Environmental Toxicology and Chemistry, Vol. 32, No. 5, pp. 969–971, 2013
# 2013 SETAC
Printed in the USA
DOI: 10.1002/etc.2211
ET&C Impact Papers
PHOTO-ENHANCED TOXICITY: SERENDIPITY OF A PREPARED
MIND AND FLEXIBLE PROGRAM MANAGEMENT
JOHN P. GIESY,*y JOHN L. NEWSTED,z and JAMES T. ORISx
yToxicology Centre and Department of Biomedical Veterinary Sciences, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
zCardno-ENTRIX, East Lansing, Michigan, USA
xDepartment of Biology, Miami University, Oxford, Ohio, USA
(Submitted 25 September 2012; Returned for Revision 31 October 2012; Accepted 5 November 2012)
because it was the time of the oil embargo of the 1970s and the
U.S. Department of Energy and the U.S. EPA were involved in a
Synthetic Fuels Program. The 100-m–long mesocosms had been
constructed and colonized over a three-year period. The system
was fitted with a number of monitoring probes, and then the
model chemical anthracene was added to the system at about
6:00 AM. After being up all night preparing for the initiation of
the experiment, the principal investigator went back to catch a
few “Z’s” on the floor of his office, He had left instructions to
call him if any problems arose. He had only just arrived in his
office when he received a call that all of the fish had begun dying
within 20 min of adding the anthracene. The study was designed
as a “fates” study, and the concentrations used—which were
based on laboratory studies—should not have caused any
toxicity.
While at first bemoaning the fact that the huge experiment
was ruined, the investigators soon became intrigued by this
unexpected result and were determined to discover what was
causing it. At first, it was thought the effect could be due to the
carrier solvent (ethanol) or some interaction between the solvent
and the PAHs; but the patterns of where and when toxicity was
observed and which organisms seemed to be more sensitive gave
rise to a working hypothesis of an interaction between sunlight
and anthracene. The most obvious explanation was a photochemical reaction, and the focus settled on the potential toxicity
of reaction products of photolysis; but the obvious product,
which was benzoic acid, was known to be insufficiently toxic to
cause the observed lethality. After a call to the U.S. EPA
program officer, H. Holm, in the Athens Laboratory (Athens,
GA, USA), the University of Georgia team was green-lighted to
“work out what was causing the unexpected toxicity.” The
toxicity had occurred first at the upstream end of the systems, and
it was postulated that a transformation product of anthracene was
the cause. Within a day, a study using the six replicate channels
with sections covered upstream or downstream allowed us to
determine that it was not a degradation product but rather the
parent anthracene that was causing the toxicity. The effect was
dramatic, with lethality in full sunlight occurring within minutes.
Further studies were designed and methods developed to
monitor for incident solar radiation, and eventually it was
determined that the toxicity was a function of the amount of
anthracene in the organism and exposure to solar radiation [5,6].
It was further determined, through use of selective filters, that
ultraviolet (UV) radiation in the UV-A region with a wavelength
range between 320 and 400 nm was causing the effect. It so
happens that anthracene has a “red-shifted” absorption spectrum
that allows the molecule to absorb light at wavelengths greater
than the 284-nm cut-off of the atmosphere. Subsequent studies
The book entitled The Structure of Scientific Revolutions by
Thomas Khun discusses how normal science proceeds and how
seminal discoveries occur [1]. The discovery of photo-enhanced
toxicity of polycyclic aromatic hydrocarbons (PAHs) was an
archetypical paradigm shift as described by Khun. It is a story of
being in the right place at the right time; but even more, it was
the vision of the U.S. Environmental Protection Agency’s
(U.S. EPA) to recognize the opportunity and to have the
flexibility to allow the researchers to follow up on a unique
observation. It is also the story of some young students’
willingness take a chance and follow up on an observation, their
readiness to develop the methodologies, and their ability to
conduct a number of difficult assays that resulted in the
comprehensive understanding and accurate predictive models
that were presented in what would become one of the top 100
most cited articles in Environmental Toxicology and Chemistry
[2]. Finally, it is the story of being able to pull together
information in disciplines ranging from physical chemistry, to
bioaccumulation, to toxicology, to quantitative structure–
activity relationship simulation modeling to develop an overall
predictive model. It was only when all of these elements came
together that the seminal advancement was possible.
The phenomenon of photo-enhanced toxicity has now
become “normal science,” with papers routinely published on
the topic and sessions at national and international meetings.
Sometimes entire meetings are organized around this topic, and
there are entire journals devoted to the phenomenon. At the 25th
Annual Dioxin Meeting held in Toronto, Canada, in 2005,
photo-enhanced toxicity of PAHs to aquatic organisms [2] was
listed as one of the 25 most influential discoveries of the
preceding 25 years (http://www.dioxin20xx.org/pdfs/history/
Dioxin2005.pdf). Photo-enhanced toxicity has now been
included in the development of water and sediment quality
criteria.
Like many of the most interesting discoveries in science, the
discovery of photo-enhanced toxicity was the result of the
unexpected rather than that of a specific design. We were
conducting a large mesocosm study at the University of Georgia
as part of a program to develop an environmental fate model for
organic chemicals (FOAM: Fate of Organic Molecules) [3,4]. It
had been decided to focus on PAHs as model compounds
All Supplemental Data may be found in the online version of this article.
See Table S1 for the number of citations and rank of all the “Top 100”
papers, which in this essay is reference [2].
To whom correspondence may be addressed
(John.Giesy@usask.ca).
Published online in Wiley Online Library
(wileyonlinelibrary.com).
969
970
Environ. Toxicol. Chem. 32, 2013
with other organisms including daphnids [7,8], fish [9–11], and
algae [12–15] supported the original study’s findings that solar
radiation enhanced the toxicity of anthracene. The phenomenon
was then shown to occur under field conditions [16]. It was
demonstrated with a range of PAHs that the phenomenon could
be described by use of physical models based on first principles
of photochemistry and that the mechanism of effect was a
singlet-oxygen–mediated oxidative stress that disrupted membranes [2,16–18]. The degree of toxicity could be described as
a function of concentration of PAH and intensity of solar
irradiance. Several PAHs were found to exhibit the phenomenon,
and the model was further refined to predict toxicity based on the
octanol–water partition coefficient (KOW) that predicted how
much of the chemical would accumulate, the molar absorptivity
of the individual compounds, and the probability of forming
singlet oxygen that could initiate production of free radicals,
which could be predicted from the singlet–triplet splitting
energies of individual compounds [2,10]. Finally, a predictive
model based solely on theoretical first principles related to the
structure of the individual molecules was developed that had
100% correct predictive power [19].
We were all very excited about these results, but convincing
the scientific community that this phenomenon had any
environmental relevance was a hard sell because most people
had been taught that UV light does not penetrate to significant
depths in aquatic systems. We then took our experiments to the
Laurentian Great Lakes [16] and Lake Tahoe [20,21]. Lake
Tahoe is very transparent to UV light [22] and is also at an
elevation that would result in greater amounts of UV radiation.
Against much resistance, we were eventually able to demonstrate
that the phenomenon does in fact occur, and it occurs at
environmentally relevant concentrations of PAHs and UV
radiation. The toxicity of some PAHs under natural conditions of
solar irradiance was 50,000-fold more toxic than under
laboratory conditions in the absence of UV light. In tests with
daphnids, median times to effect were on the order of seconds. In
fact, at one point early in the work at the University of Georgia,
when we were having trouble reproducing results, we found that
the lab technician had been carrying an uncovered tray of
daphnids in cups containing PAHs outside from one trailer to
another. The 30 s in full sunlight was long enough to cause
lethality.
It is our belief that dogma prevented the discovery of the
phenomenon in the natural environment sooner. Polycyclic
aromatic hydrocarbons have been known photosensitizers in
humans for 100s if not 1,000s of years [23]. Anecdotal
information indicates that PAH photo-induced toxicity was
observed in fish as early as the 1950s, but the cause of toxicity
was not explored at the time of the report. In fact, at the time of
our discovery, scientists working with PAHs were conducting
studies under yellow lights to avoid photodegradation during
incubation. This practice as much as anything prevented the
discovery from being made sooner. The incorporation of field
tests of laboratory predictions; strong foundations in biology,
chemistry, and physics; and a team of scientists who were willing
to explore unanticipated and seemingly negative results enabled
the discovery.
This was very much a situation of serendipity [24]; but the
moral of the story is to expect the unexpected and then be willing
to set aside preconceived notions and, yes, the original intent of
the study and original experimental design to follow up on
unexpected but interesting observations. Never stop observing
and questioning and do not be afraid to follow up on things that
do not go the way they were designed. Great discoveries [25] are
J.P. Giesy et al.
made by people who are in the right place at the right time and
who have a prepared mind and a flexible approach to research
that allows them to surmount dogma and the resistance of
“normal science.”
SUPPLEMENTAL DATA
Table S1. (49 KB PDF).
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Supplemental Table 1. Ranking by citation frequency of Top 100 (102) papers published in Environmental Toxicology and Chemistry. Rank Title Authors Publication Volume Year 1996 15 Pages 194-­‐202 Total Citations 818 1 Inhibition of testicular growth in rainbow trout (Oncorhynchus mykiss) exposed to estrogenic alkylphenolic chemicals Jobling S, Sheahan D, Osborne JA, Matthiessen P, Sumpter JP 2 Estrogenic activity of surfactants and some of their degradation products assessed using a recombinant yeast screen Routledge EJ, Sumpter JP 1996 15 241-­‐248 752 3 Technical basis for establishing sediment quality criteria for nonionic organic-­‐chemicals using equilibrium partitioning Di Toro DM, Zarba 1991 CS, Hansen DJ, Berry WJ, Swartz RC, Cowan CE, Pavlou SP, Allen HE, Thomas NA, Paquin PR 10 1541-­‐1583 727 4 Ecological risk assessment of atrazine in North American surface waters Solomon KR, Baker 1996 DB, Richards RP, Dixon DR, Klaine SJ, LaPoint TW, Kendall RJ, Weisskopf CP, Giddings JM, Giesy JP, Hall LW, Williams WM 15 31-­‐74 461 5 Biotic ligand model of the acute toxicity of metals. 1. Technical basis Di Toro DM, Allen HE, Bergman HL, Meyer JS, Paquin PR, Santore RC 20 2383-­‐2396 423 6 Toxicity of cadmium in sediments -­‐ Di Toro DM, 1990 The role of acid volatile sulfide Mahony JD, Hansen DJ, Scott KJ, Hicks MB, Mayr SM, Redmond MS Estrogenic activity in five United Harries JE, Sheahan 1997 Kingdom rivers detected by DA, Jobling S, measurement of vitellogenesis in Matthiessen P, Neall caged male trout M, Sumpter JP, Taylor T, Zaman N 9 1487-­‐1502 392 16 534-­‐542 390 Critical appraisal of the evidence Matthiessen P, for tributyltin-­‐mediated endocrine Gibbs PE disruption in mollusks 17 37-­‐43 321 7 8 2001 1998 9 Groundwater ubiquity score -­‐ A simple method for assessing pesticide leachability Gustafson DI 10 Predicting modes of toxic action from chemical structure: Acute toxicity in the fathead minnow (Pimephales promelas) 11 Determination of octanol water partition-­‐coefficients for hydrophobic organic-­‐chemicals with the slow-­‐stirring method 12 Effects of the synthetic estrogen 17 alpha-­‐ethinylestradiol on the life-­‐cycle of the fathead minnow (Pimephales promelas) 13 A survey of estrogenic activity in United Kingdom inland waters 14 1989 8 339-­‐357 304 Russom CL, 1997 Bradbury SP, Broderius SJ, Hammermeister DE, Drummond RA Debruijn J, Busser F, 1989 Seinen W, Hermens J 16 948-­‐967 290 8 499-­‐512 282 Lange R, Hutchinson 2001 TH, Croudace CP, Siegmund F, Schweinfurth H, Hampe P, Panter GH, Sumpter JP Harries JE, Sheahan 1996 DA, Jobling S, Matthiessen P, Neall P, Routledge EJ, Rycroft R, Sumpter JP, Tylor T 20 1216-­‐1227 281 15 1993-­‐2002 264 Degradation of azo dyes by environmental microorganisms and helminths Chung KT, Stevens SE 1993 12 2121-­‐2132 261 15 Estrogenic potency of chemicals detected in sewage treatment plant effluents as determined by in vivo assays with Japanese medaka (Oryzias latipes) 20 297-­‐308 259 16 Biochemical responses in aquatic animals -­‐ A review of determinants of oxidative stress Metcalfe CD, 2001 Metcalfe TL, Kiparissis Y, Koenig BG, Khan C, Hughes RJ, Croley TR, March RE, Potter T Digiulio RT, 1989 Washburn PC, Wenning RJ, Winston GW, Jewell CS 8 1103-­‐1123 252 17 Sorption dynamics of hydrophobic Karickhoff SW, pollutants in sediment Morris KR suspensions 4 469-­‐479 251 1985 18 Nanomaterials in the environment: Behavior, fate, bioavailability, and effects 19 20 2008 27 1825-­‐1851 249 Induction of testis-­‐ova in Japanese Gray MA, Metcalfe medaka (Oryzias latipes) exposed CD to p-­‐nonylphenol 1997 16 1082-­‐1086 248 Analysis of acid-­‐volatile sulfide (AVS) and simultaneously extracted metals (SEM) for the estimation of potential toxicity in aquatic sediments Predicting toxicity in marine sediments with numerical sediment quality guidelines Allen HE, Fu GM, Deng BL 1993 12 1441-­‐1453 246 Long ER, Field LJ, MacDonald DD 1998 17 714-­‐727 236 21 (B) Principal response curves: Analysis Van den Brink PJ, of time-­‐dependent multivariate Ter Braak CJF responses of biological community to stress 1999 18 138-­‐148 236 23 Overview of a workshop on screening methods for detecting potential (anti-­‐) estrogenic/androgenic chemicals in wildlife Ankley G, Mihaich E, 1998 Stahl R, Tillitt D, Colborn T, McMaster S, Miller R, Bantle J, Campbell P, Denslow N, Dickerson R, Folmar L, Fry M, Giesy J, Gray LE, Guiney P, Hutchinson T, Kennedy S, Kramer V, LeBlanc G, Mayes M, Nimrod A, Patino R, Peterson R, Purdy R, Ringer R, Thomas P, Touart L, Van der Kraak G, Zacharewski T 17 68-­‐87 225 21 (A) Klaine SJ, Alvarez PJJ, Batley GE, Fernandes TF, Handy RD, Lyon DY, Mahendra S, McLaughlin MJ, Lead JR 24 Environmental-­‐factors affecting the formation of methylmercury in low pH lakes 25 Winfrey MR, Rudd JWM 1990 9 853-­‐869 221 Biotic ligand model of the acute Santore RC, Di Toro toxicity of metals. 2. Application to DM, Paquin PR, acute copper toxicity in Allen HE, Meyer JS freshwater fish and Daphnia 2001 20 2397-­‐2402 218 26 Polybrominated diphenyl ethers and hexabromocyclododecane in sediment and fish from a Swedish river Sellstrom U, Kierkegaard A, de Wit C, Jansson B 1998 17 1065-­‐1072 215 27 Bioconcentration and tissue distribution of perfluorinated acids in rainbow trout (Oncorhynchus mykiss) Martin JW, Mabury SA, Solomon KR, Muir DCG 2003 22 196-­‐204 212 28 Assimilation efficiencies of chemical contaminants in aquatic invertebrates: A synthesis Wang WX, Fisher NS 1999 18 2034-­‐2045 208 29 Effects of mercury on wildlife: A comprehensive review Wolfe MF, Schwarzbach S, Sulaiman RA 1998 17 146-­‐160 207 30 Factors affecting mercury accumulation in fish in the upper Michigan peninsula Grieb TM, Driscoll CT, Gloss SP, Schofield CL, Bowie GL, Porcella DB 1990 9 919-­‐930 203 31 Acetylcholinesterase inhibition in Fulton MH, Key PB estuarine fish and invertebrates as an indicator of organophosphorus insecticide exposure and effects 2001 20 37-­‐45 198 32 Technical basis and proposal for deriving sediment quality criteria for metals Ankley GT, DiToro DM, Hansen DJ, Berry WJ 1996 15 2056-­‐2066 197 33 The effects of water chemistry on the toxicity of copper to fathead minnows Erickson RJ, Benoit DA, Mattson VR, Nelson HP, Leonard EN 1996 15 181-­‐193 193 34 Distribution of acidic and neutral drugs in surface waters near sewage treatment plants in the lower Great Lakes, Canada Metcalfe CD, Miao XS, Koenig BG, Struger J 2003 22 2881-­‐2889 192 35 Dietary accumulation and depuration of hydrophobic organochlorines: Bioaccumulation parameters and their relationship with the octanol/water partition coefficient Fisk AT, Norstrom RJ, Cymbalisty CD, Muir DCG 1998 17 951-­‐961 191 36 Survey of estrogenic activity in United Kingdom estuarine and coastal waters and its effects on gonadal development of the flounder Platichthys flesus Allen Y, Scott AP, 1999 Matthiessen P, Haworth S, Thain JE, Feist S 18 1791-­‐1800 189 37 An equilibrium-­‐model of organic-­‐
chemical accumulation in aquatic food webs with sediment interaction Thomann RV, Connolly JP, Parkerton TF 1992 11 615-­‐629 188 38 Polycyclic aromatic hydrocarbons in sediments and mussels of the western Mediterranean sea Baumard P, Budzinski H, Garrigues P 1998 17 765-­‐776 186 39 Assessing the toxicity of fresh-­‐
water sediments Burton GA 1991 10 1585-­‐1627 185 40 Description and evaluation of a short-­‐term reproduction test with the fathead minnow (Pimephales promelas) Ankley GT, Jensen KM, Kahl MD, Korte JJ, Makynen EA 2001 20 1276-­‐1290 184 41 Daphnia magna mortality when exposed to titanium dioxide and fullerene (C-­‐60) nanoparticles Lovern SB, Klaper R 2006 25 1132-­‐1137 183 42 (A) Toxicokinetics in aquatic systems: Model comparisons and use in hazard assessment Landrum PF, Lee H, Lydy MJ 1992 11 1709-­‐1725 181 42 (B) Analysis of estrogenic hormones in municipal wastewater effluent and surface water using enzyme-­‐
linked immunosorbent assay and gas chromatography/tandem mass spectrometry Huang CH, Sedlak DL 2001 20 133-­‐139 181 44 Survey of receiving-­‐water environmental impacts associated with discharges from pulp-­‐mills: 2. Gonad size, liver size, hepatic erod activity and plasma sex steroid levels in white sucker Munkittrick KR, 1994 Vanderkraak GJ, McMaster ME, Portt CB, Vandenheuvel MR, Servos MR 13 1089-­‐1101 180 45 Desorption kinetics of Cornelissen G, chlorobenzenes, polycyclic vanNoort PCM, aromatic hydrocarbons, and Govers HAJ polychlorinated biphenyls: Sediment extraction with Tenax(R) and effects of contact time and solute hydrophobicity 1997 16 1351-­‐1357 179 46 Is the per capita rate of increase a good measure of population-­‐level effects in ecotoxicology? Forbes VE, Calow P 1999 18 1544-­‐1556 178 47 Bioaccumulation and toxicity of silver compounds: A review Ratte HT 1999 18 89-­‐108 176 48 Aquatic toxicity testing using the Williams PL, nematode, Caenorhabditis elegans Dusenbery DB 1990 9 1285-­‐1290 173 49 Dynamics of organochlorine compounds in herring gulls: 3. Tissue distribution and bioaccumulation in Lake Ontario gulls Braune BM, Norstrom RJ 1989 8 957-­‐968 167 50 Polychlorinated biphenyl residues and egg mortality in double-­‐
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