) agents. All of these (Daughton, comp.). Potency, dose, tim- compose the various lists of regulated stressors can interact in complex, un- ing, duration, and numerous other vari- pollutants. Many of these are the “high foreseen ways, sometimes greatly ables all must be known to fully assess production volume” industrial chemi- synergizing each other. The chemical risk. Any single one of these param- cals (and manufacturing by-products) sea to which an organism is exposed eters is insufficient. and those substances specifically de- washes against critical windows of vul- Stressor Interactions Confounding signed to kill pests. It is important to nerability (e.g., developmental stages Anticipated Toxicity. As one of many note, however, that these chemicals or diurnal physiological phases). The examples of the importance of the 4Ts, comprise but a very small portion of poison is made not just with the dose, the complexity surrounding the numer- the numbers of distinct xenobiotics but also with its duration and timing. ous factors involved with exposure, and

Winter 2005 renewable Resources Journal 15 16 renewable Resources Journal Winter 2005 the unanticipated ways in which even upon by regulatory assessments and to risk assessment. These types of ef- vastly dissimilar stressors can interact, which usually focus on acute toxicity fects include very subtle shifts in be- consider two recent examples dealing and on one stressor at a time. havior or intelligence that pass through with amphibians, which have been un- Epidemiology and Post Hoc Ergo generations. On the other side of the dergoing worldwide population de- Propter Hoc—It’s All in the Timing. coin are questions regarding what con- clines. The first reports the greatly en- A natural consequence of developing stitutes the norm. For example, care hanced toxicity of the carbamate pes- a systems-level understanding of expo- must be exercised in determining if ticide, carbaryl, toward amphibians sure and effects would be the minimi- malformations and sex trait character- when experiencing predatory stress. zation of confusion resulting from in- istics commonly observed in aquatic Carbaryl concentrations from short- ferring causal relationships between organisms are “abnormal” (possibly term acute exposure that ordinarily observed adverse effects and exposure resulting from chemical stressors) or would not adversely affect growth or to particular chemical stressors that whether they are simply part of a natu- survival can prove lethal when the ex- happen to co-occur with the effect. ral and normal distribution among posure period is increased or when the Correlating exposure (to particular populations. exposure occurs in the presence of chemical stressors) with an observed “What Is Normal? What Is Natu- predatory stress (Relyea, 2003). The effect can result in concluding that an ral?” In the context of post hoc ergo end effect is as if the concentration of exposure causes an effect simply be- propter hoc, a major phenomenon that the chemical stressor were magnified cause of a temporal connection—“af- leads to the conclusion that chemical many fold by the increased exposure ter this, therefore because of this” (post pollutants lead to adverse environmen- time or by the non-chemical stressor hoc ergo propter hoc). Conclusions re- tal effects is the extent, frequency, and (in this case, a predator cue). The sec- garding causality must take into con- prevalence of seemingly abnormal ond reports the greatly enhanced stres- sideration the 4Ts rather than just co- characteristics in aquatic organisms, sor action of normally benign con- incidental connections. Formulating such as skewed sex ratios and devel- centrations (the levels of toxicants actual cause-effect relationships can be opmental “malformations.” These “ab- often occurring in the environment) of a very complex, long-term undertak- normalities,” for example, frequently the fungicide fenpropimorph to tad- ing (e.g., DDT and eggshell thinning). are cited as evidence of exposure to poles when they are developing in the Subtle Shifts Leading to Overt endocrine modulators (e.g., the syn- presence of a predator (Teplitsky et al., Change—A New Paradigm? Acute thetic estrogen, ethynylestradiol, in 2005). The combined action of a preda- toxicity, carcinogenesis, teratogenicity, treated sewage). It is critical to con- tory stress cue (such as merely sensing and direct endocrine disruption are sev- sider, however, that the baseline occur- the presence of a predator) and the low- eral of the highly visible toxicological rence of these characteristics in pris- level fungicide resulted in delayed and endpoints that historically have at- tine “wild” populations often is un- smaller maturation that could adversely tracted the most concern. The hypoth- known and therefore causalities cannot impact the fitness of the population. A esis has been raised, however, involv- justifiably be inferred. multitude of non-chemical factors pro- ing the significance of less overt toxi- Exactly Where, How, and When We foundly can affect the outcome of ex- cological endpoints, such as immuno- Search Dictates What We’ll Find. posure to chemical stressors. With hu- disruption, neurobehavioral change, Analogous to the problems with target- mans, for example, interactive expo- protein misfolding diseases, and other analysis, it is hard to find causes for sure to certain chemicals together with subtle effects (Daughton and Ternes, which we are not looking. It can be noise can synergistically degrade hear- 1999). Could immediate biological equally hard to observe effects not ing (ototoxicity; e.g., see Fechter and actions on non-target species be imper- looked for, especially subtle ones. This Pouyatos 2005). Interactions among ceptible but nonetheless lead to adverse problem is evident particularly when disparate stressor groups, as opposed impacts as a result of continual accre- considering the overlooked ability of to effects mediated solely by one group tion over long periods? Could subtle certain toxicants to elicit adverse out- such as chemicals, is an under-investi- effects accumulate so slowly (perhaps comes far after exposure has ceased and gated area of research. Interactions seeming to be part of natural variation) thereby escape the formulation of between stressors can be extraordinar- that major outward change cannot be causal connections. Such delayed-on- ily complex and lead to completely ascribed to the original cause? Could set toxicity almost never is considered unanticipated outcomes. Because of latent damage accumulate, only surfac- in epidemiological studies simply be- the complexity, rarely can these fac- ing later in life? Effects that are suffi- cause of the daunting challenge, for tors be accounted for in conventional ciently subtle that they are undetect- example with cancer clusters. Irrevers- ecotoxicity testing protocols relied able or unnoticed present a challenge ible delayed-onset toxicity can mani-

Winter 2005 renewable Resources Journal 17 fest itself weeks, months, or years after in toxicology is the NOEL (No-Ob- and lower. Effects even can occur at exposure in the form of carcinogenic- served-Effect Level) and its variants, concentrations well below NOELs. ity (aflatoxins, asbestos), teratogenicity such as the NOAEL (no-observed- As advances in treatment technology (e.g., thalidomide), hepatotoxicity adverse-effect level). The NOEL is a continually lower the concentrations of (e.g., pyrrolizidine alkaloids), or neu- stressor’s maximum dose that fails to chemical residues in treated waters, rotoxicity (e.g., organophosphorus elicit a detectable change under defined and as analytical chemists reduce the nerve agents). Such prolonged latency conditions of exposure. The NOEL is detectable levels further, the toxico- between exposure and onset of effects used in calculating other widely used logical significance of ultra-low-dose not only makes establishment of cau- toxicity measures, such as the “acute/ exposure needs to be better understood. sality extremely difficult, it can lead chronic ratio” (ACR; where chemicals Concern is heightened for those organ- to formulation of erroneous associa- having significant chronic toxicity, as isms (such as in aquatic environments) tions with chemical stressors that by measured by the lower levels impart- that suffer continual, multigenerational happenstance are present during the ing effects, compared with acute tox- exposure to complex mixtures of low- onset of the symptoms. Delayed-onset icity, have higher ratios). The NOEL, level toxicants. The toxicology of most toxicants also could play major roles however, can easily mislead as it only xenobiotics is poorly understood at low in acts of sabotage. can be calculated for known effects levels. Particularly needed is to eluci- Beyond the DNA-RNA-Protein endpoints that are pre-determined. Ef- date the significance of low-level ef- Dogma—Inherited Effects Without fects endpoints that we are not aware fects in the range where so-called Genetic Change. Beyond the central of or that are so subtle they elude de- “paradoxical” dose responses are dogma of DNA governing the pheno- tection can possibly lower NOEL val- prevalent, where the non-conventional type of an organism (via translation to ues. In reality, the lowest NOEL can- U- or J-shaped nature of dose-response RNA and transcription of RNA to pro- not be determined until all the salient curves becomes evident. An example tein), an aspect that steadily has been toxicological endpoints are understood. is hormesis (e.g., see BELLE, 2004), attracting more attention is “epi- The Alchemy of Somethin’ from a dose-response phenomenon where genetics,” which comprises a number Nothin’—When a Little Might Be a noninhibitory effects occur below pre- of processes that regulate trans- Lot, or When Less Is More. There are viously established NOELs. Despite generational effects. These heritable growing questions regarding the per- hormesis being proposed as a justifi- changes in gene function can be passed vasiveness, significance, and ramifica- cation for permitting or justifying low- across multiple generations without tions of exposure to “low” levels of dose exposures (e.g., because one of any alteration to the genetic code. This chemical stressors (so-called “micro- its common outcomes is growth stimu- is accomplished by activation or inac- pollutants”). There are many unknowns lation), it is important to remember tivation of genes by chemical modifi- and controversies regarding such ex- that: (i) any effect (regardless of its cation of chromatin by processes such posures. Of course, “low” is a relative anthropocentric interpretation) that as methylation of the DNA (e.g., the term, one usually deriving its meaning perturbs homeostasis has the potential so-called, non-RNA-coding “junk” as being “lower” than previously stud- to ultimately result in an adverse out- DNA), acetylation of the proteinaceous ied or documented. For analytical come and (ii) real-life exposures are histones, and RNA interference. These chemists today (and sometimes toxi- to multiple stressors, some of which processes can be modulated or inter- cologists), “low” often refers to con- can share the same mechanism (or fered with by various xenobiotics. A centrations at or below the parts-per- mode) of action, thereby effectively recent example of the relevance of billion or nanomolar ranges. These having a combined concentration epigenetics to environmental exposure concentrations are orders of magnitude higher than the hormetic level for a is the work of Anway et al. (2005), who below those that could be studied just single stressor in isolation from all oth- reported that exposure of pregnant rats two decades ago. There are also ques- ers. These limitations, and others, have to the pesticides methoxychlor or tions, however, regarding the innate now been formally articulated by vinclozolin led to male offspring with toxicity of a chemical (e.g., under labo- Thayer et. al. (2005). reduced fertility. This heritable change ratory conditions) versus its ability or Symptoms from Nowhere—the was passed through four generations potential to actually elicit toxicity in Nocebo. An additional way in which after the original exposure to the the real world. Regardless, certain effects can manifest from human ex- mother. chemicals (e.g., ethynylestradiol) do posure to seemingly minuscule concen- “No-Observed-Effect Level”—You have the ability to impart effects at trations of pollutants is via the so- Get What You Want, Not Necessarily concentrations of one part-per-trillion called nocebo response (Daughton, What You Need. A standard measure 2004). The nocebo effect (the opposite

18 renewable Resources Journal Winter 2005 of the placebo effect) is a real, physi- cation of actual hazard/risk and how come dynamic thresholds that are a ologically adverse outcome caused the risk actually is perceived. This will function of prior exposure history. simply by the suggestion or belief that prove especially important with the Like-Minded Chemicals of Similar something (such as a chemical) is growing need to reuse water or to re- Persuasions—Too Much of Nothin.’ harmful, regardless of any inherent tox- cycle it for drinking. Another way in which a little can mean icity. The nocebo effect could play a A Special Concern Regarding Low- a lot can be illustrated simply by the key role in the manifestation of adverse Dose Effects—TILT. One specific is- scenario of simultaneous exposure to health consequences from exposure sue regarding low-level human expo- multiple chemicals at low concentra- even to non-toxic trace levels of con- sure specifically concerns toxic effects tions. A special case where low con- taminants—simply by the power of from exposures that on prior occasions centrations of chemicals could prove suggestion. Public education and a bet- proved benign. Controversy surrounds significant is by exposure to multiple ter understanding of how risk is per- the significance of exposure to minute stressors, each perhaps at a concentra- ceived and how it best be communi- quantities of xenobiotics, whether from tion below which an effect could oc- cated are important particularly for food, drink, skin, or air. Exposure by cur, but which share the same mecha- minimizing the incidence of the so- nism or mode of action. The overall, called nocebo response. combined concentrations of all those Same Chemicals, Different Out- New sources of chemicals with the same mechanisms comes. The nocebo effect presents a of action could very well exceed a tox- fascinating juxtaposition against the pollutants include icity threshold. This poses very diffi- adage “familiarity breeds boredom.” not just chemicals cult regulatory challenges, whether The way in which risk is perceived can these like-mechanism chemicals origi- lead to ironic and even contradictory newly introduced to nate from the same industry or from outcomes, pointing to a need for ma- different industries. Traditional toxic- jor improvement in the way risk is com- commerce but also ity testing could show that no single municated. One paradox in risk percep- new ways to produce chemical may have any effect at the tion relates to the relatively high con- level it occurs in the environment. In centrations and types of a plethora of and use them, this way, risk could be consistently chemicals formulated in personal care underestimated. As the numbers of dif- products that are applied directly to the which in turn create ferent types of chemicals increases in skin or in the mouth, versus the con- new opportunities the environment, the potential for this centrations of some of these very same scenario increases. chemicals that might be found in drink- for their entry into Merging onto a “Toxicity Appor- ing water but at many orders of mag- tionment” Regulatory Freeway from nitude lower concentrations than in the environment. the Dead-end Chemical-by-Chemical commercial products. The high con- Road? The continual introduction of centrations of various chemicals in special subpopulations or during criti- new chemicals to commerce casts personal care products routinely are cal windows of vulnerability (e.g., fe- doubts as to whether a chemical-by- deemed by the user to be risk-free but tal development) has been reported (but chemical approach to regulation of not the very same chemicals, in minute not without controversy) to lead to water pollutants will continue to be concentrations, in drinking water. toxicant-induced loss of tolerance sustainable on a comprehensive scien- Another example involves the occur- (TILT) (or “multiple chemical sensi- tific footing (Daughton, 2003a; rence of minuscule traces of drugs in tivity”) (Winder, 2002). In TILT, an Daughton and Ternes, 1999). Many certain drinking waters, which can fos- initial exposure (perhaps to a larger emerging pollutants, such as PPCPs, ter the formation of negative mental quantity) purportedly promotes hyper- have totally new mechanisms of action and emotional images for the con- sensitivity. Subsequent exposures to (MOAs), most have multiple MOAs, sumer, regardless of the water’s over- levels far below those previously tol- and the actual MOAs rarely are even all purity, as a result of the fact that erated then trigger symptoms. An ob- understood fully. With respect to the the origin of these drugs often derives vious question is whether an ecologi- “exposure universe,” and in a manner solely from human excretion cal version of TILT exists, where ef- analogous to source apportionment, (Daughton, 2004). A better understand- fects levels can be driven downward by consideration could be devoted to de- ing is needed of the origins of the prior exposure—where NOELs be- veloping the capability of “toxicity chasm existing between the communi- apportionment.” The objective would

Winter 2005 renewable Resources Journal 19 be to assign toxicity an integrative pollute the environment is that between microreactors will eventually prove measure of the total numbers and quan- inorganic and organic chemicals. In capable of widespread and dispersed tities of stressors present, without the contrast to the latter (even for DDT, production (on an individually small need to know their actual identities in halogenated dioxins/furans, PCBs), scale but on a continual basis) of ex- advance. The ultimate objective would which have limited life expectancies, otic and highly hazardous chemicals be to close the exposure envelope the former often have indefinite life with little knowledge or intervention around all chemical-exposure constitu- expectancies (e.g., elemental lead) or by technical experts, and (v) acceler- ents—both naturally occurring and simply transform into related species ated access to exotic chemicals by con- anthropogenic. This alternative ap- until they are “recycled” in the envi- sumers, resulting in myriads of point proach could consider basing water ronment back to the parent forms (e.g., sources for environmental contamina- monitoring programs on assays de- various forms of mercury and arsenic). tion as a result of the combined contri- signed around evolutionarily conserved Although pollution postponement and butions from personal actions, activi- biochemical features and MOAs rather pollutant alchemy might sometimes be ties, and behaviors, as well as the need than on individual chemical entities. the best way to delay the entry of these for disposing of leftover and unwanted The ultimate question is whether the chemicals to the environment, pollu- materials. With regard to the last point, initial target of regulation might be the tion prevention and pollution minimi- the quality of source drinking waters potential for actual biological effects zation are preferred. For perspective, depends in part on the diffuse impacts instead of chemicals themselves. This extensive examples of stewardship ap- of the collective activities of multitudes approach could be a better way to au- proaches for minimizing the entry of of individuals—from each of whom tomatically account for a multitude of PPCPs to the environment have been minuscule (and seemingly insignifi- stressors sharing a common MOA (cu- proposed (Daughton 2003a,b). cant) contributions combine to yield mulative exposure), stressors newly detectable levels of certain pollutants introduced to commerce, and pollut- Peeking at the Future that otherwise have little origin from ants not yet identified. industrial activities. In addition to these Environmental Stewardship versus While it is not possible to predict the sources are the unknowns associated Pollution Postponement, Pollutant future regarding the many dimensions with sabotage of our environment with Musical Chairs, and Pollutant Al- of chemical pollution, several concerns exotic chemicals (including those de- chemy. Since purposeful, direct dis- and opportunities, just now emerging, signed for military use) by terrorists. charge of chemicals to the environment might be useful to consider. Given the potential for new pollut- is inherently undesirable, many ways Early Warning—Monitoring for ants to enter the environment, it would to reduce these emissions have been Emerging Contaminants and Home- be most useful to know about their developed. These include numerous land Security. New sources of pollut- presence as soon as possible. An ulti- physical removal technologies (rang- ants include not just chemicals newly mate objective of any program de- ing from simple filtration and sedimen- introduced to commerce but also new signed to deal with emerging pollut- tation to reverse osmosis for wastewa- ways to produce and use them, which ants should be to create a mechanism ters), volume reduction (e.g., evapora- in turn create new opportunities for for identifying their presence in the tion), or storage (e.g., landfills). All of their entry into the environment. environment as early as possible—well these physical approaches essentially Several examples include: (i) commer- before becoming pervasive. A mecha- eliminate discharge today in exchange cial introduction of new drugs (in- nism for the real-time detection of new for risking potential discharge at a later cluding potent illicit designer drugs) pollutants in water is important, not just date (“pollution postponement”). They with MOAs never before encountered for protecting the environment and simply transfer pollutants from one by biological systems, (ii) transgenic public health from the effects of inad- place to another, delaying the way and production of therapeutants and vac- vertent pollution. It also would help in time by which they can gain entry to cines by genetically altered plants protecting water supplies from chemi- the environment. Even destructive pro- (especially edible crops), also known cal sabotage, a concern for homeland cesses (e.g., oxidation and combustion, as plant-made pharmaceuticals security. The sheer number of poten- including incineration) sometimes (PMPs), by “molecular farming” or tial new contaminants clearly would serve to transform existing pollutants “biopharming,” (iii) newly invented pose insurmountable obstacles for con- into new chemicals (“pollutant al- nanomaterials and their ill-defined ventional target-based monitoring ap- chemy”), a form of pollutant musical products that could result from natural proaches. A straightforward way to chairs. The most significant demarca- weathering processes, (iv) the advent sidestep this limitation would be to tion among classes of chemicals that of micro-process technology, where design an early warning system around

20 renewable Resources Journal Winter 2005 the simple approach of detecting com- frastructure requires considerable in- ure 1 in Shiklomanov 1999). The grow- positional “change”—where any per- vestment for repair and upgrading. An ing shortage of freshwater could drive turbation in a sample’s normal chemi- additional infrastructure need is to re- a transition from centralized munici- cal “fingerprint” (distribution pattern duce the occurrence of unpermitted pal water treatment and distribution to of types and quantities of solutes) straight-piping, septic systems, and truly distributed water reuse—where would trigger an immediate in-depth privies, which serve to maximize the wastewater is both treated and reused chemical analysis to determine the release of xenobiotics to the environ- close to its origin, eventually directly cause (identify the chemicals respon- ment (to both surface waters and on site. Such distributed water reuse sible for the change). Such an approach groundwaters) via raw sewage. systems pose unique challenges regard- circumvents the many inherent limita- Toward a Holistic Solution. The ing public acceptance and effective tions of target-based monitoring. The growing number and sources of chemi- communication of risk (see Daughton, timely elucidation of newly emerging cals with the potential to enter the en- 2004). However, they also offer fun- (or previously unrecognized) pollutants vironment via wastewater is challeng- damental advantages regarding inde- also is critical to uncovering trends in ing our ability to treat these wastes. pendence and the inherent design ad- geographic pollutant distribution, Actions to reduce any of the associated vantage of ultimate security from large- prevalence, and loads. Having available variables contributing to this vulner- scale sabotage. Another advantage of long-term change-detection data could ability would be prudent. The major recycling water generated directly from greatly assist epidemiological studies, vulnerability for humans results from the point of original use (as opposed especially those involving cancer clus- the nature of the water cycle, where the to collective water from centralized ters, which long have been a bane of historic practice of treating domestic domestic, municipal, and industrial toxicologists. Another approach is to wastewaters for discharge to surface generators) is that the universe of leverage the involvement of amateur waters can result in contamination of microcontaminants that need to be re- observers to report unusual phenomena source waters destined for drinking moved is vastly reduced and the types in nature that possibly are the result of (whether surface or ground). The ma- and number of chemicals that the con- chemical stressors; one such proposal jor requirement has been the design of sumer will discard to sewerage would was noted by the Royal Commission water systems having sufficient spatial be reduced as a result of personal in- on Environmental Pollution (2003). and temporal hydraulic “disconnect” so centive (Daughton, 2004). Inadequate and Decaying Water In- as to “erase” from the consumer’s mind “Futuring” and the Precautionary frastructure. In the absence of effec- any memory of the original source of Principle. The traditional list-based, tive proactive pollution prevention the water (Daughton, 2004). The con- chemical-by-chemical approach must schemes, reactive pollution control is tinually diminishing supplies of high- wait for emerging pollutants to estab- required. Domestic wastewaters are a quality freshwater, however, is increas- lish an environmental presence before major emerging source of pollution ing pressure to actively recycle and action can be taken. Regardless of how (from the combined activities of mul- reuse waters, even from human waste. timely this approach can become, it is titudes of individuals). Conventional This will lead to ever-shortening spa- at best a reactive one. The fact that municipal sewage treatment facilities tial and temporal hydraulic connectiv- corrective reactions can be required never were designed to remove exotic ity between the point of wastewater long after chemicals achieve environ- anthropogenic chemicals with struc- discharge and the point of use for drink- mental footholds leads to discussions tures and mechanisms of biological ing (the recycle loops will continually of the controversies surrounding the action that are foreign to biological shrink). The ultimate rendition of this precautionary principle (see links at degradative/transformation systems. is the so-called “toilet-to-tap” ap- Daughton, comp. 2005d). An early ren- Indeed, the ubiquitous, albeit low level, proach. While this approach has been dition of the precautionary principle as presence of PPCPs in treated sewage vilified by many (primarily as a result codified in law would be the European effluent reflects this limitation. Even of the way in which risk is perceived), Commission’s proposed new European if existing waste treatment and water if properly implemented it could solve Chemicals Agency and regulatory treatment facilities functioned accord- many problems faced by areas facing framework for chemicals—REACH ing to original specifications, the types water shortages. (Registration, Evaluation and Auth- and quantities of xenobiotics in treated Decentralized Water Re-Use. Less orisation of Chemicals) (EC, comp. water could continue to rise, partly as than one percent of all the world’s 2005). A new paradigm, however, a result of the introduction of new freshwater resources are readily acces- would adopt a proactive approach chemicals to the marketplace and sible, representing less than 0.01 per- where future concerns are anticipated, partly because the nation’s water in- cent of all the world’s water (see Fig- long before any preventive or remedi-

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