“Emerging” Chemicals as Pollutants in the Environment: a ... · HPV (high production volume chemicals) quantity (manufactured/imported in U.S. in annual amounts >1 million pounds)

6 renewable Resources Journal Winter 2005

Editor's Note—Pesticides, pharma-ceuticals, industrial chemicals,nanoparticles, and personal care prod-ucts are being detected increasinglythroughout the environment. These sub-stances are being detected in tissuesof humans, terrestrial animals, amphib-ians, and fish. We believe that a basicunderstanding of existing and poten-tial threats posed by these substanceshas become prerequisite knowledge fornatural resources managers, profes-sionals in related disciplines, and thosein government whose decisions affectmonitoring and regulatory activities.Thus, we have dedicated this issue ofthe Renewable Resources Journal to anexpansive overview of the extent andnature of challenges we face. The nextissue of our journal will extend the ex-amination by presenting findings andrecommendations stemming from

RNRF’s upcoming Congress on Assess-ing and Mitigating Environmental Im-pacts of Emerging Contaminants,scheduled for December 1-2, 2005, inWashington, D.C.

Abstract

Defying comprehension is the com-plexity of the chemical sea that sur-rounds, sustains, and constitutes all life.From this sea, never-ending challengesare faced by organisms striving to de-fend against those multitudes of chemi-cals that cause cellular stress or harm.Biological mechanisms have evolvedfor maintaining organism homeostasisduring contact with these harmful sub-stances. Most of these chemical stres-sors have long existed or are producedby myriads of human activities. How-ever, for those chemicals that are rela-tively new to the world, the mecha-nisms for homeostasis maintenance arenot necessarily adequate. Chemicalsfor which organisms have had the leasttime to adapt are those that only re-cently have emerged as environmentalcontaminants.

Essentially limitless combinations ofa very small set of atomic elements canyield a seemingly infinite number ofunique chemicals—a universe knownas “chemical space.” Although thou-sands of chemical pollutants or con-

taminants are regulated under interna-tional, federal, and state programs,these represent but a minuscule frac-tion of the universe of chemicals thatoccur in the environment as a result ofboth natural processes and human ac-tivities. This array of chemical pollut-ants (or occupational hazards) mightat first seem large, but it pales com-pared with the universe of knownchemicals, and would become insig-nificant if compared with those chemi-cals yet-to-be identified, waiting to besynthesized, and that are just now“emerging.” A key assumption is im-plicit in the limited and selective listsor menus of chemicals targeted byregulations—namely that these are in-deed the chemicals responsible for themost significant share of risk to eco-logical integrity, economic impair-ment, and human health. Given themyriads of other chemicals that areignored or escape notice by regulatoryprocesses, a multitude of questions canbe posed regarding society’s relation-ship with chemical pollutants, particu-larly with respect to whether a moreholistic understanding of risk might berequired. With the immense size of thechemical universe, this is a dauntingchallenge. How would we know whenwe have narrowed the chemical uni-verse to the most significant hazardsworthy of our attention? Not necessar-

“Emerging” Chemicalsas Pollutants in the Environment:a 21st Century Perspective

Christian G. Daughton

Daughton is chief, EnvironmentalChemistry Branch, U.S. Environmen-tal Protection Agency. This article hasbeen subjected to peer review. TheUnited States Environmental Protec-tion Agency through its Office of Re-search and Development funded andmanaged the research described here.It has been subjected to the agency’sadministrative review and approved forpublication as an EPA document.

Winter 2005 renewable Resources Journal 7

ily will the continued emergence ofnew pollutants pose the biggest chal-lenge. A larger unknown might be theoccurrence of myriads of chemicalsthat remain hidden from our view. Per-haps more daunting will be gaining abetter understanding of the unantici-pated ways in which these substancescan interact with the environment andthe creation of a new paradigm for theirmanagement or stewardship. Addingyet additional challenge is the emerg-ing realization that society is averse toexposure to certain chemicals, even inthe absence of any hazard, simply be-cause these chemicals occur where theyare not expected or desired—thechemical equivalent of “weeds.”

Outlined in this paper is a samplingof some of the many alternative per-spectives regarding chemical pollutants(especially those that are new to ourattention—the so-called “emerging”pollutants) and their ramifications forbiological systems and society’s val-ues. A primary objective in presentingthese alternative views of chemical pol-lution is the hope of catalyzing dialogand debate regarding new approachesfor its management, not to make rec-ommendations for implementing solu-tions.

Introduction

Tremendous investments continue tobe made in the prevention, control, andmitigation of environmental pollutionby chemicals. Nevertheless, how canwe be sure that these are the most im-portant chemicals with respect to pro-tecting humans and the ecology? Dowe sufficiently understand the pro-cesses that dictate exposure to thesepollutants and its aftermath? Is the in-troduction of new chemicals to com-merce outrunning our ability to fullyassess their significance in the environ-ment or to human health?

This article is intended to foster dis-cussion aimed at establishing a moreholistic view of xenobiotic exposure

and its ramifications. More emphasisneeds to be placed on non-regulatedpollutants, especially those consideredto be “emerging.” Over the last fewyears, the appellation “emerging” hasbeen applied to chemical pollutantswith such frequency that its meaningis becoming confused. In reality, thosepollutants that are truly “emerging”(for example, those that have justgained entry to the environment be-cause they are new to commerce) aresometimes confused with those whoseenvironmental presence just has been

elucidated but which have long beenpresent. There are a number of differ-ent perspectives from which to view themany dimensions of “emerging”(Daughton, comp. 2005a). One ex-ample is that of PPCPs (pharmaceuti-cals and personal care products; seeDaughton, comp. 2005b), which in-clude many substances that long havebeen present in the environment butwhose presence and significance onlynow are beginning to be elucidated.“Emerging” also sometimes is intendednot to refer to the pollutant itself, but

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rather to a newly hypothesized concernregarding an old pollutant. For ex-ample, pollutants that long have occu-pied our attention can gain new noto-riety with the revelation of new aspectsof their occurrence, fate, or effects; theproduction of acrylamide during thecooking of certain foods is but one ex-ample.

A source of on-going confusion isthe proliferation of acronyms for thedifferent categorizations of chemicalpollutants. Various groupings of chemi-cal pollutants (see Table 1) haveevolved, and each looks at chemicalsfrom a different perspective. Eachgroup tends to contain some but notmost of the chemicals from othergroups; each group slices the chemi-cal universe pie in a different dimen-sion. In this sense, members of “emerg-ing” pollutants can each belong to oth-ers of these groups.

The discussion that follows willhighlight some of the less appreciatedaspects of chemical pollution (with“emerging” pollutants as a commonthread) and place these in the contextof hazard and exposure, and whetherrisk can be assessed more holistically.

The Chemical Universeand Exposure 101

An ever-expanding universe ofunique chemicals, untold numbers ofwhich have yet to be recognized or re-vealed, continually perfuse our envi-ronment and contact living systems.Multitudes of chemicals originate bothfrom natural processes and from an-thropogenic sources, including synthe-sis-by-design of new molecular enti-ties and inadvertent formation of by-products from these syntheses or fromthe molecule’s destruction (incinera-tion is an example). Sometimes, thechemicals produced by humans are thesame as those produced in nature (thishas led to long-standing confusion overthe meaning of “organic”). Many ofthese chemicals have existed through-

out the course of life on Earth. Someare inherently harmful, some are essen-tial for sustaining life, and others shareboth characteristics depending on theirconcentrations or when exposure oc-curs during the course of an organism’sdevelopment or natural rhythms. Ex-posure, however, is not sufficient fortoxicity. All organisms have evolved acomplex repertoire of defense mecha-nisms for coping with exposure to thosechemicals foreign to their normal ex-istence (xenobiotics). Living systemshave developed protective, defensive,or adaptive mechanisms for minimiz-ing exposure or even the toxicity ofmany of the otherwise harmful, natu-rally occurring chemicals. For those“new” chemicals that only recentlyhave emerged, however, and to whichbiological systems never have beenexposed, these defensive mechanismssometimes can be inadequate.

Chemicals Are Chemicals, ButThey Are All Different. Whether fromnature or from industry, chemicals arechemicals—both naturally occurringand anthropogenic. However, theircharacteristics and properties can dif-fer dramatically. The quantities in theenvironment and the toxicities of indi-vidual chemicals span an extraordinar-ily broad range. The types and quanti-ties of individual chemicals in a widearray of environmental compartments(soil, sediment, water, air, biota) alsovary dramatically over time. Theirpresence is not necessarily static, of-ten varying temporally and spatially inboth absolute amounts and in relativeproportions. Concentrations of chemi-cals in any one sample can range frompercent to parts-per-million to less thanthe yocto-molar range—a span exceed-ing 20 orders of magnitude. The inter-actions of living systems with chemi-cals (part of the study of “exposure”)can result in myriads of biological re-sponses or changes (“effects”), rang-ing from adverse to benign to even ben-eficial. Chemical exposure is an extra-ordinarily complex and dynamic

process, which takes place under con-tinually changing conditions. Expo-sure, for example, can range fromshort-term contact with a small, selectgroup of chemical stressors (“toxi-cants”) at relatively high concentra-tions (acute exposure), to extendeddurations of exposure with lower con-centrations (chronic) of multitudes ofchemicals in extraordinarily complexmixtures. Effects can range from overt,where adverse consequences are elic-ited quickly (e.g., from a lethal dose),to subtle, where effects are not readilyapparent or easily measured (e.g.,slight but gradual shifts in mentalhealth and behavior). Some stressorscan elicit delayed effects that becomeapparent only weeks, months, or yearsafter an initial exposure (delayed on-set toxicity). The relative concentra-tions of stressors can change continu-ally. Likewise, the types and vulner-abilities of biological receptors thatinteract with the stressors also canchange (as a function of the organism’soverall health status). Windows of par-ticular vulnerability can exist duringcertain critical times, such as specificdevelopment stages and biologicalrhythms. Chemicals of environmentalconcern can have origins from bothpurposeful human activities as well asfrom nature. One of many examplesincludes the endogenous estrogenic andandrogenic steroidal hormones synthe-sized and excreted by humans and othermammals, the plant-produced phtyo-estrogens consumed in our diet, and theanthropogenic, synthetic versions ofthese naturally occurring chemicalssuch as ethynylestradiol (synthetic ana-log of estradiol; an extremely potentactive ingredient in reproduction regu-lators).

Legal or Illicit Chemicals—All inthe Pollutant Family. The environmentdoes not discriminate between pollu-tion from legal or illegal chemicals.Whether the pollutant is chlordane,codeine, or cocaine, whether methylm-ercury or methamphetamine, biologi-


cal receptors interact without regard tothe chemical’s legal standing or itssource. All can impart effects. Even so,the legal standing of chemicals seemsto affect the degree to which they arestudied. For example, while prescrip-tion and over-the-counter pharmaceu-ticals have gained much attention aspollutants since the late 1990s, littleeffort has been devoted to uncoveringthe environmental prevalence of illicitdrugs, such as cocaine or any of thenumerous amphetamines. The first re-ports of illicit drugs occurring as tracepollutants in environmental waters re-cently were published by Jones-Leppet al. (2004) and Zuccato et al. (2005).

Real or Fake—It’s All the Same.“Exotic” chemicals that are found inthe environment might seem, on firstexamination, to originate from humanactivities. An accurate perspective,however, also must recognize that someof these chemicals have naturalsources. Microorganisms (bacteria,fungi, and algae) and plants are highlyversed at synthesizing a bewilderingarray of chemicals, most of whichmight at first seem to be foreign to liv-ing systems. Many possess extremeacute and chronic toxicity. Indeed,many of these chemicals are involvedin the unrelenting chemical warfare andsignaling that occurs between organ-isms. Natural abiotic processes (suchas sunlight and natural combustionsuch as forest fires and lighting) alsoare capable of catalyzing the formationof other xenobiotics. Some chemicals(even certain persistent organochlo-rines, including certain dioxins) canoriginate from both natural and humanactivities.

With this very brief and oversimpli-fied overview of the intersection of theuniverse comprising chemicals with theworld of biological systems, a numberof questions can be posed with respectto how this nexus can be managed tominimize risk to the environment andhuman health. We also can exploresome of the many facets of this inter-

section in more detail to reveal poten-tial oversimplifications of the varioustenets we long have held, and how wemight want to alter these to better ac-commodate reality.

Regulated Pollutants: Minor Ingre-dients in a Small Slice from the WholeRisk Pie? Since the 1970s, the impactof chemical pollution has focused al-most exclusively on lists (or menus) ofconventional pollutants, especiallythose collectively referred to as “per-sistent, bioaccumulative toxicants”(PBTs) or “persistent organic pollut-ants” (POPs); see Table 1. This rela-tively small number of primarily con-

ventional, regulated pollutants, how-ever, represents but one piece of a muchlarger universe of potential pollut-ants—one of largely unknown scope.That biological systems can suffer ex-posure to countless chemical stressors,only a small number of which are regu-lated, poses many currently unanswer-able questions regarding risk. As ofAugust 2005, over 26 million organicand inorganic substances (excludingbiosequences such as proteins andnucleotides) had been indexed by theAmerican Chemical Society’s Chemi-cal Abstracts Service in their CAS Reg-istry (CAS, 2005a). One-third of these

(nearly 9 million) were commerciallyavailable, representing a 12 percentincrease over the prior year. In contrast,fewer than a quarter million (240,000)were inventoried or regulated by gov-ernment bodies worldwide (CAS,2005b).

“Chemical Space.” While theknown universe of organic chemicalsmight seem large, the universe of po-tential organic chemicals (those thatpossibly could be synthesized andthose that already exist but whichhave not yet been identified) is un-imaginably immense. So-called“chemical structure space” essentiallyis unexplored. If chemical space is de-fined as comprising all possible struc-tural configurations up to a certainnominal molecular size, it is estimatedto contain between 1030 and 10200

unique structures, depending on howthe estimate is calculated and the up-per boundary for the molecular size(Bohacek et al., 1996; Dobson, 2004).The types of possible organic chemi-cals essentially are limitless in theirever-expanding structural universe. Theefforts of synthetic organic chemists,using advanced combinatorial chemis-try and exploring new forms of mattersuch as nanomaterials and superatomclusters, are only beginning to revealthe complex dimensions of chemicalspace. The ramifications for risk asses-sors and regulators indeed are pro-found. Historically, we only have stud-ied and regulated the tip of the chemi-cal space iceberg.

Looking Glass to Parallel Chemi-cal Worlds—Stereochemicals andChirality. Strewn about in chemicalspace are parallel chemical worlds,where certain molecules (those withasymmetrical structures) exist in mul-tiple forms whose mirror images arenot superimposable. Known as chiralmolecules, one of the simplest ex-amples is bromochlorofluoromethane,which contains a single carbon atombonded to four different elements (hy-drogen, bromine, chlorine, and fluo-

An ever-expandinguniverse of uniquechemicals, untoldnumbers of which

have yet to berecognized or revealed,

continually perfuseour environment

and contactliving systems.


rine). Pairs of chiral molecules areknown as “enantiomers” or as “opticalisomers.” Chirality (“handedness”)plays critical roles in the environmen-tal chemistry and toxicology of myri-ads of chemicals. A chemical compris-ing chiral forms can have properties oftwo or more distinct chemicals (de-pending on its number of points ofasymmetry), but each having the samecomposition and two-dimensionalstructure. Chiral chemicals composedof equal parts of their optical isomersare known as racemates. Isomers ofmore complex chiral molecules thatpossess at least two stereogenic cen-ters can either be enantiomers or dias-tereomers (stereoisomers that are notmirror images). Isomers of achiralmolecules possessing at least twostereogenic centers are called meso iso-mers (stereoisomers that are super-imposable). A ubiquitous pollutantnotorious for its complex stereochem-istry is the flame retardant hexabromo-cyclodecane (HBCD), which com-prises six enantiomeric pairs and fourmeso forms, a total of 16 steroisomers,all having identical compositions butdifferent chemical properties.

Many synthetic chemicals (e.g., cer-tain pesticides) are regulated as theirracemates or isomeric mixtures. Ofmost significance, however, is that theenvironmental fate and toxicity of theindividual isomers can differ, some-times dramatically. For example, oneisomer might by more readily degrad-able, while the other persists. Onemight have much greater toxicity (orbeneficial effect), while the other canhave completely different effects (ornone at all). The well-known drug tha-lidomide is but one example, where oneof its enantiomers has the designed ef-fect of sedation but the other is a po-tent teratogen (causes fetal malforma-tions). Countless other examples wouldshow how the different forms ofstereochemicals can have different andunpredictable ramifications with re-spect to exposure and effects. This is

one reason that the pharmaceutical andpesticide industries have been movingtoward the design of optically purechemicals that cannot racemize amongenantiomers. A significant major ques-tion, however, is how a regulatory sys-tem can best deal with stereochemicalmixtures, especially when it can beextremely difficult to distinguish be-tween them during environmentalmonitoring.

Chemicals Unlike Themselves. Forthose chemicals with optical isomers,the seeming paradox exists wherechemically identical molecular struc-tures can have wildly different chemi-cal or biological properties. Nanoscalechemicals (also called nanoscale par-ticles or materials) constitute anotherpotentially immense class of chemicalswhere an analogous conundrum exists;superatom clusters (whose atoms takeon the properties of other elements) areanother example. Nanoscale materials(which are much larger than most mol-ecules, but with one dimension smallerthan 100 nanometers) are distinguishedby having chemical and biologicalproperties that differ profoundly fromthose of their chemical constituents.The size and shape of nanoscale mate-rials (which, for example, dictates verylarge surface-to-volume ratios, whichin turn have enormous potential forcatalyzing reactions) impart uniqueproperties.

Regulatory conundrums result fromthe fact that although the constituentchemicals already might be regulated,the nanomaterial does not resemble oract like its constituents. This problemis exacerbated further by the fact thatnatural weathering processes could yetfurther alter these materials, produc-ing “structurally undefinable ubiqui-tous xenobiotics” (SUDUX), whichmay not be measurable for monitoringpurposes. The potential is unknown fornanoscale pollutants resulting fromnanomaterial weathering to create ex-ponentially more xenobiotics, an un-

known portion of which may be newto organisms.

Whither the Bull’s Eye—Are WeAiming at the Correct Target? Twodistinct approaches can be used by ana-lytical chemists to gage or probe themolecular make-up of an environmen-tal sample and hence reveal some ofits toxicological hazards. The preva-lent, most cost-effective approach uses“target” analysis, where the chemicalsconsidered for measuring (known as“analytes”) are preselected from a stan-dardized “menu.” This is the approachthat necessarily drives the environmen-tal monitoring dictated by regulatorypriorities—where various chemicalsare “listed.” The second approach isthrough non-target “characterization,”where the universe of chemicals thatmight compose a sample are all sub-ject to discovery by the analyst—theanalysis does not begin with predefinednotions as to what the search will en-compass or what it might reveal. Thisapproach, which is used in “environ-mental forensics,” is much more timeconsuming and costly. The latter ap-proach can uncover the presence ofmany more chemicals than can targetedanalysis, but even it eventually is sub-ject to the gross limitations of even themost advanced analytical tools, whichstill are incapable of revealing thestructures or even the presence of in-calculable numbers of chemicals in anyenvironmental or biological sample.

Even thorough chemical character-ization does not account for an un-known portion of organic chemicals.These comprise those chemicals thatcannot be detected or identified. Sig-nificantly, these unidentified or uniden-tifiable compounds almost alwayscomprise an unknown fraction of allthose present, so the toxicological sig-nificance of their presence is rarelyknown. These unidentified chemicalsare neglected, ignored, omitted, oroverlooked because of any number oflimitations or idiosyncrasies of themany tools employed by the analyti-


cal chemist (see Figure 1 in Daughton,2003a). The salient question is whetherany significant risks for living systemsare associated with the target analytes,with the non-targeted chemicals, orboth. Exactly where is the toxicologi-cal target, and are we aiming for thebull’s eye? The proliferation of newanthropogenic chemicals coupled withthe continued discovery of new chemi-cals produced in nature will continueto challenge analytical chemists andregulators alike. On the other side ofthe coin, however, one can argue thatthose very few chemicals that we moni-tor in the environment, and to whichwe know organisms are exposed, alsocan be viewed as serving as surrogatesfor the presence of untold numbers ofother chemicals possessing similarphysicochemical properties. By regu-lating one (e.g., via removal duringwaste treatment), untold others coin-cidentally are controlled.

Analytical Chemists—The Regu-lator’s Worst Friend? Analytical chem-istry plays a key role in expanding andrefining our ever-changing perspectiveof the chemical sea in which we findourselves. As the power of analyticalchemistry increases, the types of chem-icals that can be detected and identi-fied increase, and the limits of concen-tration at which they can be measuredcontinually are lowered. By ever ex-panding the horizon of the knownchemical universe, analytical chemistsunwittingly add to the burden of re-sponsibility for risk assessors and regu-lators. Lowering the limits of detectionchallenges our concepts of “purity,”“zero,” and “safe,” which must then berevised. The extraordinarily wide rangeof concentrations at which chemicalscan occur imposes seemingly insur-mountable hurdles for risk communi-cators. The lay public’s bewildermentwith the jargon required for express-ing these concentrations has fosteredthe perception that essentially all con-centrations are the same—whether theyare minuscule or large. The number of

chemical contaminants at “trace” lev-els can exceed those present at higherlevels. Largely stemming from thisability to reveal ever more pollutants,environmental analytical chemists of-ten are perceived as problem makers—not as problem solvers. It becomes in-creasingly difficult to assess risk andto design regulatory programs for newand moving targets. Where shouldregulatory limits be placed? Does“zero” even exist? The chemicals ofpotential concern comprise the broadspectrum of anthropogenic chemicals(those purposefully synthesized andindirectly produced by human activi-ties) as well as “natural products”(those created both by natural physi-cochemical or biological processes).Using drinking water to illustrate, thegasoline oxygenate additive MTBE(methyl-tert-butylether), tris (4-chloro-phenyl)methanol, and halogenated dis-infection by-products (DBPs) are threeof countless examples of widespreadanthropogenic contaminants. Arsenicand geosmin (the off-flavor bicyclicalcohol produced by certain algae andfungi) are examples of naturally occur-ring contaminants. Some chemicals(e.g., DBPs and acrylamide) can origi-nate from both natural and anthropo-genic processes. Multitudes of ques-tions languish unanswered. Is a newparadigm required for more efficientlyand effectively assessing and protect-ing the world from whatever risksmight be posed by those stressors com-prising the chemical sea in which alllife forms must sustain their homeo-stasis?

Chemical-by-Chemical Regulation:Thoroughfare or Dead-end for Pro-tecting Ecological and HumanHealth? An ultimate question iswhether the approaches that haveevolved over the last half century forregulating chemicals will be sustain-able. The challenge increases as ana-lytical chemists and toxicologists con-tinue to redefine and expand the scopeof concern by discovering more poten-

tial chemical stressors, at lower andlower concentrations. Add this to thework of synthetic chemists designingnew chemicals with abilities to impartnew types of biological effects, some-times at exquisitely low concentrations.The approaches used worldwide allrely on assessing hazard on a chemi-cal-by-chemical basis (through various“listing” processes). Some recentprogress has been made toward con-sidering “cumulative” and “aggregate”regulation of certain groups or classesof chemicals. Examples of such a groupare those that share a well-definedmechanism of action, or to which weare exposed from multiple routes ororigins, including the cholinesterase in-hibiting organophosphorus and car-bamate pesticides.

To illustrate the substantial (and per-haps insurmountable) challenges to thesustainability of a chemical-by-chemi-cal approach for regulating the occur-rence of pollutants in the environment,consider the particularly diverse spec-trum of ubiquitous pollutants that origi-nate from the daily activities and ac-tions of countless individuals—thePPCPs. There are myriads of other an-thropogenic chemicals whose occur-rence in the environment originatesfrom the behavior and activities of con-sumers. Using PPCPs as an example,as of August 2005, more than 140,000bioactive compounds were in variousphases of drug research and develop-ment (Prous Science, 2005). The rapidevolution of the “omics” revolutionundoubtedly will feed an expansion ofnew drug entities that already has beenunderway (Daughton, 2003a). Newdrug entities, many with mechanismsof action never before encountered bybiological systems, can be expected toenjoy continued introduction to com-merce. All will have the potential toenter the environment merely as a re-sult of their daily use (e.g., introduc-tion to surface and ground waters viaexcretion, bathing, or disposal to sew-age systems).


By following a road mapped out bya chemical-by-chemical approach, dowe risk going in the wrong directionor heading for a dead end? Will target-lists (or menus) of pollutants blind usto more important pollutants, includ-ing truly emerging pollutants? Targetchemical menus can never be suffi-ciently large to satisfy our appetite tominimize potential risk. By restrictingourselves to a single slice from the riskpie, are we getting the best toxicologi-cal value for our investment of re-sources in environmental monitoring?

Ubiquity and Ubiety: EverythingCan Be Found Everywhere. One mightsurmise that the number of chemicalsthat can be found in any environmen-tal sample increases as the detectionlimits achievable by chemists are re-duced. Perhaps exponentially moretypes of chemicals occur at incremen-tally (or exponentially) lower concen-trations. Those chemicals with distinctchemical structures that are detected(or are detectable) compose the minor-ity of the total number of uniquechemicals present in any sample. Inother words, most of a sample’s iden-tified contaminant molecules are asso-ciated with a minor part of the overallchemical diversity of a sample—themajority of the molecules in a samplebelong to a minority of the uniquestructures present. On the other hand,the majority of the unique chemicalstructures present (i.e., the highest di-versity of chemical types) comprise aminority of the total molecules present.The realm of chemical unknowns in-creases at lower concentrations (Fig-ure 1) because modern analytical tech-nology cannot yet identify these count-less chemicals.

At a certain range of infinitesimallylow concentrations, we may be ap-proaching the off-the-cuff truism: “Ev-erything can be found everywhere.”With this concept of chemical diaspora,the notion of “pristine” is relative.What then when molecules of vastlydifferent types of chemicals can be

found in just about any type of sample?What challenges will be faced by riskcommunicators, toxicologists, and riskassessors. Will the way in which riskis perceived be altered dramatically,will chemical exposure be more ac-cepted as a fact of life, or will risk per-ception become a major obstacle forour increasingly technological world?

Alternative PerspectivesRegarding Chemical Pollution

Persistence, Bioaccumulation, Tox-icity—the Only Talents for HazardousChemical Celebrities? Over the years,a consensus view has emerged of threefactors that purportedly dictate thehighest propensity for adverse effectsfrom exposure to chemical stressors.Such stressors need to: (1) possessstructural stability (which imparts en-vironmental persistence from longhalf-lives); (2) be lipophilic andthereby more amenable to passivelycrossing cellular membranes (resulting

in concentration by and accumulationin lipids and fat; bioconcentration thenleading to bioaccumulation via thefood chain); and (3) possess acute orchronic toxicity in their own right.While each of these factors is unques-tionably significant and has contributedto the notoriety of certain pollutants(i.e., the “dirty dozen”), less appreci-

ated is that they are not necessarily re-quired for a chemical to pose risks inthe environment. These three factorsdeserve further consideration with re-spect to their restrictiveness in defin-ing risk.

Reassessing “Persistence”—theWeak Become Stronger. One of thethree hallmarks distinguishing thoseenvironmental pollutants that are thefocus of regulatory actions is environ-mental persistence, which results fromresistance of chemicals to structuralalterations (e.g., the making and break-ing of covalent bonds) by biological orphysicochemical transformation. Ex-

Figure 1: Increasing Chemical Diversity at Lower Concentrations. The realm of chemicalunknowns also expands at lower concentrations.


posure to chemicals that easily aretransformed was thought to be insig-nificant. Possible outliers to this re-quirement, however, are those un-known numbers of pollutants that areconveyed to open waters by sewagetreatment plants and septic systems.The continual release of these pollut-ants gives them a “pseudo-persistence”in any aquatic or marine environment,regardless of their structural instabil-ity. This alternative view was first for-mulated with respect to PPCPs (see p.761 in Daughton, 2003a), many ofwhich can have a continual environ-mental presence, regardless of environ-mental half-life, simply because theirdegradation is offset by constant re-plenishment.

Reassessing Bioaccumulation andToxicity—“Me Too” Chemicals.Bioaccumulation is dictated largely bya chemical’s lipophilicity (fat solubil-ity). Many pollutants, once ingested,rely on passive transport across the gutwall or across the dermis, facilitatedby lipid solubility. Lipophilic chemi-cals gain access to intracellular do-mains by passive diffusion within cel-lular lipids. This process serves to con-tinually extract trace residues of thesechemicals from the environment untilsignificant levels have bioconcentrated.Subsequent consumption of this con-taminated tissue by organisms in highertrophic levels of the food chain servesto further concentrate these chemicals,leading to biomagnification. This is theclassic way in which ubiquitous pol-lutants such as the organohalogens gainsignificant presence in biological tis-sues and disperse worldwide. It also iswhy seemingly insignificant, minutelevels of these pollutants in the ambi-ent environment can be important toregulate. Less recognized, however, isthat certain hydrophilic chemicals(those that readily dissolve in water)also have the potential to bio-concentrate. Some of these chemicalscan be transported actively via cellu-lar systems whose purpose it is to ac-

tively carry (transport) chemicallysimilar endogenous chemicals impor-tant to the cell’s function. Others cangain indiscriminate, promiscuous intra-cellular access in the absence of highlipid-water partition coefficients byother mechanisms. Some examples ofthese mechanisms are provided below.

One example of an alternative routefor bioaccumulation is illustrated bycertain drugs that are transported ac-tively, including ones that are hydro-philic. In fact, one of the current strat-egies under investigation for improveddrug delivery is the design of drugs thatcapitalize on active transport (seeDaughton, 2003a). This property couldallow such chemicals, as water-solublepollutants, to bioconcentrate, seem-ingly in defiance of predictions basedon lipophilicity. A second example in-volves the small, subcellular scale ofnanoparticles, which can facilitate theirpromiscuous entry to intracellular do-mains, thereby circumventing cellulardefenses. The size and conformationof these materials alone (rather thantheir actual chemical composition)holds the potential to adversely affectbiological systems, such as via surface-mediated effects (e.g., sorption andcatalysis) or the ability to evade hostdefenses by freely penetrating or per-meating cellular membranes. Certainnanoparticles may have the potentialto indiscriminately concentrate withintheir porosities or on their surfaces awide spectrum of chemicals andthereby serve as Trojan horses for fer-rying their chemical hitchhikers acrossbiological membranes (facilitatedtransport), irrespective of cellular de-fensive barriers such as efflux pumps(cellular “bilge pumps”). Indeed, thisability is being pursued in the designof more effective approaches to drugdelivery. Moreover, simply the sorptionof endogenous proteins to nano-particles within an organism couldtheoretically elicit an immune responseas a result of altering the native con-formation of the exposed protein. Dis-

cussions regarding the possible envi-ronmental ramifications of nano-materials are just emerging (e.g.,CBEN, 2005).

Hazards from “Non-toxic” Chemi-cals. Although generally recognizedthat any chemical can pose a risk whenexposure occurs at a sufficiently highdose (“the dose makes the poison,”Paracelsus), certain chemicals poserisks even when exposure is at levelswhere overt effects cannot be measuredfrom exposure to the chemical in iso-lation from other toxicants. These “in-direct” chemical stressors possess noinherent toxicity of their own at benignexposure levels but they can potenti-ate or amplify the toxicity of otherchemical stressors. An example of thisphenomenon involves the cellularefflux pump systems, which are evo-lutionary conserved across taxa andwhich particularly are important foraquatic organisms as a defensivemechanism against toxicant exposure.These systems also are called multi-xenobiotic transporters, and confer re-sistance for the organism to a wide ar-ray of ordinarily toxic substances(Daughton, 2001). These efflux pumpsystems serve to physically removexenobiotics that gain entry to a cell, aswell as waste products generated dur-ing normal metabolism. They roughlyare analogous to bilge pumps on ships.By preventing sufficient exposure,efflux systems allow an organism tomaintain its homeostasis in an environ-ment surrounded by pollutants thatmight otherwise prove toxic. A widenumber of chemicals, however, havethe ability to inhibit these efflux en-zyme systems (the best known ex-amples are certain drugs), thereby al-lowing access to the cell by any extra-cellular toxicants that previously hadbeen excluded by the pumps. Toxicitytesting currently has no way to accountfor these so-called “non-toxic hazards.”

Another example of indirect toxi-cants includes certain manufacturednanoparticles. These substances can


have extraordinarily large surface-to-size ratios. Even if not possessing tox-icity of their own, their surface areasnonetheless possess high potential forcatalyzing reactions involving otherchemicals. This single characteristic ofthe nanoscale imparts nanomaterialswith properties that differ dramaticallyfrom those of their “macro” counter-parts made from the exact same el-emental constituents. Whether theproducts of these catalyzed reactionsare toxic themselves, damaging freeradicals (oxidized chemicals with un-paired electrons) frequently are pro-duced as by-products. Nanoparticles,in this sense, are examples of indirecttoxicants, where exposure to the par-ent chemical alone is insufficient foradverse effects.

Living Systems Not Just Victims, butAlso Creators, Perpetuators, and Vec-tors of Pollutants. Nearly all organ-isms, ranging from microorganisms,plants, and wildlife to humans, activelyand passively are involved in exposureto xenobiotics. While exposure holdsthe potential to elicit adverse conse-quences, these same organisms also cancreate chemicals that serve as stressorsfor others, either purposefully (e.g.,natural products biosynthesized forestablishing allelopathy—chemicalwarfare between plants) or inadvert-ently (e.g., methylation of mercury).Less appreciated, however, is that or-ganisms also can serve as vectors fordistributing pollutants worldwide. So-called “biotransport” of lipid-solublepollutants by migrating wildlife canoccur, for example, via bird droppings(Blais et al., 2005).

Not Everything That Can Be Mea-sured Is Worth Measuring, and NotEverything Worth Measuring Is Mea-surable—Chemicals in Hiding. Thedata collected from water monitoringcan be biased in two ways: i) limita-tions in the actual analytical protocolor the measurement technology, and ii)a consequence of ignoring large classesof potential chemical stressors as a re-

sult of the exigency to focus on lists ofpreselected analytes (“target-based”analysis). The use of water monitoringdata based on “free” (dissolved) con-centrations to predict total environmen-tal loads of a particular pollutant hasthe potential to yield misleading val-ues that are biased low (perhaps evenby orders of magnitude). This is trueparticularly for those pollutants thatreside in alternative physicochemicalforms that serve as hidden reservoirs,

such as excreted metabolic conjugates(which can be reconverted back to theirparent forms) and residues tied up asligands or reversible precipitates orsorbed to suspended particulates orsediments. In reality, a multitude ofchemicals can be overlooked, ignored,or omitted by environmental monitor-ing for any number of reasons.

Maybe Gone but Not Forgotten. Itis not just the original (“parent”)chemical that may play a significantrole in the environment. Often of sig-nificance are the transformation prod-ucts that result from its metabolism

(animal, plant, and microbial) and theproducts from abiotic processes suchas sunlight and chemical-mediated re-actions. Some parent chemicals canyield a multitude of so-called “break-down” products or “degradates.” Justbecause the original “parent” chemi-cal might be gone, does not mean thatits presence is no longer felt. Naturalmetabolism and engineered wastetreatment processes can create aplethora of transformation products,many of which can have bioactivity oftheir own, sometimes greater than thatof the parent chemical. Carbamaze-pine, for example, is an anticonvulsantdrug that occurs frequently in openwaters (from treated sewage), but itsmetabolism yields a host of productsthat also can occur (Miao and Metcalfe,2003). These types of transformedchemicals usually remain hidden fromall probing except by the curious ana-lytical chemist.

With respect to obtaining a holisticview of risk, target-based environmen-tal monitoring necessarily yields a dis-torted, filtered view of environmentaloccurrence by purposefully and inad-vertently neglecting an unknown (andperhaps substantial) portion of uniden-tified constituents (see Daughton,2003a). In the final analysis, consider-ation should be given to a quip, adaptedfrom a purported Einstein quotation,“Not everything that can be measuredis worth measuring, and not everythingworth measuring is measurable”(Daughton, 2003a).

Interfaces and Microenviron-ments—Where the Action Is. We tendto examine the obvious places, such asopen bodies of water, for pollutants andhow they behave in the environment.Nevertheless, the less obvious nichesalso can prove significant. As one ex-ample, interfaces and their associatedheterogeneous microenvironments atthe junctures of dissimilar phases canact as cauldrons for complex interac-tions and transformation of water pol-lutants. Interfacial phenomena are in-

Rarely is any organismexposed to but a single

chemical stressorat any time, in isolation

from all others.Development of a

real-worldunderstanding ofexposure involves

organisms continuallyinteracting with

mixtures of multiple ormultitudes of stressors.


sufficiently understood with respect tothe removal or storage of xenobioticsas well as the creation of new pollut-ants. Complex and poorly understoodinterface processes pose numerousquestions. As an example, consider thelow levels of dissolved antibiotics inenvironmental waters. Levels moni-tored in the dissolved aqueous environ-ment, which usually are orders of mag-nitude below those required to selectfor antibiotic resistance, may be irrel-evant if interface phenomena can serveto bring together much higher concen-trations at solid surfaces where biofilmsdevelop. Could microenvironments andniches (such as interfaces occupied bybiofilms) serve to maximize exposureconcentrations as well as resistance-gene selection and horizontal genetransfer (the movement of genes fromone organism to another)? Upstreamsewage trunk lines are one example andbiosolids (e.g., treated sewage sludgedisposed to land) are another where thiscould occur (Daughton, 2002). Thewater-air interface, where monomo-lecular films of lipophilic and amphi-philic pollutants (also called amphi-pathic or amphiphatic; containingstructural features that are attracted toboth lipid and water) can concentrate,add yet further complexity and a hostof other questions.

Reassessing Exposureand Chemical Diaspora

Holistic Exposure Assessment. Theexposure environment to which envi-ronmental toxicologists traditionallyhave focused their attention is limitedto the “conventional” pollutants thatcompose the various lists of regulatedpollutants. Many of these are the “highproduction volume” industrial chemi-cals (and manufacturing by-products)and those substances specifically de-signed to kill pests. It is important tonote, however, that these chemicalscomprise but a very small portion ofthe numbers of distinct xenobiotics

from the universe to which organismscan and do experience exposure. As wehave seen, the chemicals composingthese high-profile categories are notrepresentative of the full spectrum ofknown chemical stressors or the mul-titudes of transformation products. Themultifactorial complexity faced by riskassessment includes the exposure fre-quency and timing, exposure duration,exposure complexity or “totality” (cu-mulative and aggregate exposure, syn-ergism, and other multiple-stressor in-teractions), prior exposure history (thefoundation for determining exposure“trajectory”), or other factors includ-ing delayed-onset toxicity or cross-gen-erational effects. Given these limita-tions, it is important that progress bemade toward more holistic assessmentsthat account for the wide range of po-tential environmental pollutants and topinpoint those pollutant scenarios withhighest health-effects potential.

The 4Ts and Homeostasis—the Poi-son Is Made by More Than Just ItsDose. Rarely is any organism exposedto but a single chemical stressor at anytime, in isolation from all others. De-velopment of a real-world understand-ing of exposure involves organismscontinually interacting with mixturesof multiple or multitudes of stressors,the composition of which continuallycan vary through time in terms of thespecific chemical constituents and theirabsolute and relative concentrations. Afurther complication is that stressors formany organisms include not justchemicals (the subject of this article),but also physical (e.g., thermal), psy-chological (e.g., fear), and biological(e.g., pathogenic) agents. All of thesestressors can interact in complex, un-foreseen ways, sometimes greatlysynergizing each other. The chemicalsea to which an organism is exposedwashes against critical windows of vul-nerability (e.g., developmental stagesor diurnal physiological phases). Thepoison is made not just with the dose,but also with its duration and timing.

Longer exposure durations can drivedown the dose needed for the same ef-fects. Completely different types ofbiological effects can occur at differ-ent exposure concentrations. Such amultitude of variables and possible in-teractions poses complex challengesfor predicting the trajectory of expo-sure outcomes for an organism. Thesefactors are part of the overall consid-eration of the “4Ts” of exposure, ashorthand term that captures the com-plete context of an organism’s cumu-lative exposure to chemical stressors.The “4Ts” describe “toxicant totalitytolerance trajectory” and account foran organism’s complete exposure timeline (a trajectory traced in part by priormultidimensional exposure history)and the fact that a major objective ofall organisms is to maintain homeosta-sis in the face of continual perturba-tion by stressors. Homeostasis can bemaintained only within the tolerancebounds for the organism’s regulatoryand biochemical defensive repertoire.Therefore, the paradigm of the 4Ts setsthe stage for the overall true risk asreflected by the sum total of exposureto all toxicants (anthropogenic andnaturally occurring) throughout the his-torical multidimensional space and tra-jectory of all other exposure variables.A key aspect to this concept is the criti-cal state as determined by the 4Ts—that state at which an additional singleexposure event can result in an irrevers-ible adverse effect, one that pushes theorganism beyond its ability to main-tain homeostasis. A cartoon illustrationof the 4Ts is shown in Figure 2 (page16), with more information available(Daughton, comp.). Potency, dose, tim-ing, duration, and numerous other vari-ables all must be known to fully assessrisk. Any single one of these param-eters is insufficient.

Stressor Interactions ConfoundingAnticipated Toxicity. As one of manyexamples of the importance of the 4Ts,the complexity surrounding the numer-ous factors involved with exposure, and



the unanticipated ways in which evenvastly dissimilar stressors can interact,consider two recent examples dealingwith amphibians, which have been un-dergoing worldwide population de-clines. The first reports the greatly en-hanced toxicity of the carbamate pes-ticide, carbaryl, toward amphibianswhen experiencing predatory stress.Carbaryl concentrations from short-term acute exposure that ordinarilywould not adversely affect growth orsurvival can prove lethal when the ex-posure period is increased or when theexposure occurs in the presence ofpredatory stress (Relyea, 2003). Theend effect is as if the concentration ofthe chemical stressor were magnifiedmany fold by the increased exposuretime or by the non-chemical stressor(in this case, a predator cue). The sec-ond reports the greatly enhanced stres-sor action of normally benign con-centrations (the levels of toxicantsoften occurring in the environment) ofthe fungicide fenpropimorph to tad-poles when they are developing in thepresence of a predator (Teplitsky et al.,2005). The combined action of a preda-tory stress cue (such as merely sensingthe presence of a predator) and the low-level fungicide resulted in delayed andsmaller maturation that could adverselyimpact the fitness of the population. Amultitude of non-chemical factors pro-foundly can affect the outcome of ex-posure to chemical stressors. With hu-mans, for example, interactive expo-sure to certain chemicals together withnoise can synergistically degrade hear-ing (ototoxicity; e.g., see Fechter andPouyatos 2005). Interactions amongdisparate stressor groups, as opposedto effects mediated solely by one groupsuch as chemicals, is an under-investi-gated area of research. Interactionsbetween stressors can be extraordinar-ily complex and lead to completelyunanticipated outcomes. Because ofthe complexity, rarely can these fac-tors be accounted for in conventionalecotoxicity testing protocols relied

upon by regulatory assessments andwhich usually focus on acute toxicityand on one stressor at a time.

Epidemiology and Post Hoc ErgoPropter Hoc—It’s All in the Timing.A natural consequence of developinga systems-level understanding of expo-sure and effects would be the minimi-zation of confusion resulting from in-ferring causal relationships betweenobserved adverse effects and exposureto particular chemical stressors thathappen to co-occur with the effect.Correlating exposure (to particularchemical stressors) with an observedeffect can result in concluding that anexposure causes an effect simply be-cause of a temporal connection—“af-ter this, therefore because of this” (posthoc ergo propter hoc). Conclusions re-garding causality must take into con-sideration the 4Ts rather than just co-incidental connections. Formulatingactual cause-effect relationships can bea very complex, long-term undertak-ing (e.g., DDT and eggshell thinning).

Subtle Shifts Leading to OvertChange—A New Paradigm? Acutetoxicity, carcinogenesis, teratogenicity,and direct endocrine disruption are sev-eral of the highly visible toxicologicalendpoints that historically have at-tracted the most concern. The hypoth-esis has been raised, however, involv-ing the significance of less overt toxi-cological endpoints, such as immuno-disruption, neurobehavioral change,protein misfolding diseases, and othersubtle effects (Daughton and Ternes,1999). Could immediate biologicalactions on non-target species be imper-ceptible but nonetheless lead to adverseimpacts as a result of continual accre-tion over long periods? Could subtleeffects accumulate so slowly (perhapsseeming to be part of natural variation)that major outward change cannot beascribed to the original cause? Couldlatent damage accumulate, only surfac-ing later in life? Effects that are suffi-ciently subtle that they are undetect-able or unnoticed present a challenge

to risk assessment. These types of ef-fects include very subtle shifts in be-havior or intelligence that pass throughgenerations. On the other side of thecoin are questions regarding what con-stitutes the norm. For example, caremust be exercised in determining ifmalformations and sex trait character-istics commonly observed in aquaticorganisms are “abnormal” (possiblyresulting from chemical stressors) orwhether they are simply part of a natu-ral and normal distribution amongpopulations.

“What Is Normal? What Is Natu-ral?” In the context of post hoc ergopropter hoc, a major phenomenon thatleads to the conclusion that chemicalpollutants lead to adverse environmen-tal effects is the extent, frequency, andprevalence of seemingly abnormalcharacteristics in aquatic organisms,such as skewed sex ratios and devel-opmental “malformations.” These “ab-normalities,” for example, frequentlyare cited as evidence of exposure toendocrine modulators (e.g., the syn-thetic estrogen, ethynylestradiol, intreated sewage). It is critical to con-sider, however, that the baseline occur-rence of these characteristics in pris-tine “wild” populations often is un-known and therefore causalities cannotjustifiably be inferred.

Exactly Where, How, and When WeSearch Dictates What We’ll Find.Analogous to the problems with target-analysis, it is hard to find causes forwhich we are not looking. It can beequally hard to observe effects notlooked for, especially subtle ones. Thisproblem is evident particularly whenconsidering the overlooked ability ofcertain toxicants to elicit adverse out-comes far after exposure has ceased andthereby escape the formulation ofcausal connections. Such delayed-on-set toxicity almost never is consideredin epidemiological studies simply be-cause of the daunting challenge, forexample with cancer clusters. Irrevers-ible delayed-onset toxicity can mani-


fest itself weeks, months, or years afterexposure in the form of carcinogenic-ity (aflatoxins, asbestos), teratogenicity(e.g., thalidomide), hepatotoxicity(e.g., pyrrolizidine alkaloids), or neu-rotoxicity (e.g., organophosphorusnerve agents). Such prolonged latencybetween exposure and onset of effectsnot only makes establishment of cau-sality extremely difficult, it can leadto formulation of erroneous associa-tions with chemical stressors that byhappenstance are present during theonset of the symptoms. Delayed-onsettoxicants also could play major rolesin acts of sabotage.

Beyond the DNA-RNA-ProteinDogma—Inherited Effects WithoutGenetic Change. Beyond the centraldogma of DNA governing the pheno-type of an organism (via translation toRNA and transcription of RNA to pro-tein), an aspect that steadily has beenattracting more attention is “epi-genetics,” which comprises a numberof processes that regulate trans-generational effects. These heritablechanges in gene function can be passedacross multiple generations withoutany alteration to the genetic code. Thisis accomplished by activation or inac-tivation of genes by chemical modifi-cation of chromatin by processes suchas methylation of the DNA (e.g., theso-called, non-RNA-coding “junk”DNA), acetylation of the proteinaceoushistones, and RNA interference. Theseprocesses can be modulated or inter-fered with by various xenobiotics. Arecent example of the relevance ofepigenetics to environmental exposureis the work of Anway et al. (2005), whoreported that exposure of pregnant ratsto the pesticides methoxychlor orvinclozolin led to male offspring withreduced fertility. This heritable changewas passed through four generationsafter the original exposure to themother.

“No-Observed-Effect Level”—YouGet What You Want, Not NecessarilyWhat You Need. A standard measure

in toxicology is the NOEL (No-Ob-served-Effect Level) and its variants,such as the NOAEL (no-observed-adverse-effect level). The NOEL is astressor’s maximum dose that fails toelicit a detectable change under definedconditions of exposure. The NOEL isused in calculating other widely usedtoxicity measures, such as the “acute/chronic ratio” (ACR; where chemicalshaving significant chronic toxicity, asmeasured by the lower levels impart-ing effects, compared with acute tox-icity, have higher ratios). The NOEL,however, can easily mislead as it onlycan be calculated for known effectsendpoints that are pre-determined. Ef-fects endpoints that we are not awareof or that are so subtle they elude de-tection can possibly lower NOEL val-ues. In reality, the lowest NOEL can-not be determined until all the salienttoxicological endpoints are understood.

The Alchemy of Somethin’ fromNothin’—When a Little Might Be aLot, or When Less Is More. There aregrowing questions regarding the per-vasiveness, significance, and ramifica-tions of exposure to “low” levels ofchemical stressors (so-called “micro-pollutants”). There are many unknownsand controversies regarding such ex-posures. Of course, “low” is a relativeterm, one usually deriving its meaningas being “lower” than previously stud-ied or documented. For analyticalchemists today (and sometimes toxi-cologists), “low” often refers to con-centrations at or below the parts-per-billion or nanomolar ranges. Theseconcentrations are orders of magnitudebelow those that could be studied justtwo decades ago. There are also ques-tions, however, regarding the innatetoxicity of a chemical (e.g., under labo-ratory conditions) versus its ability orpotential to actually elicit toxicity inthe real world. Regardless, certainchemicals (e.g., ethynylestradiol) dohave the ability to impart effects atconcentrations of one part-per-trillion

and lower. Effects even can occur atconcentrations well below NOELs.

As advances in treatment technologycontinually lower the concentrations ofchemical residues in treated waters,and as analytical chemists reduce thedetectable levels further, the toxico-logical significance of ultra-low-doseexposure needs to be better understood.Concern is heightened for those organ-isms (such as in aquatic environments)that suffer continual, multigenerationalexposure to complex mixtures of low-level toxicants. The toxicology of mostxenobiotics is poorly understood at lowlevels. Particularly needed is to eluci-date the significance of low-level ef-fects in the range where so-called“paradoxical” dose responses areprevalent, where the non-conventionalU- or J-shaped nature of dose-responsecurves becomes evident. An exampleis hormesis (e.g., see BELLE, 2004),a dose-response phenomenon wherenoninhibitory effects occur below pre-viously established NOELs. Despitehormesis being proposed as a justifi-cation for permitting or justifying low-dose exposures (e.g., because one ofits common outcomes is growth stimu-lation), it is important to rememberthat: (i) any effect (regardless of itsanthropocentric interpretation) thatperturbs homeostasis has the potentialto ultimately result in an adverse out-come and (ii) real-life exposures areto multiple stressors, some of whichcan share the same mechanism (ormode) of action, thereby effectivelyhaving a combined concentrationhigher than the hormetic level for asingle stressor in isolation from all oth-ers. These limitations, and others, havenow been formally articulated byThayer et. al. (2005).

Symptoms from Nowhere—theNocebo. An additional way in whicheffects can manifest from human ex-posure to seemingly minuscule concen-trations of pollutants is via the so-called nocebo response (Daughton,2004). The nocebo effect (the opposite


of the placebo effect) is a real, physi-ologically adverse outcome causedsimply by the suggestion or belief thatsomething (such as a chemical) isharmful, regardless of any inherent tox-icity. The nocebo effect could play akey role in the manifestation of adversehealth consequences from exposureeven to non-toxic trace levels of con-taminants—simply by the power ofsuggestion. Public education and a bet-ter understanding of how risk is per-ceived and how it best be communi-cated are important particularly forminimizing the incidence of the so-called nocebo response.

Same Chemicals, Different Out-comes. The nocebo effect presents afascinating juxtaposition against theadage “familiarity breeds boredom.”The way in which risk is perceived canlead to ironic and even contradictoryoutcomes, pointing to a need for ma-jor improvement in the way risk is com-municated. One paradox in risk percep-tion relates to the relatively high con-centrations and types of a plethora ofchemicals formulated in personal careproducts that are applied directly to theskin or in the mouth, versus the con-centrations of some of these very samechemicals that might be found in drink-ing water but at many orders of mag-nitude lower concentrations than incommercial products. The high con-centrations of various chemicals inpersonal care products routinely aredeemed by the user to be risk-free butnot the very same chemicals, in minuteconcentrations, in drinking water.

Another example involves the occur-rence of minuscule traces of drugs incertain drinking waters, which can fos-ter the formation of negative mentaland emotional images for the con-sumer, regardless of the water’s over-all purity, as a result of the fact thatthe origin of these drugs often derivessolely from human excretion(Daughton, 2004). A better understand-ing is needed of the origins of thechasm existing between the communi-

cation of actual hazard/risk and howthe risk actually is perceived. This willprove especially important with thegrowing need to reuse water or to re-cycle it for drinking.

A Special Concern Regarding Low-Dose Effects—TILT. One specific is-sue regarding low-level human expo-sure specifically concerns toxic effectsfrom exposures that on prior occasionsproved benign. Controversy surroundsthe significance of exposure to minutequantities of xenobiotics, whether fromfood, drink, skin, or air. Exposure by

special subpopulations or during criti-cal windows of vulnerability (e.g., fe-tal development) has been reported (butnot without controversy) to lead totoxicant-induced loss of tolerance(TILT) (or “multiple chemical sensi-tivity”) (Winder, 2002). In TILT, aninitial exposure (perhaps to a largerquantity) purportedly promotes hyper-sensitivity. Subsequent exposures tolevels far below those previously tol-erated then trigger symptoms. An ob-vious question is whether an ecologi-cal version of TILT exists, where ef-fects levels can be driven downward byprior exposure—where NOELs be-

come dynamic thresholds that are afunction of prior exposure history.

Like-Minded Chemicals of SimilarPersuasions—Too Much of Nothin.’Another way in which a little can meana lot can be illustrated simply by thescenario of simultaneous exposure tomultiple chemicals at low concentra-tions. A special case where low con-centrations of chemicals could provesignificant is by exposure to multiplestressors, each perhaps at a concentra-tion below which an effect could oc-cur, but which share the same mecha-nism or mode of action. The overall,combined concentrations of all thosechemicals with the same mechanismsof action could very well exceed a tox-icity threshold. This poses very diffi-cult regulatory challenges, whetherthese like-mechanism chemicals origi-nate from the same industry or fromdifferent industries. Traditional toxic-ity testing could show that no singlechemical may have any effect at thelevel it occurs in the environment. Inthis way, risk could be consistentlyunderestimated. As the numbers of dif-ferent types of chemicals increases inthe environment, the potential for thisscenario increases.

Merging onto a “Toxicity Appor-tionment” Regulatory Freeway fromthe Dead-end Chemical-by-ChemicalRoad? The continual introduction ofnew chemicals to commerce castsdoubts as to whether a chemical-by-chemical approach to regulation ofwater pollutants will continue to besustainable on a comprehensive scien-tific footing (Daughton, 2003a;Daughton and Ternes, 1999). Manyemerging pollutants, such as PPCPs,have totally new mechanisms of action(MOAs), most have multiple MOAs,and the actual MOAs rarely are evenunderstood fully. With respect to the“exposure universe,” and in a manneranalogous to source apportionment,consideration could be devoted to de-veloping the capability of “toxicityapportionment.” The objective would

New sources ofpollutants includenot just chemicals

newly introduced tocommerce but also

new ways to produceand use them,

which in turn createnew opportunitiesfor their entry intothe environment.


be to assign toxicity an integrativemeasure of the total numbers and quan-tities of stressors present, without theneed to know their actual identities inadvance. The ultimate objective wouldbe to close the exposure envelopearound all chemical-exposure constitu-ents—both naturally occurring andanthropogenic. This alternative ap-proach could consider basing watermonitoring programs on assays de-signed around evolutionarily conservedbiochemical features and MOAs ratherthan on individual chemical entities.The ultimate question is whether theinitial target of regulation might be thepotential for actual biological effectsinstead of chemicals themselves. Thisapproach could be a better way to au-tomatically account for a multitude ofstressors sharing a common MOA (cu-mulative exposure), stressors newlyintroduced to commerce, and pollut-ants not yet identified.

Environmental Stewardship versusPollution Postponement, PollutantMusical Chairs, and Pollutant Al-chemy. Since purposeful, direct dis-charge of chemicals to the environmentis inherently undesirable, many waysto reduce these emissions have beendeveloped. These include numerousphysical removal technologies (rang-ing from simple filtration and sedimen-tation to reverse osmosis for wastewa-ters), volume reduction (e.g., evapora-tion), or storage (e.g., landfills). All ofthese physical approaches essentiallyeliminate discharge today in exchangefor risking potential discharge at a laterdate (“pollution postponement”). Theysimply transfer pollutants from oneplace to another, delaying the way andtime by which they can gain entry tothe environment. Even destructive pro-cesses (e.g., oxidation and combustion,including incineration) sometimesserve to transform existing pollutantsinto new chemicals (“pollutant al-chemy”), a form of pollutant musicalchairs. The most significant demarca-tion among classes of chemicals that

pollute the environment is that betweeninorganic and organic chemicals. Incontrast to the latter (even for DDT,halogenated dioxins/furans, PCBs),which have limited life expectancies,the former often have indefinite lifeexpectancies (e.g., elemental lead) orsimply transform into related speciesuntil they are “recycled” in the envi-ronment back to the parent forms (e.g.,various forms of mercury and arsenic).Although pollution postponement andpollutant alchemy might sometimes bethe best way to delay the entry of thesechemicals to the environment, pollu-tion prevention and pollution minimi-zation are preferred. For perspective,extensive examples of stewardship ap-proaches for minimizing the entry ofPPCPs to the environment have beenproposed (Daughton 2003a,b).

Peeking at the Future

While it is not possible to predict thefuture regarding the many dimensionsof chemical pollution, several concernsand opportunities, just now emerging,might be useful to consider.

Early Warning—Monitoring forEmerging Contaminants and Home-land Security. New sources of pollut-ants include not just chemicals newlyintroduced to commerce but also newways to produce and use them, whichin turn create new opportunities fortheir entry into the environment.Several examples include: (i) commer-cial introduction of new drugs (in-cluding potent illicit designer drugs)with MOAs never before encounteredby biological systems, (ii) transgenicproduction of therapeutants and vac-cines by genetically altered plants(especially edible crops), also knownas plant-made pharmaceuticals(PMPs), by “molecular farming” or“biopharming,” (iii) newly inventednanomaterials and their ill-definedproducts that could result from naturalweathering processes, (iv) the adventof micro-process technology, where

microreactors will eventually provecapable of widespread and dispersedproduction (on an individually smallscale but on a continual basis) of ex-otic and highly hazardous chemicalswith little knowledge or interventionby technical experts, and (v) acceler-ated access to exotic chemicals by con-sumers, resulting in myriads of pointsources for environmental contamina-tion as a result of the combined contri-butions from personal actions, activi-ties, and behaviors, as well as the needfor disposing of leftover and unwantedmaterials. With regard to the last point,the quality of source drinking watersdepends in part on the diffuse impactsof the collective activities of multitudesof individuals—from each of whomminuscule (and seemingly insignifi-cant) contributions combine to yielddetectable levels of certain pollutantsthat otherwise have little origin fromindustrial activities. In addition to thesesources are the unknowns associatedwith sabotage of our environment withexotic chemicals (including those de-signed for military use) by terrorists.

Given the potential for new pollut-ants to enter the environment, it wouldbe most useful to know about theirpresence as soon as possible. An ulti-mate objective of any program de-signed to deal with emerging pollut-ants should be to create a mechanismfor identifying their presence in theenvironment as early as possible—wellbefore becoming pervasive. A mecha-nism for the real-time detection of newpollutants in water is important, not justfor protecting the environment andpublic health from the effects of inad-vertent pollution. It also would help inprotecting water supplies from chemi-cal sabotage, a concern for homelandsecurity. The sheer number of poten-tial new contaminants clearly wouldpose insurmountable obstacles for con-ventional target-based monitoring ap-proaches. A straightforward way tosidestep this limitation would be todesign an early warning system around


the simple approach of detecting com-positional “change”—where any per-turbation in a sample’s normal chemi-cal “fingerprint” (distribution patternof types and quantities of solutes)would trigger an immediate in-depthchemical analysis to determine thecause (identify the chemicals respon-sible for the change). Such an approachcircumvents the many inherent limita-tions of target-based monitoring. Thetimely elucidation of newly emerging(or previously unrecognized) pollutantsalso is critical to uncovering trends ingeographic pollutant distribution,prevalence, and loads. Having availablelong-term change-detection data couldgreatly assist epidemiological studies,especially those involving cancer clus-ters, which long have been a bane oftoxicologists. Another approach is toleverage the involvement of amateurobservers to report unusual phenomenain nature that possibly are the result ofchemical stressors; one such proposalwas noted by the Royal Commissionon Environmental Pollution (2003).

Inadequate and Decaying Water In-frastructure. In the absence of effec-tive proactive pollution preventionschemes, reactive pollution control isrequired. Domestic wastewaters are amajor emerging source of pollution(from the combined activities of mul-titudes of individuals). Conventionalmunicipal sewage treatment facilitiesnever were designed to remove exoticanthropogenic chemicals with struc-tures and mechanisms of biologicalaction that are foreign to biologicaldegradative/transformation systems.Indeed, the ubiquitous, albeit low level,presence of PPCPs in treated sewageeffluent reflects this limitation. Evenif existing waste treatment and watertreatment facilities functioned accord-ing to original specifications, the typesand quantities of xenobiotics in treatedwater could continue to rise, partly asa result of the introduction of newchemicals to the marketplace andpartly because the nation’s water in-

frastructure requires considerable in-vestment for repair and upgrading. Anadditional infrastructure need is to re-duce the occurrence of unpermittedstraight-piping, septic systems, andprivies, which serve to maximize therelease of xenobiotics to the environ-ment (to both surface waters andgroundwaters) via raw sewage.

Toward a Holistic Solution. Thegrowing number and sources of chemi-cals with the potential to enter the en-vironment via wastewater is challeng-ing our ability to treat these wastes.Actions to reduce any of the associatedvariables contributing to this vulner-ability would be prudent. The majorvulnerability for humans results fromthe nature of the water cycle, where thehistoric practice of treating domesticwastewaters for discharge to surfacewaters can result in contamination ofsource waters destined for drinking(whether surface or ground). The ma-jor requirement has been the design ofwater systems having sufficient spatialand temporal hydraulic “disconnect” soas to “erase” from the consumer’s mindany memory of the original source ofthe water (Daughton, 2004). The con-tinually diminishing supplies of high-quality freshwater, however, is increas-ing pressure to actively recycle andreuse waters, even from human waste.This will lead to ever-shortening spa-tial and temporal hydraulic connectiv-ity between the point of wastewaterdischarge and the point of use for drink-ing (the recycle loops will continuallyshrink). The ultimate rendition of thisis the so-called “toilet-to-tap” ap-proach. While this approach has beenvilified by many (primarily as a resultof the way in which risk is perceived),if properly implemented it could solvemany problems faced by areas facingwater shortages.

Decentralized Water Re-Use. Lessthan one percent of all the world’sfreshwater resources are readily acces-sible, representing less than 0.01 per-cent of all the world’s water (see Fig-

ure 1 in Shiklomanov 1999). The grow-ing shortage of freshwater could drivea transition from centralized munici-pal water treatment and distribution totruly distributed water reuse—wherewastewater is both treated and reusedclose to its origin, eventually directlyon site. Such distributed water reusesystems pose unique challenges regard-ing public acceptance and effectivecommunication of risk (see Daughton,2004). However, they also offer fun-damental advantages regarding inde-pendence and the inherent design ad-vantage of ultimate security from large-scale sabotage. Another advantage ofrecycling water generated directly fromthe point of original use (as opposedto collective water from centralizeddomestic, municipal, and industrialgenerators) is that the universe ofmicrocontaminants that need to be re-moved is vastly reduced and the typesand number of chemicals that the con-sumer will discard to sewerage wouldbe reduced as a result of personal in-centive (Daughton, 2004).

“Futuring” and the PrecautionaryPrinciple. The traditional list-based,chemical-by-chemical approach mustwait for emerging pollutants to estab-lish an environmental presence beforeaction can be taken. Regardless of howtimely this approach can become, it isat best a reactive one. The fact thatcorrective reactions can be requiredlong after chemicals achieve environ-mental footholds leads to discussionsof the controversies surrounding theprecautionary principle (see links atDaughton, comp. 2005d). An early ren-dition of the precautionary principle ascodified in law would be the EuropeanCommission’s proposed new EuropeanChemicals Agency and regulatoryframework for chemicals—REACH(Registration, Evaluation and Auth-orisation of Chemicals) (EC, comp.2005). A new paradigm, however,would adopt a proactive approachwhere future concerns are anticipated,long before any preventive or remedi-


ation measures would have major eco-nomic, health or environmental rami-fications. To minimize the emergenceof unanticipated concerns, more re-sources need to be invested in trulyanticipatory research programs and inthe process of “futuring,” which are allrequired for making progress towardsustainability.

An Emerging Societal Realiza-tion—Chemicals as “Weeds.” Just asweeds are plants growing where theyare neither desired, wanted, norneeded, an alternative definition ofpollutants or contaminants is out-of-place chemicals. This is true particu-larly for those chemicals that achieveunexpected footholds in surprisingplaces. Examples include pharmaceu-tical and illicit drug residues in drink-ing water sources (Daughton 2004).Given that the vast majority of chemi-cals or their complex mixtures occur-ring in the environment cannot conclu-sively be linked with adverse ecologi-cal or human health effects, regulatorsare hard-pressed to justify any actions.Despite the canyons of absence of dataand mountains of data of absence, thepublic often is averse to the occurrenceof even trace residues of certain pol-lutants in water, food, or air. The ac-tual concentrations of these contami-nants, regardless of how minuscule,often are irrelevant in society’s “questfor zero.” Missing in the risk commu-nication process is the failure to real-ize that zero often is sought not neces-sarily because of any perceived riskfrom particular exposure levels, butrather simply because these chemicalsdo not belong where they occur. Theyare chemical weeds. Using the weedanalogy might lead to a new paradigmwhere focus could be diverted awayfrom basing regulation on toxicologi-cal hazard and risk (and the associatedmeasures that span numerous magni-tudes of abstruse jargon—from parts-per-million to yocto-molar) and insteadtoward active management of chemi-cals simply as weeds. Perhaps all that

is needed is to implement economicallysustainable measures designed to mini-mize the introduction of all chemicalsto the environment. Of special interestwould be those originating from con-sumer use and which therefore pervadethe environment. Progress is possibleusing a balanced repertoire of compre-hensive pollution prevention andsource reduction measures and wastetreatment technologies, coupled withongoing environmental monitoring togauge whether these measures are ef-fective at maintaining these chemicalweeds at whatever levels society deemsacceptable.

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“Emerging” Chemicals as Pollutants in the Environment: a ... · HPV (high production volume chemicals) quantity (manufactured/imported in U.S. in annual amounts >1 million pounds)