antimicrobial agents are both a boon and 
 threat to human health , 
 with questions about their proper design , useful application , disposal 
 and regulatory framework looming large for scientists , the medical 
 community , regulators and consumers of antiseptic personal care products . in the late 1930s and early 1940s
, it was discovered that the substitution 
 on aromatic rings of hydrogen atoms with chlorine , yielded a novel 
 chemistry of powerful biocides , including antimicrobials .
the resultant synthetic organohalides , which 
 are either absent or rare in natural environments , immediately 
 were put to large volume , worldwide use as biocides . however , within 
 a few years , many of these compounds and formulations showed adverse 
 effects , including human toxicity , ecotoxicity , and unwanted environmental 
 persistence and bioaccumulation , quickly leading to regulatory bans 
 and phase - outs .
for example , hexachlorophene , 
 introduced in 1948 as a binuclear aromatic organohalide carrying six 
 chlorine substituents , was banned from 
 most uses by the 1970s .
curiously , triclocarban ( tcc ) 
 and triclosan ( tcs ) , two persistent antimicrobials first introduced 
 to commerce in 1957 and 1964 , respectively , feature a very similar chemistry ( i.e. , two benzene rings carrying 
 multiple chlorines ) yet continue to be produced and consumed to this 
 day at high volume . indeed , the consumption 
 of tcs and tcc and the abundance of antimicrobial 
 products have increased in the u.s . and abroad over the past two decades , 
 due to relaxed regulation , aggressive and widespread advertising , 
 and media reports driving fears of potent and sometimes lethal microbial 
 infections acquired in everyday - life by unsuspecting victims .
this 
 multibillion dollar market has saturated supermarkets worldwide and 
 vastly accelerated the consumption of antimicrobial products ; today , 
 tcc and more so tcs can be found in soaps , detergents , clothing , carpets , 
 paints , plastics , toys , school supplies , and even in pacifiers , with 
 over 2000 antimicrobial products available in 2014s $ 1.4 billion 
 u.s .
despite labeling requirements , 
 consumer awareness of harmful active ingredients in household products 
 remains low .
by contrast , tcc sees far 
 more limited applications , mostly in bar soap formulated to concentrations 
 of about 2% by weight , higher than the 0.10.5% content of 
 tcs - enabled antimicrobial products .
supermarket shelves , likely bring home a product containing 
 either tcs or tcc . in 1999/2000 ,
tcs or tcc were present in 75% of 
 liquid soaps and 29% of bar soaps in the u.s .
more than 
 a decade into the accelerated use of polychlorinated 
 aromatic antimicrobials , there now are unmistakable signs of these 
 chemicals taking a toll on the health of the environment and possibly on susceptible human populations .
environmental protection agency ( epa ) , food and drug administration ( fda ) , as well as the centers for disease control and prevention , and the european union . on the state - level , efforts have begun to curtail the use of antimicrobials after the discovery of tcs , tcc , and their dioxin - like 
 chemical progeny in minnesota s treasured water resources . in parallel to the discovery of environmental pollution and 
 new 
 health risks of antimicrobials , concerns about the 
 emergence of microbial pathogens resistant to multiple groups of antibiotics 
 of medical import have triggered the 
 need for reassessing the status quo of antimicrobial 
 usage .
the present feature article takes 
 a look at the knowledge timeline concerning tcc and tcs , starting 
 with their mid 20th century introduction into commerce and culminating 
 with an assessment of today s information gaps as well as a 
 glimpse of what the future may hold for the age - old chemical war on 
 microbes .
enabled by advances in 
 analytical chemistry detection methods , 
 most notably gas and liquid chromatography / mass spectrometry ( gc - ms 
 and lc - ms , respectively ) , tcs and tcc emerged as important environmental 
 pollutants in disparate times and ways .
triclosan  a broadspectrum 
 bacteriostat and fungicide  garnered 
 the attention of environmental chemists soon after its large volume 
 use in the early 1970s .
after its patenting in 1964 and worldwide 
 production , tcs was detected within 14 years as an environmental contaminant , 
 first in u.s .
wastewater , river water , and sediment , and shortly thereafter in its methylated form , methyl - tcs , in fish 
 from tokyo bay .
these early and subsequent 
 environmental detections of tcs were enabled by its amenability to 
 gc - ms analysis .
this changed in 2002 , however , when the united 
 states geological survey ( usgs ) reported tcs as one of the top 10 
 contaminants of american rivers in its first national reconnaissance 
 of 95 pharmaceuticals , hormones , and organic wastewater contaminants .
triclocarban  a fungicide and bacteriostat with activity 
 against methicillin - resistant staphylococcus aureus ( mrsa ) and vancomycin - resistant enterococci ( vre)emerged as a contaminant of emerging concern ( cec ) 
 much later , enabled by lc - ms rather than gc - ms detection techniques . 

contrary to tcs , tcc can not be analyzed by standard gc methods , thereby 
 concealing for decades tcc s presence in environmental samples 
 acquired , extracted and analyzed for the occurrence of anthropogenic 
 pollutants . for tcc to travel through a standard gc column and
relief from this conundrum arrived in 2004 with 
 a simple lc - ms technique allowing direct detection of underivatized 
 tcc .
use of this tool on samples from 
 baltimore , maryland , showed the presence of tcc in every urban stream 
 monitored .
when applied to the city s 
 groundwater , drinking water , wastewater , and sewage sludge , tcc was 
 detected in many of these matrices and consistently in samples also 
 containing tcs .
significant co - occurrence 
 of tcc and tcs ( r = 
 0.988 ) can be easily understood from their similar uses , chemical 
 structures , and down - the - drain disposal mode . upon entering usgs national 
 data on tcs into the forecasting algorithm , 

tcc emerged in 2005 as a previously unrecognized cec that had been 
 overlooked by environmental analysts for almost half a century ; it 
 was predicted to rank in the top 10 cecs in occurrence rate and in 
 the top 20 in maximum concentration among 96 water pollutants .
follow - up research using tandem mass spectrometry 
 ( lc - ms / ms ) confirmed these predictions and adoption of lc - based analytical tools by laboratories around 
 the world quickly accelerated the discovery of tcc pollution in the 
 environment and in humans .
today , tcs and tcc rank in the list of top contaminants of 
 concern 
 worldwide .
streams 
 have a 60100% likelihood of containing detectable quantities 
 of tcs and tcc .
tcs has been detected in drinking 
 water resources , 75% of urine samples representative 
 of the u.s .
breast milk samples , and combined 
 tcs and tcc constitute over 60% of the total mass of 96 pharmaceuticals 
 detectable in municipal sludge using epa method 1694 .
indeed , the environmental ubiquity of both chemicals has escalated 
 such that tcs , tcc or both compounds are now detectable in house dust 
 worldwide , in ocean water , and 
 locations as remote as the water loop of spacecraft . to understand this phenomenon of ubiquitous pollution , 
 it is important to examine their production rates , distribution mechanisms , 
 and long - term persistence upon environmental release .
this behavior 
 may be understood best when viewed through the lens of green chemistry and engineering .
sustainably 
 produced green chemicals serve their intended purpose without creating 
 hazardous conditions for either people or the planet during chemical 
 production , use , and following disposal . of particular 
 concern for the epa
are chemicals featuring one or multiple of the 
 following characteristics : ( i ) persistence in the environment , 
 ( ii ) bioaccumulation in animals and humans ; and ( iii ) toxicity to humans and ecosystems .
as with other problematic chemicals , early warnings existed for decades concerning pbt properties of 
 tcs and tcc , and the unsustainability of their large - volume uses .
the cradle - to - grave life 
 cycle of tcs and tcc can be characterized as an open loop that violates 
 multiple principles of green chemistry and engineering .
structurally related to highly 
 toxic and carcinogenic dioxins , tcs had been labeled a predioxin as 
 early as 1993 by the u.s .
technical grade tcs contains traces 
 of the most toxic member of the dioxin family , 2,3,7,8-tetrachlorodibenzo - p - dioxin ( 17.2  1,712 ng / kg ) , and 2,3,7,8-tetrachlorodibenzofuran 
 ( 0.7  207.3 ng / kg ) .
producers of antimicrobial 
 products to source tcs from tightly monitored european chemical suppliers 
 as opposed to lower - cost competitors in the asian markets . furthermore ,
mixing of tcs with chlorinated 
 drinking water can result in the formation of carcinogenic chloroform and , upon release into surface water and irradiation 
 with sunlight , of additional toxic polychlorinated dioxins and less toxic dichlorinated dioxins , for example , 
 2,8-dichlorodibenzo - p - dioxin .
similarly , tcc also contains toxic , carcinogenic manufacturing 
 byproducts , such as 4-chloroaniline and 3,4-dichloroaniline , and can 
 release more of these carcinogens upon chemical , physical , and biological 
 attack .
durations of utility , i.e. , useful 
 lifespans , of tcs and tcc in personal care products are short , on 
 the order of seconds , but their environmental 
 after - lives are much longer , measured at time - scales of up to several 
 decades . upon disposal by consumers ,
both compounds are washed 
 down the drain and typically are conveyed to municipal wastewater 
 treatment plants ( wwtps ) .
these facilities remove both tcs and tcc 
 from raw sewage at a high efficiency of 9798% , leading to low ng / l levels in effluent discharged to surface waters
. however , removal from sewage does not necessarily equal degradation . 
 during wastewater treatment ,
both antimicrobials distribute themselves 
 preferentially into carbon- and lipid - rich sewage sludge , thereby 
 accumulating in this abundant byproduct of biological sewage treatment . during anaerobic sludge digestion
, losses can occur as a result 
 of biodegradation of tcs and tcc but concentrations also may increase 
 due to a reduction in volume by gasification of natural organics to 
 methane .
levels of tcs and tcc in digested sewage 
 sludge as high as 133 and 441 mg / kg dry weight , respectively , have 
 been reported by the epa ; however , mean concentrations are closer 
 to 16  65 and 39  59 mg / kg dry weight ( standard 
 deviation ) , respectively .
wwtps in substantial quantities ( 227  000454  000 
 kg / y for tcc and 170  000970  000 kg / yr for tcs ) are known to break through wwtps and subsequently 
 can harm algae in surface waters at ng / l concentrations .
detected concentrations have been observed to 
 exceed an acute - based predicted no - effect concentration ( pnec ) of 
 4.7
ng / l in the river elbe at 75% of monitoring locations , and can accumulate in sediments to mg / kg levels , where they may persist for several decades . in the u.s .
, sewage sludge is either incinerated ( 15% of 
 total volume ) which can release more carcinogenic dioxins from tcs , or deposited in landfills ( 30% ) and on land ( 55% ) , 
 from where antimicrobials and their carcinogenic transformation products 
 may leach into adjacent surface water to impact the composition of 
 microbial communities .
antimicrobials applied as sewer 
 sludge on land constitute a pathway for transfer of these chemicals 
 into animal feed and crops destined for human consumption .
the volume of antimicrobials reentering the environment in sewage 
 sludge after initial successful capture from wastewater is substantial ; 
 57  000  233  000 and 140  000  211  000 
 kg / yr of tcs and tcc , respectively , are applied on u.s .
land annually ; 
 for tcc , this is equivalent to a staggering 4.848.2% of its 
 total u.s .
crops 
 shown to take up antimicrobials from soil include barley , meadow fescue , 
 carrots , and pinto beans .
human exposure to antimicrobials 
 occurs mostly as a result of elective topical application to the human 
 body . showering for 15 min with a 0.6% tcc containing antimicrobial 
 soaps
was demonstrated to lead to concentrations in the blood of volunteers 
 sufficiently high to potentially cause local inhibition of enzyme 
 soluble epoxide hydrolase .
use of tcs - containing 
 toothpaste , typically formulated to 0.3% by weight , is another important 
 source of human exposure .
other known 
 or suspected human exposure routes of lesser importance include the 
 inhalation of antimicrobial - laden house dust , consumption 
 of contaminated drinking water , and 
 ingestion of food contaminated with antimicrobials either during the 
 growing season or postharvesting from antimicrobial - containing 
 packaging materials .
unsuspected environmental exposures 
 to tcs and tcc have attracted attention by news media and the general 
 public but the magnitude of these exposures is easily eclipsed by 
 elective , topical use of antimicrobial personal care products .
tcs and tcc are known 
 toxicants but there still is a paucity of data on adverse effects 
 in humans from elective and incidental environmental exposures .
europe emphasized the need for caution but 
 remain an anomaly , caused by misuse of antimicrobials in conditions 
 not applicable to present day uses .
acute and chronic health 
 effects of tcs and tcc observed in humans and animals following exposure 
 include irritation of eyes and skin , sensitization 
 to aeroallergens and food , immunologic 
 reactions such as allergies , developmental and reproductive toxicity , inhibition of muscle function , as 
 well as in vivo genotoxicity . while 
 limited , the number of studies involving human subjects is increasing
. an emerging additional 
 toxic outcome of concern is endocrine disruption , meaning an interfering of tcs and tcc with essential signaling 
 systems in animals and humans , thereby adversely affecting development , 
 sexual maturation , metabolism , and behavior .
endocrine disruption was observed after exposure of male rats to 
 tcc , of rats to tcs , and of frogs to tcs .
of particular 
 human health concern are the adverse effects of tcs on thyroid homeostasis 
 and of tcc on reproductive health .
a long recognized 
 potential human health threat of antimicrobials 
 is their ability to induce cross - resistance to medically important 
 antibiotics in human pathogens and commensal microbes , thereby turning 
 environmental microbial communities into a reservoir of antibiotic 
 drug resistance .
concerns about tcs - induced cross - resistance 
 to antibiotics used in human medicine were voiced as early as 2001 and have since been substantiated by scientists 
 worldwide .
whereas tcs resistance can 
 decrease susceptibility to as many as seven antibiotics simultaneously , the applicability of such data to environmental 
 settings and the actual risk remain uncertain .
available studies concentrated on household settings rather than on environmental locales , where 
 the development and proliferation of drug resistance is more likely . 

one such unexplored locale is sewage sludge , where an abundance of pathogens , multiple antimicrobials and extended 
 contact times creates a large and risky setting for the emergence 
 of drug resistance .
ecotoxicological 
 risks also 
 result for other biota enduring antimicrobial contact times that are 
 infinitely longer than the few seconds these persistent antimicrobials 
 reside on consumers hands during their intended use .
these 
 unwanted long - term exposures of biota to high concentrations of antimicrobials 
 take place in environments not targeted for disinfection . in the built water environment , for example , 
 inputs and accumulation of antimicrobials in activated sludge units 
 during wastewater treatment are of potential concern , as it may diminish 
 treatment efficacy and microbial diversity while also potentially 
 creating reservoirs of drug resistance .
similar risks also exist in soil environments subject to the application 
 of biocide - laden sewage sludge . here , as mentioned earlier , the proximity 
 of large quantities of commensal and pathogenic bacteria with extremely 
 high levels of antimicrobials is of particular concern , as is the 
 uptake of the compounds into higher organisms , such as plants and 
 animals .
natural environments also feature multiple compartments 
 where unwanted antimicrobial residues come in immediate and long - term 
 contact with fauna and flora . here , the 
 native , multicellular biota are known to be orders of magnitude more 
 susceptible to the killing power of antimicrobials than are microorganisms .
contrary to the situation described for hand 
 washing ( exposure times of a few seconds ) , these environmental toxic 
 exposures are not temporal , but rather extend over the entire lifespan 
 of aquatic and terrestrial organisms and across multiple generations . 

tcs and tcc are 1001000 times more effective in inhibiting 
 and killing algae , crustaceans and fish than they are in killing microbes .
shallow sediments in surface waters receiving 
 treated wastewater inputs are known to contain high g / kg to 
 low mg / kg quantities of tcs and tcc , levels that make impossible the 
 survival and activity of many different species .
sediments also represent 
 a latent source of antimicrobials and can release the compounds back 
 into the water column upon disturbance .
application of sewage sludge 
 in forestry and nonagricultural settings also can lead to decade long 
 exposure of plants , soil - dwelling biota and their predators over multiple 
 generations .
bioconcentration , bioaccumulation 
 and biomagnification of antimicrobials 
 have been observed in multiple organisms , including algae , aquatic blackworms , fish , and even dolphins , whereas affected terrestrial organisms include earth worms and higher species up the food 
 chain .
documented accumulation of antimicrobials 
 in worms and plant material and subsequent uptake by higher organisms 
 is a known pathway for ecological risks from exposure of vertebrae , 
 including songbirds .
bioaccumulation 
 of antimicrobials also occurs in humans but to a much lesser extent , because well - known 
 detoxification reactions result in the rapid elimination of parental 
 tcs and tcc . despite this ,
the need for continuous 
 elimination of antimicrobials by the human detoxification machinery 
 has been speculated to potentially prevent expulsion of more harmful 
 agents , such as dioxins , but scientific data are lacking .
although tcs and 
 tcc are effective in killing microorganisms when applied judiciously 
 by professionals in health care settings , their proliferating use by the general population , which accounts 
 for the vast majority of the chemicals production volume , 
 lacks convincing data on health benefits , according to epidemiological 
 studies .
these seemingly contradictory 
 findings between antimicrobials efficacy in clinical settings 
 and their failure to perform in household settings can be understood 
 easily when considering the contact time between the chemicals and 
 their microbial targets .
thoroughly designed clinical studies reproducibly 
 yield favorable results from hand washing times of 30 s to several 
 minutes
. however , hand - washing routines 
 of the general population differ significantly from this optimal standard . 
 in real - world settings ,
the application of soaps on the hands of consumers 
 is followed immediately by rinsing away of the active antimicrobial 
 ingredients .
thus , for the majority of household consumers , effective 
 contact times amount to an average of six seconds , too short to provide a measurable impact on antimicrobial 
 efficacy . in 2005 ,
an expert panel convened by the fda had concluded 
 by a 
 vote of 11-to-1 that use of antiseptics does not provide a measurable 
 benefit to consumers .
this assessment 
 apparently has not changed in years since , as the fda has issued in 
 late 2013 a notice to industry of its intent to institute tighter 
 regulations in the near future . in the u.s . , 
 regulating tcs and tcc has been challenging over the course of the 
 past half century , due in part to the desire to cover multiple uses 
 and multiple compounds under a single umbrella guidance document , 
 namely the topical antimicrobial drug products over - the - counter ( otc ) 
 drug monograph of the fda ( figure 1 ) .
this regulation was first drafted in 1974 , tentatively 
 finalized in 1978 , and updated in 1994 but never finalized . in 2010 , 

the natural resources defense council ( nrdc ) filed a complaint against 
 the fda in an effort to force the agency to act .
this legal action culminated in a consent decree , with 
 the fda agreeing in 2013 to finalize the monograph , at least with 
 respect to tcs .
the year 2014 marks 
 the 40th anniversary of issuance of the yet to be finalized initial 
 draft legislation ( figure 1 ) . in 1972 , in contrast , 
 the fda had acted much more swiftly , by banning the antimicrobial 
 hexachlorophene over concerns of its neurotoxicity . at the time
, hexachlorophene - containing personal 
 care products had multiplied in the market similar to tcs - containing 
 formulations today and adverse effects including accumulation in breast 
 milk also had been reported for hexachlorophene .
technically , the fda could regulate tcs and tcc over environmental 
 concerns alone but such action would be without precedence ; instead , 
 the fda has deferred to the epa , which regulates tcs but not tcc as 
 registered pesticides under the federal insecticide , fungicide , and 
 rodenticide act ( fifra ) .
timeline of scientific 
 and regulatory events concerning the use 
 and occurrence of triclosan ( tcs ) and triclocarban ( tcc ) in the united 
 states , with particular emphasis on the tentative final monograph 
 ( tfm ) of the food and drug administration ( fda ) .
so who should use antimicrobials ? for 
 what purpose ? and what is the acceptable extent of collateral damage 
 to ecological health and human populations ? answering these questions 
 should best be left to public health experts , physicians , risk assessors , 
 and sustainability scientists .
sixty years into the use of polychlorinated 
 binuclear aromatic antimicrobials , multiple lessons can be learned 
 from the past .
hexachlorophene was responsible for the first bloom 
 of antimicrobial products , giving rise to over 400 hexachlorophene - containing 
 personal care products ; this episode lasted only a few years , though , 
 before this active ingredient was banned over concerns of its neurotoxicity . the second bloom in u.s .
antimicrobial products 
 from a few dozens to the current count of > 2000 was triggered by 
 the 
 fda s removal of antimicrobial soaps from the drug category 
 of the tentative final monograph ( tfm ) in 1994 ( figure 1 ) .
this history suggests that regulatory boundaries are critical 
 in preventing imprudent uses of potentially harmful substances in 
 personal care products .
restricting nonmedical 
 uses of tcs and tcc is an approach championed by diverse scholars 
 and health care professionals , including the american medical association 
 ( ama ) , the alliance for the prudent use of antibiotics ( apua ) , an 
 expert group of the american academy for microbiology , and members of the american public health association 
 ( apha ) .
any known and potential 
 adverse effects of the usage of antimicrobials should be balanced 
 with immediate and measurable benefits reaped . with respect to tcs 
 and tcc , scientific evidence points
to known benefits from their application 
 in health care settings by health care professionals , and possibly 
 from tcs - containing toothpaste used by individuals diagnosed with 
 gingivitis .
exclusive sale of tcs / tcc - containing 
 soaps in pharmacies and prescription requirements for tcs in toothpaste 
 may aid in effecting the desirable reduction in unsustainable consumption 
 patterns and with it associated adverse effects .
this tiered approach 
 worked well for the now restricted hexachlorophene , whose allowable 
 and prudent applications continue to this date , as a preservative 
 at concentrations of up to 0.1% by weight .
regulations proved effective 
 in throttling back hexachlorophene production ; today , the compound 
 is present at levels below the detection limit in u.s .
wastewaters , 
 detectable only at low concentrations ( 0.180.37 mg / kg dry 
 weight ) in raw and treated sewage sludge , where it accumulates similarly 
 to tcs and tcc .
the question of 
 what collateral damage to people and the planet 
 is acceptable will be informed not only by cost - benefit analyses but 
 also by broader sustainability considerations .
evidence abounds for tcs and tcc to represent 
 nongreen chemicals whose current usage volumes are unsustainable , 
 as indicated by large - scale pollution that needlessly places stress 
 on the environment , animals and human populations .
these findings suggest the need for next - generation antimicrobials 
 to overcome some of the identified shortcomings of tcs and tcc , while 
 preserving their essential benefits .
so 
 what will greener , more sustainable antimicrobials 
 of the future look like ? desirable properties of next - generation antimicrobial 
 include broad - spectrum action and high efficacy toward pathogens but 
 low toxicity to nontarget , multicellular organisms , including aquatic 
 and terrestrial biota and humans . furthermore , future - use antimicrobials 
 should have no or very low potential for fostering antimicrobial drug 
 resistance , should undergo rapid biodegradation in conventional wastewater 
 treatment plants , and pose no risk of bioaccumulation .
ideally , the 
 compounds also should be sourced from renewable feedstock and lack 
 occupational hazards during production , storage , and use . upon disposal 

they should return their benign elemental building blocks to the environment , 
 to complete a more environmentally friendly cradle - to - cradle life - cycle .
sustainability 
 considerations already are informing the design of green pharmaceuticals , and adopting this approach for antimicrobials promises to yield 
 important benefits to people and the planet .
 the polychlorinated 
 aromatic antimicrobials triclosan and 
 triclocarban are in widespread use for killing microorganisms indiscriminately , 
 rapidly , and by nonspecific action . 
 while their utility in healthcare 
 settings is undisputed , benefits to users of antimicrobial personal 
 care products are few to none . yet 
 , these latter , high - volume uses 
 have caused widespread contamination of the environment , wildlife , 
 and human populations . 
 this feature article presents a timeline of 
 scientific evidence and regulatory actions in the u.s . concerning 
 persistent polychlorinated biocides , showing a potential path forward 
 to judicious and sustainable uses of synthetic antimicrobials , including 
 the design of greener and safer next - generation alternatives . 
Introduction