Perspective

Reflections on the Origins and Evolution of GeneticToxicology and the Environmental Mutagen Society

John S.Wassom,1{ Heinrich V. Malling,2 K. Sankaranarayanan,3

and Po-Yung Lu4*1Oak Ridge National Laboratory (retired), Oak Ridge, Tennessee2National Institute of Environmental Health Sciences, Chapel Hill,

North Carolina3Department of Toxicogenetics (retired), Leiden University Medical Centre,

Leiden, The Netherlands4Oak Ridge National Laboratory, Oak Ridge, Tennessee

This article traces the development of the eld ofmutagenesis and its metamorphosis into theresearch area we now call genetic toxicology. In1969, this transitional event led to the founding ofthe Environmental Mutagen Society (EMS). Thecharter of this new Society was to encourageinterest in and study of mutagens in the humanenvironment, particularly as these may be of con-cern to public health. As the mutagenesis eldunfolded and expanded, new wording appearedto better describe this evolving area of research.The term genetic toxicology was coined andbecame an important subspecialty of the broadarea of toxicology. Genetic toxicology is now setfor a thorough reappraisal of its methods, goals,and priorities to meet the challenges of the 21stCentury. To better understand these challenges, we

have revisited the primary goal that the EMS found-ers had in mind for the Societys main mission andobjective, namely, the quantitative assessment ofgenetic (hereditary) risks to human populationsexposed to environmental agents. We also havereected upon some of the seminal events over thelast 40 years that have inuenced the advancementof the genetic toxicology discipline and the extentto which the Societys major goal and allied objec-tives have been achieved. Additionally, we haveprovided suggestions on how EMS can furtheradvance the science of genetic toxicology in thepostgenome era. Any oversight or failure to makeproper acknowledgment of individuals, events, orthe citation of relevant references in this article isunintentional. Environ. Mol. Mutagen. 51:746760, 2010. Published 2010 Wiley-Liss, Inc.y

Key words: mutation research; history of genetic toxicology; chemical mutagenesis; EnvironmentalMutagen Society

I prefer to think of the present as a singularity. . .through which the future has got to pass to become thepresent. John Lewis Gaddis, Yale Historian

INTRODUCTION

A portion of this article was published in this journal

during 1989 in celebration of the Environmental Mutagen

Societys (EMS) 20th anniversary [Wassom, 1989]. The

editors of this special issue, assembled to celebrate the

Societys 40th anniversary, asked the authors to update

the earlier article as part of this special issue. We have

done as requested, but readers should keep in mind that

history is a collection of events that people interpret

through their own experiences. Even though, in this

update, we have not chronicled all events, players, and

publications that have inuenced the eld of genetic toxi-

This work was supported in part by the NIH, National Institute of Envi-

ronmental Health Sciences intramural research program.

This manuscript has been authored by UT-Battelle, LLC, under contract

DE-AC05-00OR22725 with the U.S. Department of Energy. The United

States Government retains and the publisher, by accepting the article for

publication, acknowledges that the United States Government retains a

non-exclusive, paid-up, irrevocable, worldwide license to publish or

reproduce the published form of this manuscript, or allow others to do

so, for United States Government purposes.

*Correspondence to: Po-Yung Lu, Oak Ridge National Laboratory; 1060

Commerce Park Drive; Oak Ridge, TN 37830.

E-mail: lupy@ornl.gov

{Deceased.

Received 18 December 2009; provisionally accepted 3 March 2010; and

in nal form 20 March 2010

DOI 10.1002/em.20589

Published online 28 April 2010 in Wiley Online Library

(wileyonlinelibrary.com).

Published 2010Wiley-Liss, Inc. yThis article is a US Government work and,as such, is in the public domain in the United States of America.

Environmental andMolecular Mutagenesis 51:746^760 (2010)

cology and stimulated the formation of EMS, we have

attempted to (a) record some of the seminal happenings

that contributed to the founding of EMS, (b) provide a

broad overview of developments in mutation research be-

ginning in the early 1900s and in genetic toxicology from

the late 1960s to the present, (c) compare genetic risk esti-

mation for ionizing radiation with that for environmental

chemical mutagens, (d) review efforts at protecting humans

from adverse biological effects of radiation and chemicals,

and (e) discuss some of our views on the way forward in

genetic risk assessment for chemicals. However hard we

have tried, we no doubt let our own biases creep in, so you

may agree or disagree with us. Either way, we hope we

have stimulated you to think about the origins of genetic

toxicology, accomplishments made, future needs, and the

organization that we today call the EMS.

Genetic toxicology, as a subspecialty of toxicology,

aims to identify and analyze the action of agents with tox-

icity directed toward the hereditary components of biolog-

ical systems. Agents specically producing genetic altera-

tions at subtoxic exposure levels that result in organisms

with altered hereditary characteristics are called geno-

toxic. Genotoxic substances usually have chemical or

physical properties that facilitate interaction with DNA,

the universal target molecule that provides the scientic

basis for the eld of genetic toxicology [Brusick, 1980].

The Section that follows on the formative years of genetic

toxicology has been shortened and some new information

added from the earlier article. Interested readers should

consult the earlier article for the entire text that examines

genetic toxicologys formative years.

Text from the rst article dealing with the formation of

the EMS was left intact because of its importance to this

organizations 40-year existence.

THE FORMATIVE YEARS OFGENETIC TOXICOLOGY

As reviewed in the earlier article [Wassom, 1989], in

searching for the earliest efforts exploring how and why

agents (physical, chemical, or biological) induce genetic

changes, we must go back to Europe at the turn of the

century. The lore of the eld tells us that, in the early

months of 1900, investigators in The Netherlands [de

Vries, 1900a,b, 1910, 1950 (English translation of de

Vries, 1900b)], Germany [Correns, 1900, 1950 (English

translation of Correns, 1900)], and Austria [Tschermak-

Sysenegg, 1900] rediscovered the work of Gregor Mendel

[1866]. The resurrection of Mendels classic article, which

had been buried in the literature for some 30 years,

launched the rapid development of the science of genet-

ics. The growth of this new science naturally set the

framework for eventual inquiry into the nature of the

gene. These investigations prompted some experimental-

ists to wonder how external factors induce changes in the

natural genetic order.

Several excellent articles have reviewed the history of

the mutagenesis and genetic toxicology research area

[Crow, 1989; Preston, 1989; Brusick, 1994, 1995; Drake,

1994; Legator, 1994; MacGregor, 1998; Frickel, 2001,

2004; Hoffmann, 2004; Malling, 2004; Zeiger, 2004]. All

these documents combined give a very lively picture of

how our eld began and evolved. Charlotte Auerbach

[1976] has provided one of the earliest of these excellent

reviews that covered the time period from about 1900 to

the mid-1970s. The work of Herman Joseph Muller on

the induction of mutations by X-rays in Drosophila germcells in 1927 and that of Auerbach et al. [1947] on muta-

tions induced by chemical mutagens some 20 years later,

also in Drosophila, generally are considered to mark theformal beginnings of genetic toxicology. These articles

highlighted the concept of mutation and reviewed

efforts at exploring how and why agents (physical, chemi-

cal, or biological) induce genetic changes that date back

to the early years of the 20th Century. One of the redis-

coverers of Mendels laws, the Dutch botanist Hugo de

Vries, coined the term mutation to describe the sudden

hereditary changes in Oenothera lamarckiana, the eveningprimrose [de Vries, 1900a,b, 19011903, 1910 (English

translation of de Vries 19011903)]. These changes, he

observed, were found to be due not to mutation but to

polyploidy, polysomy, or rare recombination events in a

very unusual karyotype. Nonetheless, the term has been

preserved for changes in the quality, quantity, and

arrangement of genes [Auerbach, 1976].

De Vries also was one of the rst to propose the idea

of the induction of directed mutations that could pro-

vide man with unlimited power over nature. In 1901,

he wrote in Volume 1 of his book, The Mutation Theory,that . . . knowledge of the principles of mutation will cer-

tainly some time in the future enable a fully planned arti-

cial induction of mutations, i.e., the creation of new prop-

erties in plants and animals. Moreover, man will likely be

able to produce superior varieties of cultivated plants and

animals by commanding the origin of mutations.

This same idea was to surface again 3 years later. In

1904, 9 years after the discovery of X-rays, de Vries,

while lecturing in America, suggested that X-rays, which

are able to penetrate living cells, could be used in an

attempt to alter the hereditary particles in germ cells

[Wassom, 1980]. This prediction came true in 1908 when

X-rays were used to induce dominant genetic effects in

rabbits [Regaud and Dubrenil, 1908]. For a review of the

early uses of radiation to induce genetic effects in mam-

mals, see the book chapter by W.L. Russell [1954] in the

three-volume book series, Radiation Biology, edited byAlexander Hollaender [1954]. These three volumes pro-

vide a comprehensive review of radiation biology from

the early 1920s through the rst few years of the 1950s.

On the chemical side, early experiments began with

microorganisms such as those conducted by Franz Wolff

Environmental and Molecular Mutagenesis. DOI 10.1002/em

Genetic Toxicology and the EMS 747

[1909] and Elizabeth Schiemann [1912] with bacteria and

fungi (Bacillus prodigious and Aspergillus niger) usingvarious oxidizing agents such as potassium chromate, po-

tassium chlorate, zinc sulfate, potassium permanganate,

and copper oxide. The experimental material was by no

means ideal, and the results were not denitive, even

though Schiemann reported a fourfold increase in muta-

tions over the spontaneous rate.

Regardless of whether the results reported by Wolff

and by Schiemann were true mutations, the fact was that

a new era in an infant eld of study had begun. Subse-

quently, investigators in many countries were to begin

thinking about whether chemicals could induce changes

in hereditary material. In the early 1900s, Thomas Hunt

Morgan brought the fruit y Drosophila melanogasterinto use as a test object for mutagenesis experiments. He

tested radiation, acids, alkalis, and other chemicals in

Drosophila in conjunction with environmental changes.These experiments were mostly disappointing. Nonethe-

less, many interesting discoveries were being made in the

eld of genetics during the rst three decades of the 20th

Century, and these discoveries stimulated thinking about

the articial induction of mutations. In the 1920s at the

University of Texas, mutation research was placed on a

rm basis by the New Yorkborn Muller, a student of Mor-

gan, who showed unequivocally that radiation was a muta-

gen [Muller, 1927]. Muller also developed the concept of

mutation rate and devised objective, efcient, and quan-

titative techniques in Drosophila for its measurement[Muller, 1928]. Mullers use of Drosophila marked its be-ginning as the organism of choice in mutation induction

studies, which would continue for the next four decades.

Spurred on by Mullers success with radiation, other inves-

tigators initiated studies to determine the mutagenicity of

chemical compounds such as alcohol, ether, morphine, qui-

nine, ammonia, acetic acid, iodine, potassium permanga-

nate, and several metal salts. However, these studies with

chemicals could not match investigators success with radi-

ation; convincing proof had been published showing that

mutations could be produced en masse by different types

of radiation. Experiments with chemicals were overshad-

owed by those with radiation until the 1940s.

Several important discoveries during the 1940s nally

established that chemicals, like radiation, could induce

heritable mutations. Auerbach and Robson in 1942 proved

that the chemical warfare agent mustard gas was muta-

genic, but, because of wartime censorship, results of this

discovery were not formally published until 1947. Franz

Oehlkers discovered in 1943 that the pharmaceutical ure-

thane, then widely used, was mutagenic; and I.A. Rapo-

ports research in 1946 and 1948 showing that ethylene

oxide, ethylenimine, epichlorohydrin, diazomethane,

diethyl sulfate, glycidol, and several other compounds

were mutagenic nally established chemical mutagenesis

as a distinct research area. The later orientation of muta-

tion research followed the logic stated by Auerbach et al.

[1947]: If, as we assume, a mutation is a chemical proc-

ess, then knowledge of the reagents capable of initiating

this process should throw light not only on the reaction

itself, but also on the nature of the gene, the other partner

in the reaction. Chemicals during this period were being

used primarily to unveil such genetic facts as the nature

of the gene and the structure of chromosomes.

In the late 1940s, the relationship between mutagenesis

and carcinogenesis also began to intrigue some investiga-

tors. A number of carcinogenic hydrocarbons had been

tested for mutagenicity as early as 1938. Interest in this as-

pect of research gained momentum during the latter part of

the 1940s and continued into the 1950s. Again it was Mul-

ler who stimulated much of this interest through his earlier

writings. In his classic article on the induction of mutations

by X-rays, Muller suggested the possibility that mutations

could cause cancer [Muller, 1927]. In a later article

[Muller, 1934], he again alluded to this possibility by stat-

ing . . . there is a similar danger of producing mutations

in somatic cells by radiation, which, in the case of tissues

in which mitosis occurs, may result in cancers, leukemia,

etc. Muller also mused at this time about whether muta-

tion would always be the tail of the cancer kite.

ANEWDIMENSION INMUTATION RESEARCH

In the mid-1950s a new chapter in the mutation

research story began to unfold. In Munich, the botanist

Alfred Barthelmess wrote an article (1956) titled Muta-

genic Drugs. Barthelmess had been interested in the

mutagenicity of chemicals for some time and had collected

numerous publications on the subject. While reviewing his

extensive literature collection, he saw that many com-

pounds listed in these documents were being used in medi-

cines, foods, and cosmetics. This observation prompted

him to write a review from his collected data. In this arti-

cle, Barthelmess made the following observation: For-

merly, therapeutical and toxicological considerations were

the main point of interest in studies on the action of drugs,

stimulants, food and mixtures, cosmetic agents, and so

forth. The results of research in genetics within the last

two decades call for increased consideration of possible

cytogenetic side effects and all their consequences.

Also, at this time, other scientists were expressing simi-

lar concerns. For example, Joshua Lederberg, a geneticist

at Stanford University and a Nobel laureate, began calling

for studies to determine if chemicals posed a hazard to

the germ cells of man. His concern was prompted by the

fact that a variety of chemicals had been shown to be mu-

tagenic in microorganisms [Lederberg, 1997]. During the

late 1950s, interest began to grow in the issue addressed

by Barthelmess, Lederberg, and others about whether

chemicals are potentially hazardous to the germline of

man and the accompanying issue of whether routine tox-

Environmental and Molecular Mutagenesis. DOI 10.1002/em

748 Wassom et al.

icity testing should include assays for mutagenicity before

approval of a chemicals use in human populations. This

interest was fueled by the work of Bill and Liane Russell

in the Biology Division of Oak Ridge National Labora-

tory. During the 1950s, these researchers developed a

very elegant system to test for inherited mutation at spe-

cic loci in mice following exposure to radiation and

chemicals. The Russells research made signicant contri-

butions to the issue of mammalian germ cell mutagenesis

and genetic risks to human populations from environmen-

tal agents [Russell, 1954].

This new dimension in the toxicity assessment of

chemicals (i.e., their assessment for adverse genetic

effects) was not to get its deserved emphasis until the

1960s, when several things happened that gave direction

to the questions and concerns raised earlier. For example,

at several important conferences in the 1960s, the ques-

tion of chemicals as a potential threat to man was dis-

cussed. At the First Erwin Bauer Memorial Lectures, held

in Germany, Auerbach delivered a paper, Chemical Mu-

tagenesis in Animals. In the section of her talk titled

Tests for Further Mutagens, she stated that as more

and more chemicals are used in therapeutics, food proc-

essing, and other industries, the testing of the substances

for mutagenic ability will become a necessary protective

measure [Auerbach, 1960].

Another signicant conference, sponsored in the United

States by the Josiah Macy, Jr., Foundation, took place in

the early 1960s and was attended by 23 prominent geneti-

cists. The third session of this conference was Mutagens

of Potential Signicance to Man and Other Species.

Avram Goldstein, a pharmacologist at the Stanford Uni-

versity School of Medicine, presented the lecture for this

session. In his opening remarks, Goldstein said, My

entire presentation here today may well be subjected to

the criticism that it is premature, that it makes much out

of little. He continued, . . . it would be improper to dis-

miss chemical mutagenesis in man merely because the

data thus far are weaker than in the case of radiation

[Goldstein, 1962].

This same problem (i.e., an imminent concern with lit-

tle experimental data to substantiate it) was expressed in

another forum in 1962. Frits H. Sobels, an internationally

known Drosophila geneticist, was asked to prepare a posi-tion paper on chemical mutagens for a World Health Or-

ganization (WHO) committee. He shared with the com-

mittee his concerns about the problems that could arise

from chemical mutagens in the human environment. Rem-

iniscing on this event over two decades later, Sobels

acknowledged that his talk before the WHO Committee

was heavy with speculation and that it aroused little im-

mediate interest; the time, he said, was just not right. The

time, however, was soon to come in 1969.

In 1963, Muller added his voice to those calling atten-

tion to the potential genetic risks to humans from environ-

mental chemicals. Muller was visiting the U.S. Food and

Drug Administration (FDA) in Washington and was

invited to give a seminar. Because he was an early pio-

neer in the eld of genetics and radiation mutagenesis, it

was thought that his seminar would dwell on the past.

Quite the contrary; when this Nobel laureate took the po-

dium, he spoke about a subject that he later admitted had

been bothering him for years. His concern was for the

health of man, not only for the present generation, but

also for those yet unborn. In his talk, Muller expressed

concern that humans were being exposed to a great num-

ber of substances (such as food additives, drugs, narcotics,

antibiotics, pesticides, cosmetics, contraceptives, air pollu-

tants, and water pollutants) not encountered by previous

generations and to which these exposed individuals had

not been specically adapted by natural selection

[Wassom, 1980]. Even though several other scientists

were expressing similar concerns, Mullers talk to the

FDA brought these concerns directly to the attention of

one of the principal regulatory agencies concerned with

protecting mans health from the adverse effects of chem-

icals.

Mullers remarks and those of others referred to above

began to take effect. Discussions among scientists

increased, and several meetings and conferences took

place. For example, in September 1966, the Genetics Study

Section of the National Institutes of Health (NIH) spon-

sored a conference on hazards to populations from induc-

tion of mutations by man-made chemicals. Some recom-

mendations made as a result of this conference would be

used later as the basic objectives around which the EMS

organization would be structured. In the discussions that

occurred during this NIH conference, James F. Crow, a

geneticist at the University of Wisconsin, made what has

become one of the most often quoted statements concern-

ing the potential danger to man from environmental chemi-

cals: There is reason to fear that some chemicals may

constitute as important a risk as irradiation, and possibly a

more serious one. Although knowledge of chemical muta-

genesis in man is much less certain than that of radiation, a

number of chemicalssome with widespread useare

known to induce genetic damage in some organisms. To

consider only radiation hazards is to ignore what may be

the submerged part of the iceberg [Crow, 1968].

ORIGIN OF THE EMS

The events described in the previous sections began to

stimulate interest and concerns in an ever-increasing num-

ber of scientists in the United States. One investigator

turned administrator, in particular, was motivated to

action, and this person would become one of the principal

driving forces in the establishment of genetic toxicology

as a distinct eld of inquiry. He was Alexander Hol-

Environmental and Molecular Mutagenesis. DOI 10.1002/em

Genetic Toxicology and the EMS 749

laender, who headed the Biology Division of Oak Ridge

National Laboratory, established in the early 1940s by the

Atomic Energy Commission, a predecessor of the U.S.

Department of Energy. The Division was one of the larg-

est and most formidable research facilities devoted to the

study of radiations biological effects. During the late

1950s and 1960s, Hollaender began to be concerned with

the potential mutagenicity of chemicals. Researchers in

his Division were allowed to wing it on their own by

trying new ideas and approaches in testing chemicals for

genetic effects. These extracurricular experiments were

done on condition that the primary work be completed on

time and all assigned project obligations met. Systems

being developed to test the genetic effects of radiation

were used to test chemicals with some notable successes.

As a result, Hollaender put his energy and resources into

this newly unfolding eld of genetic toxicology, and

some of the most notable research that helped establish

genetic toxicology as a distinct area of research came

from Hollaenders Biology Division. He recruited with a

vengeance, capturing talented investigators from through-

out the globe. He soon built up a research staff second to

none.

As a result of all that was happening in the late 1950s

and early 1960s, many scientists were becoming interested

in the issue of genetic risk. Some already were either in

positions or were later to assume positions from which

they could inuence the development of genetic toxicol-

ogy. From the ranks of these individuals (Hollaender, Fred-

erick J. de Serres, Heinrich V. Malling, Marvin S. Legator,

Ernst Freese, and Samuel Epstein), the idea arose to estab-

lish a society for those interested in this new eld of

research. In the summer of 1968, the core group formed an

ad hoc committee chaired by Hollaender to consider the

formation of a society and, to measure interest, distributed

a questionnaire to about 100 individuals, mostly in the

United States. The committee met on January 8, 1969, in

the ofces of Union Carbide Corp. in New York. Epstein,

secretary for the committee, reported that the idea of estab-

lishing a society had received overwhelming support from

respondents. The committee unanimously agreed that a so-

ciety devoted to the study of environmental mutagens

should be formed. The name EMS was considered espe-

cially apt because its initials corresponded with the abbre-

viation of the classic chemical mutagen of the day, ethyl

methane sulfonate. Naming the Society took place amid

some strong debate and discussion, but EMS was nally

chosen. EMS was formally inaugurated by its founders to

encourage the study of chemicals in the human environ-

ment for mutagenic effects and to promote scientic inves-

tigation and dissemination of information related to the

eld of genetic toxicology.

The founding members elected Hollaender the Soci-

etys rst president, Matthew Meselson vice-president,

Epstein secretary, and Legator treasurer. Elected to coun-

cil were de Serres, Freese, Malling, James Crow, and

Bruce Ames. The initial objectives outlined for the new

Society were (a) encouragement of interest in potential

hazards of mutagens in the human environment, (b) publi-

cation of a monograph on methodologies of mutagenicity

testing, (c) publication of a newsletter, and (d) formation

of a register of chemicals tested for mutagenicity in par-

ticular systems.

The secretary, Epstein, agreed to frame a constitution

for the Society, and President Hollaender and Freese con-

sented to arrange for its incorporation. Soon after the Jan-

uary meeting, the new council was enlarged; its members

invited James Neel, Ernest H.Y. Chu, Kurt Hirschhorn,

C.J. Kensler, Philippe Shubik, John Drake, George J. Cos-

mides, H.V. Gelboin, John J. Hanlon, Harold Kalter, Jack

Shubert, Leo Friedman, and Charles Edington to join. The

articles of incorporation for EMS were ofcially led

with the Recorder of Deeds, Corporation Division, Dis-

trict of Columbia, on May 12, 1969. Thus EMS was of-

cially born. The months preceding the Societys ofcial

organization and incorporation were accented by a urry

of activities. The ofcers and councilors busied them-

selves with formal meetings, phone conversations, and

correspondence as they planned the Societys future. Cat-

alyzed by Hollaenders boundless energy and enthusiasm,

committees were established to initiate activities in pur-

suit of achieving the new Societys goals and objectives

such as (a) setting up a registry of chemical mutagens, (b)

publishing a newsletter, (c) publishing a monograph series

on methods of testing for chemical mutagens, (d) sponsor-

ing roundtable discussions or workshops on specic topics

in the area of environmental mutagenesis, and (e) spon-

soring an annual meeting.

Hollaender, with his original and personal style of

motivation, encouraged these committees to action; to

catch a avor of his management style, refer to the

articles by [Setlow, 1987; Wilson and de Serres, 1987;

von Borstel and Steinberg, 1996; Gaulden et al., 2007].

At the August 4, 1969, council meeting held at the

National Academy of Sciences in Washington, the presi-

dent asked for a report on progress made to accomplish

the goals mentioned above. Following is a synopsis of

reports given by the various committee chairmen.

a. Malling announced that the EMS registry of chemicals

evaluated for mutagenic activity had been established

and formally designated as the Environmental Mutagen

Information Center (EMIC), with John Wassom

appointed its rst director. Malling also stated that an

article outlining EMICs organization was published in

the rst issue of the EMS newsletter.

b. De Serres announced that the rst issue of the EMS

newsletter had been printed (June 1969) and that 200

copies had been mailed to members and other inter-

ested individuals.

Environmental and Molecular Mutagenesis. DOI 10.1002/em

750 Wassom et al.

c. President Hollaender reported that negotiations with

Plenum Press to publish the EMS monographs were

complete and that manuscripts for the rst volume

were due to him by January 15, 1970.

d. Epstein reviewed the status of the committee on cycla-

mates appointed by the president on February 8, 1969.

Epstein reported that a proposal for funds to support a

conference on cyclamates had been drafted by the

committee for submission to appropriate government

agencies.

e. President Hollaender appointed Freese, Friedman, Lega-

tor, and Edington to the program committee that would

be responsible for the rst annual meeting.

Considerable progress was made on each of the Soci-

etys goals in a very short time. In addition to their com-

mittee work, ofcers and council members were responsi-

ble for preparing manuscripts for inclusion in the mono-

graph series rst volume as well as articles for the

newsletter. Because of the workload, the council was

enlarged by three new members during the August 4, 1969,

meeting with the addition of William L. Russell, Douglas

H.K. Lee, and Leslie E. Orgel. The program committee

appointed by President Hollaender to organize the rst an-

nual meeting had a critical responsibility; the future of the

edgling Society depended a great deal on the success of

this premier meeting. The committee recommended to the

president and council that the rst meeting be held in the

Washington, D.C., area and be structured around symposia

on topics of current interest. These general recommenda-

tions were adopted, and the program committee set out to

make the required arrangements.

The rst annual meeting was held March 2225, 1970,

at the Sheraton Park Hotel in Washington, which was

selected because it provided easy access to the meeting

by scientists within the federal government. This rst

meeting was attended by 268 people, of whom 169 were

members. The meeting was opened on Sunday evening,

March 22, by President Hollaender, who welcomed those

in attendance and briey reviewed the Societys objec-

tives and the agenda for the next few days. After his

remarks, Hollaender introduced H. Bentley Glass, who

gave the opening address. During the next 3 days, attend-

ees were exposed to 4 symposia comprising 18 invited

papers and 2 sessions of 28 contributed papers. Symposia

titles were Selected Methods of Mutagen Testing, Ba-

sic Aspects of Mutagenesis, Nitroso Compounds, and

Correlations and Population Monitoring. The two

invited paper sessions were on Effects of Environmental

Agents on Nonmammalian Systems and Effects of

Environmental Agents on Mammalian Systems. The

issues discussed during these presentations were timely

and produced considerable interest and postsession debate.

The rst annual meeting was most successful and helped

set the stage for the Societys future growth and develop-

ment.

In March 1970, the Societys membership was 452, of

whom 64 were from European countries. Because of this

interest, President Hollaender and Sobels collaborated and,

with the help of other European scientists, formed a Euro-

pean branch of EMS in the summer of 1970. In March

1989, the U.S. Society had 1,050 members, of whom 182

were from countries other than the United States. EMS

groups now can be found throughout the world and are

afliated through the International Association of Environ-

mental Mutagen Societies. Beginning in the 1980s and

intensifying in the 1990s, the Societys membership

dropped, as did the interest in environmental mutagenesis.

During this time, however, the mutation process and the

inuence of agents on genes was an area of interest in

many laboratories. Catalyzed by discoveries arising from

the Human Genome Project, the quest to discern the activ-

ities of newly discovered and sequenced genes grew signif-

icantly. Individual members of EMS were among investi-

gators conducting some of this type of work. The Society,

however, was slow to champion such experiments. Fortu-

nately, during the new century, EMS has begun to focus

more on this area. The eld has evolved considerably since

its beginning and has taken on many new dimensions.

EMS has also changed since its inception in 1969. We owe

a large debt of gratitude to the individuals who met and

took the action necessary to organize our Society formally.

Their dedication and hard work provide an excellent exam-

ple for us to follow today as EMS enters its 41st year. Cur-

rent Society leaders as well as the membership need to

adopt the enthusiasm and drive of our founders and forge

ahead with new ideas and goals.

ADVANCES IN GENETIC TOXICOLOGY TIMELINE

The1980s

MacGregor et al. [2000] have provided an excellent

review of the main developments in genetic toxicology

from the early years up to the late 1990s. Material for the

following paragraphs was obtained from this review. Fed-

eral agencies responsible for overseeing the health of peo-

ple living in the United States began recognizing the need

for testing environmental chemicals for mutagenicity.

This recognition led to the establishment of a working

group of the Department of Health, Education and

Welfare in 1974, which formulated testing requirements

in a key report issued in 1977 [DHEW, 1977]. Titled

Approaches to Determining the Mutagenic Properties of

Chemicals: Risk to Future Generations, this report

emphasized two key points: (a) the primary concern about

genotoxic damage was the potential to cause heritable

genetic alterations in the human germline and (b) quanti-

tative assessment of the risk of heritable damage was nec-

Environmental and Molecular Mutagenesis. DOI 10.1002/em

Genetic Toxicology and the EMS 751

essary and mere hazard identication was insufcient. The

landmark Toxic Substances Control Act of 1976 [see

Hollaender and de Serres, 1978] specically required the

U.S. Environmental Protection Agency (EPA) to establish

standards for the assessment of health and environmental

effects associated with mutagenesis. In retrospect, after

more than 30 years, all we can say is that we do not have

any direct evidence of a chemical inducing heritable muta-

tions in human germ cells and still are far from realizing the

second objectivequantitative health risk assessment.

In the mid-1970s, the milestone publications of Ames

et al. [1973] and McCann et al. [1975] demonstrated a

strong correlation of mutagenic activity in Salmonella withanimal carcinogenicity. The paradigm that emerged (i.e.,

that carcinogens are mutagens) and the design of the Sal-monella test system incorporating an external source ofmetabolism to identify potential carcinogens on the basis

of bacterial mutagenesis generated immense enthusiasm

that inexpensive in vitro mutagenesis screening tests could

be used to identify and control exposures to chemical

carcinogens. This important enhancement to the test proto-

cols for all in vitro test systems was conceived by one of

this manuscripts authors, Heinrich Malling, while he was

at Oak Ridge National Laboratory [Malling, 1966]. The

metabolic enhancement to in vitro tests was one criterion

used by EMS for presenting Dr. Malling with the prestigi-

ous Alexander Hollaender Award in 1988.

These publications created a restorm of activity as

many researchers saw this method as a cheap means of

identifying chemical carcinogens. As regulatory guidelines

were implemented during the 1970s and 1980s, this enthusi-

asm resulted in a shift in focus from germline mutagenesis

to control of chemical carcinogens [MacGregor, 1994].

Although these early results in Salmonella were highlypromising, it was already clear that mutations could arise

by several different mechanisms and that some of these

mechanisms would not be detected by the nutritional rever-

sion assay as measured by the Salmonella his2 reversiontest. In particular, chromosomal interchanges, DNA strand

breaks, and large chromosomal deletionsall characteristic

of damage induced by ionizing radiation (one of the envi-

ronmental mutagens of most concern during this period)

were found to be inefciently detected in the Ames assay.

Therefore, an in vitro battery of short-term tests was

devised that would detect the major classes of damage

known to result in heritable mutations [NRC, 1983]. These

early batteries typically included a bacterial test for gene

mutation, either an in vitro test for chromosomal aberra-

tions or a mammalian cell mutagenesis test, and a general

test for DNA damage. An in vivo test generally was encour-

aged, with preference for bone marrow chromosomal aber-

rations or micronucleus induction [e.g., Waters and Auletta,

1981; USFDA, 1982]. The test batteries were revisited from

time to time to incorporate modications and additions dic-

tated by experience and advances in knowledge.

The1990s

The initial conclusion that in vitro genotoxicity assays

were sensitive tools that could be used to detect genotoxic-

ity and the potential carcinogenicity of chemicals [Zeiger

et al., 1990; Ashby and Tennant, 1991] and thus to predict

human carcinogenesis [Ashby et al., 1996] was too simplis-

tic and ran into difculties [see MacGregor et al., 2000 for

details]. The view emerged that in vitro positives need to

be assessed in relevant in vivo assays. Furthermore, as ex-

perience with predictive models for carcinogenesis

increased, correlations between identied human carcino-

gens and experimental rodent carcinogens became evident,

as did the shortcomings of genotoxicity tests or their com-

bination in test batteries. Ames himself questioned the par-

adigm carcinogens are mutagens in a publication titled

Too Many Rodent Carcinogens [Ames and Gold, 1990].

Another method initiated over 40 years ago to predict

different types of biological activity including mutagenic-

ity, genotoxicity, and cancer used chemical structure to

forecast these untoward toxic events. Use of chemical

structure to predict chemical activity had intrigued investi-

gators almost from the time the structure of chemicals was

discerned and found widespread applications in medicine

and agriculture. However, it was not until the 1980s that

quantitative structure-activity relationships (QSAR) rst

found its way into the practice of most facets of toxicology.

Its staying power in the world of forecasting chemical reac-

tions may be attributed to the strength of its initial postu-

late that biological activity is a function of structure as

described by electronic attributes, hydrophobicity, and

steric properties. Methodologies and computational tech-

niques have been rapidly and extensively developed to

delineate and rene the many variables and approaches

that dene different techniques and models to predict bio-

logical events. QSAR has found favor with many toxico-

logists as a predictor for genotoxicity and is used as a

method of inference when a chemical or class of chemicals

has no toxicity data. QSAR also is used to rank chemicals

for testing in whole animals or other organisms, thus priori-

tizing the use of living systems to the best advantage.

Regardless of how good QSAR systems become, they cannot

be used as a unique substitute for animal testing. For inform-

ative reviews and applications of QSAR systems as predic-

tors of genotoxicology, see [Barratt and Rodford, 2001; He

et al., 2003; Mosier et al., 2003; Votano et al., 2004; Roth-

fuss et al., 2006; Piotrowski et al., 2007; Papa et al., 2008].

Other studies [Ashby and Tennant, 1988, 1991; Ashby

and Patton, 1993] assessing chemical structure with bio-

logical activity have provided very useful information

about relationships among molecular structure, genotoxic

activity, and carcinogenicity (primarily in rodents). The

recognition of denitive structural elements that confer

chemical reactivity, mutagenicity, and carcinogenicity

[Ashby and Tennant, 1991] has provided key structural

Environmental and Molecular Mutagenesis. DOI 10.1002/em

752 Wassom et al.

alerts for potential genotoxic or carcinogenic activity

and represents a major advance in the eld.

In 1993, the FDA published a revision of guidelines on

testing requirements for food and color additives that

included a test for gene mutations in bacteria (Salmonella);a test for gene mutations in mammalian cells in vitro with

the recommendation that the endpoint be based on an auto-

somal locus; and an assay for cytogenetic damage in vivo

with preference for a rodent bone marrow assay [USFDA,

1993]. At this time the European, Japanese, and Canadian

recommendations were essentially similar with some differ-

ences between regions and between regulatory agencies

[DNHW/DOE, 1988; Shirasu, 1988; Shelby and Sofuni,

1991; Kirkland, 1993; Purves et al., 1995]. Attempts have

been made at international harmonization of the genetic tox-

icology testing strategies and methods, and the Organization

for Economic Cooperation and Development has played a

major role in developing recommendations for internation-

ally harmonized testing protocols [see MacGregor et al.,

2000, for details]. Worth noting in this context are the activ-

ities of the International Commission for the Protection of

Environmental Mutagens and Carcinogens (ICPEMC),

which was founded in 1977 with the objectives of (a) identi-

fying and promoting scientic principles and (b) making

recommendations that might serve as the basis for guidelines

and regulations designed to minimize deleterious effects in

man and other biota due to the interaction of chemicals with

genetic material [Sobels, 1977; Lohman, 2002]. The inten-

tion was that ICPEMC would fulll a role similar to that of

the International Commission on Radiological Protection

(ICRP) in the radiation eld. However, after about two deca-

des of functioning and producing several reports, ICPEMC

has ceased to exist because of funding problems.

The 2000s (First Decade of the 21st Century)

Phenomenal advances in molecular biology during the

last few decades, sequencing of the human and other

genomes, and the formidable array of new and evolving

technologies and approaches associated with and devel-

oped for the genome projects are impacting all elds of

biomedical research. Toxicology is no exception.

Several recent articles and commentaries [e.g., NTP,

2004; Collins et al., 2008; Hartung, 2009; Hartung and

Rovida, 2009; Schmidt, 2009; Service, 2009; Sheldon and

Hubal, 2009; Stokstad, 2009; Zhu et al., 2009] and two

major reports [NRC, 2007; EPA, 2009] have assessed the

present state of the art in toxicology and the challenges

faced by the eld. The challenges include the very large

number of substances that need to be tested and the

means to incorporate and integrate recent advances in mo-

lecular toxicology, computational sciences, and informa-

tion technology. These assessments highlight the fact that

the core experimental protocols in toxicology have

remained nearly unchanged for more than 40 years and

that the testing of substances for adverse effects on

humans and the environment needs a radical overhaul if

we are to meet the challenges of ensuing health and

safety in the 21st Century [Hartung, 2009].

DEVELOPMENTS ACROSS THE GLOBE

United States

In 2004, the National Toxicology Program (NTP)

issued a document establishing an initiative to integrate

high-throughput screening and other automated screening

assays into its testing program [NTP, 2004]. The next

year, in 2005, EPA established the National Center

for Computational Toxicology. These two initiatives

prompted Francis Collins, who became the NIH Director

in 2009, to write that NTP and EPA are promoting the

evolution of toxicology from a predominantly observa-

tional science at the level of disease-specic models

in vivo to a predominantly predictive science focused on

broad inclusion of target-specic, mechanism-based bio-

logical observations in vitro [Collins et al., 2008]. Also

in 2005 EPA, with the support of NTP, asked the

National Research Council (NRC) to develop a long-range

vision for toxicity testing and a strategic plan for imple-

menting that vision. Both agencies wanted future toxicity

testing and assessment paradigms to meet evolving regu-

latory needs. The NRC Committee on Toxicity Testing

and Assessment of Environmental Agents produced two

reports, an interim one in 2006 and the nal in 2007

[NRC, 2007]. The 2007 report called for a major para-

digm shift, namely, transformation of toxicology from a

system based on whole animal testing to one founded pri-

marily on in vitro methods that evaluate changes in bio-

logic processes using cells, cell lines or cellular compo-

nents, preferably of human origin. Collins et al. [2008]

advocated a similar view: . . . we propose a shift from

primarily in vivo animal studies to in vitro assays, in vivo

assays with lower organisms, and computational modeling

for toxicity assessments.

NTP, EPA, and the National Institutes of Health Chem-

icals Genomic Center, with expertise in experimental toxi-

cology, computational toxicology, and high-throughput

technologies, respectively, are now collaborating to meet

the challenge of advancing the state of toxicology testing.

In March 2009, EPA issued its own strategic plan [EPA,

2009]. The plan asserts that the explosion of new scien-

tic tools in computational, informational, and molecular

sciences offers great promise to . . . strengthen toxicity

testing and risk assessment approaches [EPA, 2009;

Schmidt, 2009]. Thus goes the trend during this rst dec-

ade of the 21st Century in the United States to use com-

puters and databases as rst-echelon screening tools

before advancing to testing on living organisms, espe-

cially mammals.

Environmental and Molecular Mutagenesis. DOI 10.1002/em

Genetic Toxicology and the EMS 753

Europe

A different set of circumstances that precipitated the

need to reexamine the current toxicological tests in Europe

has been succinctly summarized by Hartung [2009] and

Hartung and Rovida [2009]. First, a program in the Euro-

pean Union (EU) is referred to as the Registration, Evalua-tion, and Authorization of Chemicals (REACH) Directive.The REACH Directive was introduced by legislation in

2007 for the safety assessment of chemicals. Whereas new

chemicals have been systematically evaluated in the EU

(and in the United States) for about a quarter of a century,

the safety of chemicals produced before 1981 (which

includes 97% of major chemicals in use and more than

99% of chemicals produced by volume) has not necessarily

been properly addressed. In fact, data for an estimated 86%

of these chemicals are still lacking evaluation, and the

REACH Directive or regulation seeks to redress this. The

regulation affects 27,000 companies that are required to

provide information on toxic properties and uses of 30,000

chemicals after a preregistration phase in 2008.

In recent decades, Europe has tested some 200 to 300 new

chemicals each year, making REACH an unprecedented

challenge that has and will continue to overburden existing

capacities [Hartung, 2009]. Second, when REACH was

negotiated between 2001 and 2005, several attempts were

made to estimate the regulations costs, both nancially and

in terms of the number of animals used for toxicity testing.

Hartung and Rovida [2009] have argued that complying

with REACH will require 54 million vertebrate animals and

cost 9.5 billion Eurossome 20 times more animals and 6

times the costs of ofcial estimates. Hartung [2009] argues

that these and other considerations underscore the compel-

ling need for a radical overhaul of the testing of substances

for adverse effects on humans. His vision toward a new reg-

ulatory toxicology, which has some similarities to that pro-

posed in the United States, include (a) mapping of toxicity

pathways by combining omics technologies and data

mining, (b) organotypic cell cultures and human tissues

derived from stem cells, (c) modeling of kinetics of substan-

ces (especially physiologically based pharmacokinetic mod-

eling) in an organism for extrapolating from effective tissue

concentrations to whole-organism doses, (d) in silico meth-

ods such as QSAR modeling, (e) imaging technologies and

automated testing, and (f) integration of technologies.

GENETIC TOXICOLOGY: ITS PLACE IN OLDANDPROJECTEDNEW LANDSCAPES OFTOXICOLOGICAL RESEARCH

Long-standing public policies governing chemical design,

production, and use need deep restructuring in light of new

methodology, techniques, and knowledge regarding the abil-

ity to discern the health and environmental effects or risks of

most chemicals now in commerce. Such restructuring of pro-

cedures for assessing toxicological and environmental risks

is essential to safeguarding ecosystems, human health, and

economic sustainability [Schwarman and Wilson, 2009].

The hopes of EMS founders for genetic toxicology in

the late 1960s were that (1) the eld would come to grips

quantitatively with transmissible genetic risks resulting

from exposure to environmental mutagens and (2) genetic

risks would become an integral part of toxicological con-

siderations that would provide the basis for regulatory

guidelines. The hope for such protection has not material-

ized. The elds initial emphasis on transmissible genetic

risks gave way to international testing guidelines that rely

heavily on batteries of test systems (of which germ-cell

tests are not an integral part) that permit hazard identica-

tion. Achieving the second objective, in turn, can be used

to make qualitative or semiquantitative judgment of poten-

tial human risk or to provide mechanistic information to

support quantitative carcinogenicity risk assessments. Em-

phasis in the new visions of toxicological tests also does

not appear to be on germ-cell mutagenesis. For instance, as

discussed earlier, the NRC Committee report (2007) pro-

posed in vitro testing as the principal approach with the

support of in vivo assays to ll knowledge gaps, including

tests conducted on nonmammalian species or genetically

engineered animal models. The eventual goal would be to

use genetically engineered in vitro cell systems, microchip-

based genomic technologies, and computer-based predic-

tive toxicological models to address uncertainties and to

ll knowledge gaps [Collins et al., 2008].

New policies are needed to confront the multiple chal-

lenges facing regulatory agencies as a result of the enor-

mous backlog of untested or inadequately tested chemicals.

Also needed is implementation of more-effective means to

phase out chemicals of concern and remove them before

funds are expended needlessly. There also is an urgent

need for methods that can apply emerging science to chem-

ical hazards for informing precautionary decision making.

New approaches should enable action in the face of scien-

tic uncertainty and should account for interrelated factors

affecting human health and ecosystems. Well-intentioned

environmental regulation has been plagued by the substitu-

tion of one hazard for another, such as the shifting of

chemical risks from air to water, from the general popula-

tion to workers, or from energy solutions to chemical haz-

ards [Schwarman and Wilson, 2009]. No one policy can

single-handedly prevent these missteps, but we must use

all our resources to accomplish this objective.

LET RADIATION CONTINUE AS THE PATHFINDER ANDMODEL FOR DETERMINING GENETIC RISKS FROM ANDPROTECTIVE MEASURES AGAINST TOXIC AGENTS

Quantitative Estimation of Genetic Risks ofExposure to Ionizing Radiation

The estimation of genetic risks to humans from radia-

tion exposure has been an ongoing scientic activity since

Environmental and Molecular Mutagenesis. DOI 10.1002/em

754 Wassom et al.

the late 1940s. A view gained popularity in the 1950s that

adverse genetic effects from radiation exposure would be

manifested as genetic disease in the progeny of exposed

parents and would be similar to those same diseases

occurring naturally in the population. Owing to the pau-

city of usable human radiation data, scientic committees

such as the United Nations Scientic Committee on the

Effects of Atomic Radiation (UNSCEAR) and the Biolog-

ical Effects of Ionizing Radiation (BEIR) committees of

the U.S. National Academy of Sciences devised indirect

methods to assess radiation genetic risks to humans. One

such method is called the doubling dose method that

has evolved over time and is still in use today. This

method relies on a combination of mouse data about

induced germ-cell mutations, human data on baseline fre-

quencies of naturally occurring genetic diseases, and pop-

ulation genetics theory. Current estimates of genetic risks

suggest that at low chronic doses of low linear energy

transfer (called LET) irradiations such as X or g irradia-tion (the radiation conditions traditionally used in risk

estimation), the risks are very small compared to the

baseline frequencies of genetic diseases in the population

[Sankaranarayanan and Chakraborty, 2000; UNSCEAR,

2001; BEIR, 2005]. Note that, in spite of compelling evi-dence for radiation-induced heritable germ-cell mutationsin animal systems, no direct evidence has been presentedfor radiation-induced heritable germ-cell mutationslet alone induced genetic diseasesin humans. The samegoes for chemicals. These statements hold true up to Oc-tober 2009, even after more than 60 years of intense

investigations. Genetic studies of A-bomb survivors in Ja-

pan have not shown any adverse effects in rst-generation

progeny that could be attributed to radiation exposures of

their parents (see UNSCEAR, 2001 and BEIR, 2005 for

detailed discussions).

Estimation of Genetic Risks From Chemical Mutagens andStatus of Protection

Some of the problems we face from chemicals are due

to the formidable variety of chemical compounds to

which humans may be exposed and their specicities

depending on species, strains, sex, and cell stages on

which they react and cause harm. Furthermore, this diver-

sity among chemicals in the environment gives a mixture

of denable correlations of the genetic endpoints scored

and also causes other confounding idiosyncratic activity.

The activities are due to, for instance, the lack of usable

dose-response relationships and complexities imposed by

pharmacokinetic factors (route of administration, distribu-

tion, and metabolic activation and deactivation both inside

and outside the target cells for genetic effects). On the

other hand, different kinds of ionizing radiation can be

described in terms of specic energy absorption that

allows the combining of effects of different kinds of radi-

ation on a unied basis, a luxury denied to those working

in chemical mutagenesis. For chemicals, genetic risk

assessments that rely on comparative mutagenicity tests

need to be made on a chemical-by-chemical basis and are

essentially qualitative. The recommendations on quantita-

tive limits of exposures for chemicals are based on quali-

tative assessments and extrapolations of risk to humans

from observations in test systems. In arriving at these rec-

ommendations, however, as in the case of radiation, intu-

ition and value judgments are used to supplement scien-

tic knowledge. The question remains open about whether

experience with radiation protection (other than the use of

intuition and collective wisdom to supplement scientic

knowledge) has any further lessons for protection against

chemical exposures.

Radiation Protection

Efforts at protecting people against the harmful effects

of radiation had their beginnings in the early 1900s and

have evolved over time [reviewed in Sankaranarayanan

and Wassom, 2008]. The earliest recommendations (in the

rst two to three decades of the 20th Century) were con-

cerned with avoiding threshold (deterministic) effects to

radiation workers, initially in a qualitative manner

because of the absence of a quantitative measure of radia-

tion dose. (Deterministic effects are those in which sever-

ity increases with the size of the dose; above a certain

threshold, the clinical effect is almost bound to appear,

for example, erythema or reddening and blistering of the

skin.) Protection of the public had not been an issue, in

part because facilities that could cause exposures to mem-

bers of the public were relatively few and fairly isolated.

With increasing use of radiation, the scope of radiation

protection had to be expanded considerably to take into

account the evolving new realities, including exposure to

fallout from nuclear weapon testing. With the adoption of

the roentgen (R) as the quantitative unit of radiation expo-

sure in the early 1930s, recommending dose limits to radi-

ation workers in quantitative terms became possible.

Other developments in dosimetry followed. Despite the

fact that Mullers discovery of X-ray mutagenic effects

was made in 1927, only in the mid-1950s did the view

gain momentum that genetic effects would be the princi-

pal effects of radiation at low doses. It was then that the

concept of regulating the overall average dose to the pop-

ulation and the view that the risk of genetic effects should

be used for setting dose limits (for workers, individual

members of the public, and to the population at large)

gained acceptance.

By the early 1960s, however, the radiation-protection

community recognized that cancer risks are much more

important quantitatively than are genetic risks. Over a pe-

riod of about 15 years, this shift in perspective led to the

development and adoption of a risk-based protection sys-

Environmental and Molecular Mutagenesis. DOI 10.1002/em

Genetic Toxicology and the EMS 755

tem recommended by ICRP in 1977 in which total sto-

chastic effects constitute the criterion for protection rec-

ommendations. (Stochastic effects result from damage in

a single cell for which the probability of the effect, but

not the severity, is proportional to dose size; cancer and

genetic effects are considered stochastic effects of radia-

tion, and, in the protection context, no threshold dose is

assumed for stochastic effects.) This system has been

rened over the years, with the most recent ICRP recom-

mendations appearing in 2007.

Four points deserve particular mention here. First,

within the framework of radiation protection, the relative

importance of genetic effects has progressively dimin-

ished over the years, from an estimated 25% in 1977,

18% in 1991, and 4% in 2007; this is not unexpected

because in a risk-based system of protection, cancer risks

spread among multiple organs and tissues contribute far

more to the total stochastic risks than genetic risks that

are limited to the gonads. Second, cancer risks pertain to

the exposed individuals themselves and genetic risks to

the descendants of those exposed. Therefore, these types

of risks are not strictly comparable with each other. Third,

there is no one-to-one correspondence between risks and

protection guidelines. Finally, in radiation protection, intu-

ition and collective wisdom have been and continue to be

used to supplement scientic knowledge. That is, value

judgments about the relative importance of different kinds

of risk and the balancing of risks and benets have

always been part of the decision-making process in radia-

tion protection.

TheWay Forward in Estimating the Genetic Risks ofRadiation Exposure and Possibilities forSimilar Efforts With Chemicals

Recent estimates of genetic risks from exposure of

human populations to ionizing radiation presented in the

2001 UNSCEAR report and the 2005 BEIR report incor-

porate two important concepts, namely: (a) most radia-

tion-induced mutations are DNA deletions, often encom-

passing multiple genes; however, because of structural

and functional constraints, only a proportion of induced

deletions may be compatible with viability and hence

recoverable in the progeny; and (b) viability-compatible

DNA deletions induced in human germ cells are more

likely to cause multisystem developmental abnormalities

than are single-gene diseases. The latter concept chal-

lenges the basic assumption that has dominated the eld

thus far that radiation-induced mutations will cause

genetic diseases similar to those occurring naturally as a

result of mutations in single genes.

Sankaranarayanan and Wassom [2005] believe that the

two concepts mentioned above provide a convenient

framework for computational modeling to determine

genetic risk estimation in the 21st Century using the

human genome as a starting point. They have used knowl-

edge from two contemporary elds of research, namely,

repair of DNA double-strand breaks (DSBs) in mamma-

lian somatic cells and human genomic disorders to con-

struct the framework for modeling. Knowledge from the

rst source highlights the relevance of evolutionarily con-

served DSB repair processes in the maintenance of

genomic integrity and enables us to understand how and

when the processing of DSBs by repair machinery can

generate deletions and other structural changes. Knowl-

edge from the second source (research on genomic disor-

ders) provides insights into how certain features of the

genomic architecture (e.g., presence of large segments of

repetitive DNA such as segmental duplications in specic

regions) constitute the staging ground in meiosis for

misalignment of homologous chromosomes. These fea-

tures also contribute to the occurrence of an error-prone

form of homologous recombination (HR), namely, nonal-

lelic homologous recombination (NAHR). The end results

of NAHR are large deletions or other rearrangements

characteristic of genomic disorders. Like HR, NAHR is

also associated with DSBs and their repair. Even cases of

deletions associated with human disorders whose origins

are not related to NAHR require DSBs and their repair.

Clearly, DSB repair processes underlie radiation-induced

structural changes in experimental systems and the origin

of similar changes in human genomic disorders. In their

article, the authors argue how insights from these two

areas of research can be extended to provide a framework

to (a) explain the origin of radiation-induced deletions in

stem-cell spermatogonia and oocytes, the germ-cell stages

of importance from the standpoint of radiation-induced

genetic risks and (b) predict which regions of the human

genome may be susceptible to radiation-induced large

deletions recoverable in live births.

We speculate that within the new visions of toxicology

for the 21st Century, as discussed earlier, there certainly

is room to consider approaches similar to the one dis-

cussed above for radiation that could be used to predict

potential genetic risks for specic environmental chemi-

cals or classes of chemicals with common structural fea-

tures. More specically, we envision the possibility of

integrating a body of knowledge to construct models and

run computer simulations to answer questions about the

magnitude of genetic risks posed by these chemicals. Pa-

rameters would include human genome data, nature of

mutations induced by specic chemical classes, DNA

repair processes of relevance, structure-activity relation-

ships and patterns, and levels of exposure. If needed,

appropriate animal experiments then could be carried out

to check the validity of the model predictions.

We believe that using ionizing radiation as the test agent

with the new genetic and genomic technologies will make

possible the identication of the much-needed smoking

gun that for the rst time will link human exposure to an

Environmental and Molecular Mutagenesis. DOI 10.1002/em

756 Wassom et al.

agent with the induction of heritable genetic damage. By

accomplishing this feat, the EMS reason for being, estab-

lished at its inception, will at last be vindicated.

FUTURE HISTORYCONSIDERATIONS AS EMSENTERS ITS 41ST YEAR

What does the future hold for EMS as it completes its

40th year? Clearly, there is a need for a new mission and

a specic set of goals for the Society to work towards

accomplishing. As discussed in the preceding pages, the

eld of genetic toxicology has evolved considerably since

its beginning and has taken on many new dimensions.

EMS also has changed since its inception. Since the Soci-

ety accomplished its original goals as outlined in this arti-

cle, a new course needs to be mapped. Concern over

agents in the environment that may cause inherited muta-

tions has waned during these latter years, and germ-cell

mutagenesis is hardly a concern at all. The current mis-

sion statement and goals (see Table I) are very good, but

the goals are generic. Although symposia on this subject

have been held at the Societys meetings from time to

time (including one for the 40th anniversary program), so

far, these programs have not catalyzed any tangible new

research activity. We believe this diminished interest in

mammalian germ-cell mutagenesis is, by and large, due

to our inability thus far to conclusively show that an envi-

ronmental agent, or any agent for that matter, can induce

heritable mutations in humans (in spite of substantial evi-

dence in mammalian and submammalian systems).

Why has it been difcult to obtain evidence for chemi-

cally induced heritable mutations in humans? Have we

dened what to look for? If you know what you are look-

ing for, you may or may not nd it. If you do not know

what you are looking for, you certainly will never nd it.

Is it a matter of sample sizes and dose levels? Or is it

because we have not yet come to grips with the right

indicators to measure adverse effects quantitatively? Is it

possible that the genetic risks are indeed smaller than has

been assumed? We hope EMS will ponder these ques-

tions. In the case of ionizing radiation, induced adverse

effects seem more likely to manifest themselves as multi-

system developmental abnormalities in the progeny rather

than as genetic diseases similar to those occurring natu-

rally as a result of spontaneous mutations in single genes

[Sankaranarayanan and Wassom, 2005].

Concurrently, the Society should encourage work on

evaluating the numerous high-throughput systems being

proposed for use in screening and prioritize agents requir-

ing health effects assessments for testing with focus on

mutagenic or genotoxic potential [Knight et al., 2009]. To

further strengthen the Societys foundation, it should con-

tinue its pursuit of the role that epigenetics plays in the

mutation process; thankfully, EMS has taken note of this

during the last few years. The Society also should con-

tinue to devote efforts to elucidating the mechanisms of

mutagenesis along with promoting studies on the physical,

chemical, and biological entities such as microRNAs,

stress, rogue proteins, and other physiological and genetic

factors that impact or inuence the mutation induction

process. The various special interest groups should be

continued and their activities should be integrated more

into future meeting programs. These groups are a good

source of articles on new developments and results from

their areas of interest.

The Society should institute a concerted effort to help

members deal with the problem of information access.

Genetic toxicology and related elds are experiencing an

information overload, and the InternetWorld Wide Web

only exacerbates the problem. A plea was made back in

1991 to keep EMIC or something like it going [Wassom

and von Halle, 1991], but the plea fell on deaf ears.

Something must be done to deal with this problem and

the sooner the better. Finally, the Society needs visiona-

ries, and we challenge EMS to appoint a group of such

individuals to be the vanguard of the Society with the

Environmental and Molecular Mutagenesis. DOI 10.1002/em

TABLE I. Current Mission and Goals of the Environmental Mutagen Society (EMS)

MISSIONThe EMS mission is (1) to foster scientic research and education on the causes and mechanistic bases of DNA damage and repair, mutagenesis,

heritable effects, epigenetic alterations in genome function, and their relevance to disease; and (2) to promote the application and communication

of this knowledge to genetic toxicology testing, risk assessment, and regulatory policymaking to protect human health and the environment.

GOALSProvide a broad scientic forum for basic and applied researchers, students, and teachers to share current scientic research and integrate knowledge

on detection and characterization of DNA damage from exposure to manmade or natural toxins in the environment, the molecular mechanisms of

DNA repair processes that respond to such damage, and the mechanisms of heritable changes (both mutagenic and epigenetic) that occur when

damage persists; understand how genomic and environmental factors interact to determine an individuals susceptibility to adverse health effects

and transgenerational defects from such exposure; apply this knowledge to assess the risks for adverse health consequences and damage to the

biota from environmental toxins.

Support responsible social and scientic policies by informing the public and by providing recommendations and guidelines to national and

international agencies that regulate genome-damaging agents to minimize human and environmental risks. Advance basic and applied genome

toxicity research by advocating for research support. Maintain a diverse membership that fosters and supports scientic interactions among

scientists worldwide across academia, government, and industry who are engaged in genome/epigenome toxicity research and its regulatory

applications.

Genetic Toxicology and the EMS 757

charge of monitoring scientic developments and offering

ideas for the organization to pursue.

HISTORYSEEN THROUGH THE LITERATURE

A number of articles have been written and published

related to the history of genetic toxicology and environ-

mental and chemical mutagenesis as well as timelines not-

ing signicant events that we wish to bring to the readers

attention. Some of the excellent papers listed in this article,

along with many others, can be obtained in searches via

Google (google.com) or Bing (bing.com) by using just the

terms genetic toxicology history, chemical mutagenesis his-tory, or mutagenesis history. Although timelines for theseareas are a mixed bag, we leave their value for you to

decide. Suggested keywords for timeline searching are

chemical mutagenesis timeline or mutagenesis timeline.

ACKNOWLEDGMENTS

The authors thank the editorial team appointed to put to-

gether a special issue of Environmental and Molecular Mu-tagenesis for its invitation to submit an article to help cele-brate the 40th anniversary of EMS. In a similar article writ-

ten in celebration of the Societys 20th anniversary, the

excellent assistance of Wilma J. Barnard was gratefully

acknowledged, and the article was dedicated to her for her

years of service to EMIC. Like so many workers in the

eld during the last 40 years, Wilma has passed away.

Many founding members of the Society are also gone,

along with many others who entered the eld since the be-

ginning of EMS. John S. Wassom, one of this articles

authors, passed away February 21, 2010. EMIC is also

gone, having served the Society and eld for 30 years

before it became history. Sincere thanks is given to the

many EMIC staff who pioneered the establishment of this

activity and monitored, collected, and processed the litera-

ture of chemical mutagenesis and genetic toxicology to

make this collected knowledgebase available to Society

members and others for 30 years. The authors gratefully

acknowledge all workers in the eldpast, present, and

future. You have made, are making, and will make a differ-

ence in the science on which genetic toxicology is based.

Last but most important, the outstanding editorial work of

Anne Adamson and Judy Wyrick of Oak Ridge National

Laboratory is gratefully acknowledged. They are two of

the best. Thank you, Anne and Judy.

The saddest aspect of life right now is that sciencegathers knowledge faster than society gathers wisdom.

Isaac Asimov

The history of science allows researchers to learn fromthe past, as the awareness of our intellectual roots pro-vides a basis for anticipating future goals and develop-ments. Matthias Glaubrecht

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