The Gene-Tox Program - Advances in Chemistry (ACS Publications)

8 The Gene-Tox Program

Downloaded by UNIV OF CALIFORNIA SAN DIEGO on August 24, 2015 | http://pubs.acs.org Publication Date: May 5, 1994 | doi: 10.1021/ba-1994-0241.ch008

Data Evaluation of Chemically Induced Mutagenicity Michael C. Cimino and Angela E. Auletta Office of Pollution Prevention and Toxics, Health and Environmental Review Division (7403), U . S . Environmental Protection Agency, Washington, DC 20460

The Gene-Tox Program of the U.S. Environmental

Protection Agency

is a multiphased effort to review and evaluate the existing literature in genetic toxicology (mutagenicity). In Phase I it selected assay systems for evaluation,

generated expert panel reviews of the data from

the scientific literature,

and recommended testing protocols for the

systems. Phase II established and evaluated the database for its relevance to identifying human health hazard.

The ongoing Phase III

continues reviewing the literature and updating chemical genetic toxicity data. Currently,

data exist on over 4000 chemicals in 36 assay

systems. The panel reports are published in the scientific and the data are also publicly available through the National of Medicine

TOXNET

system. Public

availability

literature, Library

should increase

Gene-Tox's utility, expand its analysis, and affect the manner and speed of its update.

T H E GENE-TOX PROGRAM o f the U . S . E n v i r o n m e n t a l P r o t e c t i o n A g e n c y ( U . S . E P A ) is a m u l t i p h a s e d effort to r e v i e w a n d evaluate the existing l i t e r ature i n c h e m i c a l l y i n d u c e d genetic toxicology. It has b e e n an o n g o i n g p r o j ect u n d e r the Office o f P o l l u t i o n P r e v e n t i o n a n d Toxics (formerly the Office of Toxic Substances) since its i n c e p t i o n i n 1979. T h e first phase o f the p r o g r a m , Phase I , was d e v o t e d to the selection of bioassays to b e evaluated, t h e evaluation o f literature b y w o r k groups o f experts i n each area, a n d the p u b lication o f reports o f the r e s u l t i n g reviews. T h e second phase, Phase I I , was d e v o t e d to t h e establishment o f a database o f chemicals evaluated b y each w o r k group a n d t h e analysis o f that database. T h e last a n d c u r r e n t phase, Phase I I I (ongoing efforts), is d e v o t e d to t h e c o n t i n u e d r e v i e w o f selected assays a n d the update o f the database. R e p o r t s o f all three phases are p u b This chapter not subject to U.S. copyright Published 1994 American Chemical Society

In Environmental Epidemiology; Draper, W.; Advances in Chemistry; American Chemical Society: Washington, DC, 1994.

ENVIRONMENTAL EPIDEMIOLOGY

90

l i s h e d i n the " R e v i e w s i n G e n e t i c T o x i c o l o g y " section o f the j o u r n a l tion Research

Muta-

(Appendix). Recently, t h e database has b e e n m a d e available

o n - l i n e t h r o u g h the Toxicology D a t a N e t w o r k system ( T O X N E T ) o f the N a tional L i b r a r y o f M e d i c i n e ( N L M ) .

Phase I Work Groups.

D u r i n g Phase I o f the P r o g r a m , w o r k groups o f ex-


perts r e v i e w e d a n d evaluated the p u b l i s h e d literature for 36 selected assays (Table I) to d e t e r m i n e the following for each system: Its v a l i d i t y ; the c h e m icals for w h i c h it was b e s t - s u i t e d (chemical-specific sensitivity o f the system); its p r o p e r test p r o t o c o l ; a n d the appropriate t e c h n i q u e s o f data analysis, i n t e r p r e t a t i o n , a n d presentation. In a d d i t i o n , each w o r k g r o u p was asked to evaluate t h e assay s ability to d i s c r i m i n a t e b e t w e e n mutagens a n d n o n m u t a g e n s or carcinogens a n d n o n carcinogens; to evaluate the s y s t e m s p e r f o r m a n c e w i t h c h e m i c a l s o f various classes a n d to identify chemicals w h o s e effects w e r e not adequately d e tected; to formulate g e n e r a l i z e d protocols a n d c r i t e r i a for data evaluation a n d validation; to identify areas r e q u i r i n g a d d i t i o n a l research o r further d e v e l o p m e n t a n d validation; a n d to p u b l i s h a n evaluation o f t h e assay i n the o p e n literature.

Literature.

L i t e r a t u r e for evaluation was p r o v i d e d to the w o r k

groups b y t h e E n v i r o n m e n t a l M u t a g e n Information C e n t e r ( E M I C ) , O a k R i d g e N a t i o n a l L a b o r a t o r y , O a k R i d g e , T e n n e s s e e . E M I C selected o n l y t h e p o r t i o n o f the available literature that m e t t h e following criteria: T h e article was a p r i m a r y p a p e r p u b l i s h e d i n a p e e r - r e v i e w e d j o u r n a l ; t h e article dealt w i t h c h e m i c a l mutagenesis,

not w i t h r a d i a t i o n - i n d u c e d mutagenesis; the

agent s t u d i e d was a p u r e c h e m i c a l ; t h e article c o n t a i n e d quantitative data; and the article was p u b l i s h e d i n E n g l i s h o r i n a language for w h i c h E M I C had easy access to a translation.

Evaluation.

T h e r e s u l t i n g articles w e r e evaluated b y the w o r k groups

for the following e l e m e n t s : p r o p e r use o f e x p e r i m e n t a l d e s i g n ; use o f positive and negative controls; p r o p e r selection o f solvents a n d v e h i c l e s ; acceptable spontaneous b a c k g r o u n d m u t a t i o n f r e q u e n c y o r rate; use o f m e t a b o l i c a c t i vation systems, i f necessary, as for i n vitro test systems; use o f a p p r o p r i a t e criteria for positive, negative, o r i n c o n c l u s i v e results; a n d p r o v i s i o n o f d o s e response information. T h i s last c r i t e r i o n was not c o n s i d e r e d critical i f all others w e r e m e t . In a d d i t i o n , each w o r k g r o u p was free to a p p l y o t h e r c r i teria that m i g h t b e specific to its p a r t i c u l a r assay. E v a l u a t e d chemicals w e r e designated

as positive

( + ), positive w i t h d o s e - r e s p o n s e

data p r o v i d e d

( + D ) , positive w i t h m e t a b o l i c activation o n l y (4- *), negative (—), o r e v a l uated b u t w i t h n o definitive c o n c l u s i o n (T).


8.

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Program

Table I. Assays Evaluated in Phase I and Updated in Phase III, Number of Chemicals in Database for Each Assay (As of April 22, 1994), and Gene-Tox Report (See Appendix)


Report Number

Number of Chemicals

Assay System Gene mutation Salmonella typhimurium" Escherichia coli Yeast Fungi Plants Drosophila sex-linked recessive lethal Chinese hamster lung cells (V79) Chinese hamster ovary cells ( C H O ) Mouse lymphoma L5178Y cells Mouse spot test Mouse visible specific locus test Chromosomal effects Yeast Fungi Plant cytogenetics Drosophila Mammalian cytogenetics in vitro Mammalian cytogenetics in vivo Micronucleus assay Dominant lethal assay Mouse heritable translocation assay D N A damage and repair Repair-proficient and -deficient bacteria Sister chromatid exchange in vitro Sister chromatid exchange in vivo Unscheduled D N A synthesis D N A repair Oncogenic transformation C e l l strains C e l l lines Viral enhancement Ancillary assays Host-mediated assay Body fluid analysis Sperm morphology a

a

a

0

0

0

0

0

0

0

0

0

0

2469 158 228 56 221 420 192 121 45 27 22

38 3 35 34 18,19,24,25 32 9 5,43 30 7 6

74 25 289 70 94 44 417 139 16

29 12,13 17,20,21,22,23 36 10 10 31,44 37 4

526

11

642 94 207 49

8,45 8,45 33 14

115 163 222

26 26 26

207 42 226

15 15 27,28

N O T E : The following assays will be added in Phase III; Drosophila SMART (somatic mutation and recombination test); Chinese hamster ovary cells (AS52); and mouse biochemical specific locus test. "Phase I assays that are being updated in Phase III.



92

Results of Phase I. B y the e n d o f Phase I , the w o r k groups h a d p u b l i s h e d 37 r e v i e w articles, 36 c o n c e r n e d w i t h assays i n genetic toxicology a n d 1 d e s c r i b i n g the establishment o f the G e n e - T o x carcinogen database ( I ; see also A p p e n d i x ) .


Phase 11 Fundamental Questions. I n a d d i t i o n to the p u b l i s h e d reports, a c o m p u t e r database of over 2000 chemicals h a d b e e n established at E M I C (2). A t the outset of the G e n e - T o x P r o g r a m , it was a n t i c i p a t e d that this database w o u l d b e amenable to t h e type of analysis that w o u l d answer a series of f u n d a m e n t a l questions i n genetic toxicology: • W h a t genetic a n d r e l a t e d e n d points are of c o n c e r n to h u m a n health? • H o w can toxicologists d i s t i n g u i s h test systems that are ready for extensive use i n testing from those that s h o u l d b e r e g a r d e d as still i n a d e v e l o p m e n t a l stage? • W h a t is the sensitivity o f each assay i n r e s p o n d i n g to specific classes o f chemicals, a n d what are t h e major strengths a n d weaknesses of each assay? • W h a t correlations exist b e t w e e n t h e mutagenesis a n d c a r c i n o genesis e n d points? • Is it possible to devise specialized batteries of bioassays that have h i g h probabilities of d e t e c t i n g t h e various types o f genetic a n d related damage i n d u c e d b y various classes of chemicals? • D o i n v i t r o mutagenesis a n d carcinogenesis bioassays p r o v i d e comparable estimates o f potency (strength o f response)? • W h a t information gaps a n d future research needs c a n b e i d e n tified, a n d what mechanisms can b e established for c o n t i n u i n g evaluation of the status of test systems? Unfortunately, c e r t a i n characteristics of t h e database have made s u c h an analysis difficult, i f not i m p o s s i b l e , to p e r f o r m .

Considerations. F o u r considerations are associated w i t h the G e n e Tox database. T h e first is that there is n o e v e n d i s t r i b u t i o n of chemicals across assay systems. F o r e x a m p l e , o f the m o r e than 1050 chemicals i n t h e Phase I Salmonella database, approximately 200 (~19%) h a d also b e e n tested i n a cancer bioassay. I n c o m p a r i s o n , 59 of t h e a p p r o x i m a t e l y 200 chemicals i n t h e mouse l y m p h o m a L 5 1 7 8 Y Phase I database (—30%) h a d b e e n tested i n a bioassay. T h e second consideration is that there has p r o v e d to b e little basis for comparative studies of mutagenesis assay systems. I n t h e Phase I database, 1559 chemicals, o r 5 9 % o f the total, h a d b e e n tested i n o n l y 1 o f t h e 36



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systems. C h e m i c a l s that h a d b e e n tested i n m o r e than one system w e r e , for the most part, e i t h e r d i r e c t - a c t i n g mutagens or those k n o w n to b e m e t a b o l i z e d to reactive intermediates b y l i v e r e n z y m e systems. T h i s may have made the sensitivity of the various systems appear u n n a t u r a l l y h i g h . T h e t h i r d consideration is that the database is s k e w e d to positive test results. W i t h the exception of the Salmonella assay, there is a paucity of negative test results i n the database i n general a n d i n the carcinogen database i n particular, i n w h i c h o n l y 61 of 506 chemicals evaluated h a d negative results. T h i s p r e p o n d e r a n c e of positive results is a reflection of the interests of the original authors, for w h o m positive results h o l d m o r e allure. It also reflects the greater ease i n p r o v i d i n g a conclusive positive result versus a conclusive negative one a n d the reluctance of scientific journals to p u b l i s h seemingly less i n t e r e s t i n g negative data. T h e fourth consideration is that the chemicals tested are u n e v e n l y d i s t r i b u t e d across the 30 c h e m i c a l classes u s e d i n the G e n e - T o x classification scheme (List 1). T h e most h e a v i l y tested classes are class 2 (acyl a n d a r y l halides, halogenated ethers a n d h a l o h y d r i n s , a n d saturated a n d unsaturated a l k y l halides), class 8 (aromatic amines, aliphatic amines, amides, a n d s u l fonamides), class 25 (benzene rings), class 29 (alcohols a n d phenols), a n d class 30 (heterocyclic rings not otherwise classified a n d unclassified c o m pounds). S u c h a d i s t r i b u t i o n makes an analysis of c h e m i c a l class specificity of the various assays difficult for a l l except the Salmonella assay, i n w h i c h a sufficient n u m b e r of chemicals have b e e n tested i n the various classes to p e r m i t a d e t e r m i n a t i o n of system performance a c c o r d i n g to c h e m i c a l class. R e s u l t s o f P h a s e I I , T h e Phase I I analysis r e s u l t e d i n three p u b l i cations o n the establishment of the database (2), the evaluation of m u t a g e n icity assays for the purpose of genetic risk assessment (3), a n d the d e v e l o p m e n t a l status of various assays for genetic toxicology testing (4; see also Appendix).

Phase 111 U p d a t i n g . A s part of the ongoing G e n e - T o x effort, c e r t a i n assays f r o m Phase I have b e e n selected for update (see Table I). I n a d d i t i o n , three assays not evaluated i n Phase I w i l l be a d d e d to the u p d a t e d database: the C h i n e s e hamster ovary ( C H O ) A S 5 2 assay, the Drosophila somatic m u t a t i o n a n d r e c o m b i n a t i o n tests ( S M A R T ) , a n d the m o u s e b i o c h e m i c a l specific locus test. A l t h o u g h the update process has b e e n s i m p l i f i e d i n c o m p a r i s o n w i t h that u s e d i n Phase I, the o v e r a l l objectives of the p r o g r a m a n d the basic w o r k - g r o u p structure r e m a i n i n place. O v e r 1500 chemicals have b e e n a d d e d to the database since the c o m p l e t i o n of Phase I, b r i n g i n g the total n u m b e r o f chemicals evaluated to over 4000. T h e basic features of the Phase III database are the same as those n o t e d for Phase I. T h e r e is still a paucity


94

ENVIRONMENTAL EPIDEMIOLOGY List 1.

Class 1 2

Chemicals

Included

Acridines, quinacridines, and benzimidazoles Acyl and aryl halides; halogenated ethers and halohydrins; and saturated and unsaturated alkyl halides Aldehydes and anhydrides Alkyl epoxides and aryl epoxides Alkyl sulfates, sulfoxides, sulfones, sulfonates, and organic sulfur compounds not otherwise classified Anthraquinones and quinones Antibiotics and mycotoxins Aromatic amines; aliphatic amines and amides and sulfonamides Aziridines and nitrogen and sulfur mustards Aromatic azo compounds, azoxy compounds, hydrazo compounds, diazoalkanes, nitriles, and azides Carbamates, ureas, thioureas, and dicarboximides Dioxins, xanthenes, thioxanthenes, and phenothiazines Halogens and inorganic derivatives, and sulfur and nitrogen oxides Hydrazides, hydrazines, and triazenes Hydroxylamines and amine N-oxides Lactones and organic peroxides Mineral fibers Nitroimidazoles, nitrofurans, nitroquinolines, nitroaromatics, and nitroalkanes Nitrosamides, nitrosoureas, and nitrosoguanidines Nitrosamines Organolead, organomercury, organophosphorus compounds, metals and derivatives, phosphoric acid esters, and phosphamides Poly cyclic aromatic hydrocarbons, fluorenones Pyrimidine derivatives, and purine derivatives Steroids Benzene ring Amino acids and derivatives Alkaloids Carbohydrates and derivatives Alcohols and phenols Heterocyclic rings not otherwise classified and unclassified compounds

3 4 5


Chemical Classification Scheme Used in Gene-Tox

6 7 8 9 10 11 12 13 14 15 16 17 18

:

19 20 21 22 23 24 25 26 27 28 29 30

o f n e g a t i v e test results; the m a j o r i t y o f t h e c h e m i c a l s e v a l u a t e d h a v e b e e n t e s t e d i n o n l y one s y s t e m , a n d c h e m i c a l class d i s t r i b u t i o n is e s s e n t i a l l y u n affected.

Analysis of the Gene-Tox Database.

T h e database for the Salmo-

nella assay n o w totals 2469 c h e m i c a l s (Table II). O f these, 326 have associa t e d c a r c i n o g e n i c i t y data (Table III): 268 are classified as c a r c i n o g e n s , a n d 58 are classified as n o n c a r c i n o g e n s . O f t h e 268 c a r c i n o g e n s , 210 are p o s i t i v e i n Salmonella, a n d 58 are n e g a t i v e . O f t h e 58 n o n c a r c i n o g e n s , 38 are n e g a t i v e i n Salmonella, a n d 20 are p o s i t i v e . " S e n s i t i v i t y " (the p r o p o r t i o n o f c h e m i c a l s t e s t i n g p o s i t i v e as b o t h m u t a g e n s a n d carcinogens versus t h e total


8.

CIMINO AND AULETTA Table II.

The Gene-Tox Program T h e Gene-Tox Salmonella Database

Test System Result

Number of Chemicals

Evaluated

2469 1100 666 416 18 880 489

Total number of chemicals evaluated Positive chemicals Positive without activation Positive with activation Positive without activation, negative with Negative Chemicals Chemicals with no definitive call


95

n u m b e r that are carcinogens) is 7 8 % ; " s p e c i f i c i t y " (the p r o p o r t i o n of tested chemicals that are b o t h n o n m u t a g e n i c a n d noncarcinogenic versus the total n u m b e r that are noncarcinogenic) is 6 5 % ; a n d " a c c u r a c y " (concordance—the p r o p o r t i o n of tested chemicals that are b o t h m u t a g e n i c a n d carcinogenic or that are b o t h n o n m u t a g e n i c a n d noncarcinogenic, versus the total n u m b e r of chemicals for w h i c h there are data i n b o t h systems) is 7 6 % . " P o s i t i v e p r e d i c t i v i t y " (the p r o p o r t i o n of tested chemicals that are b o t h carcinogenic a n d mutagenic c o m p a r e d w i t h a l l mutagens i n the assay) is 9 1 % , a n d " n e g ative p r e d i c t i v i t y " (the p r o p o r t i o n of tested chemicals that are n o n c a r c i n o genic a n d n o n m u t a g e n i c c o m p a r e d w i t h a l l nonmutagens i n the assay) is 39%.

Analysis of National Toxicology

Program (NTP) Database.

E v a l u a t i o n of the results f r o m the testing initiative of the N T P w i t h 114 chemicals (5) produces figures different f r o m those o b t a i n e d f r o m the G e n e Tox evaluation for the Salmonella assay: a sensitivity of 5 2 % , a specificity of 9 1 % , a concordance of 6 6 % , positive p r e d i c t i v i t y of 9 0 % , a n d negative p r e d i c t i v i t y of 5 5 % (Table I V ) .

Comparison of Gene-Tox and N T P Databases. I n c o n s i d e r i n g these differences i n test performances, w e s h o u l d observe several i m p o r t a n t differences b e t w e e n the G e n e - T o x a n d N T P databases. M o s t obvious is the Table III.

Result

Performance of Salmonella Assay (SAL) in Predicting Rodent Carcinogenicity ( C C G ) SAL Negative

SAL Positive

C C G positive

C C G negative

210 (78% sensitivity) (91% positive predictivity) 20

Total

230

58

38 (65% specificity) (39% negative predictivity) 96


Total 268

58

326


96 Table IV. Database

Sensitivity

Specificity

Accuracy (Concordance)

Positive Predictivity

Negative Predictivity

Gene-Tox

210/268 78%

38/58 65%

248/326 76%

210/230 91%

38/96 39%

35/67 52%

43/47 91%

75/114 66%

35/39 90%

43/78 55%

NTP

SOURCE: N T P


Comparison of the Gene-Tox and N T P Salmonella Databases

data are taken from reference 5.

o r d e r o f m a g n i t u d e difference i n t h e n u m b e r s o f chemicals for w h i c h t h e r e are data i n the t w o databases. I n the case of the Salmonella assay, the system for w h i c h t h e greatest n u m b e r o f chemicals have b e e n tested, m o r e than 2400 chemicals have test data i n G e n e - T o x versus 114 for N T P . M o r e i m portantly, the chemicals i n c l u d e d i n the N T P p r o g r a m w e r e selected a c c o r d i n g to d e f i n e d c r i t e r i a a n d w e r e tested a c c o r d i n g to p r e a r r a n g e d a n d stand a r d i z e d protocols, whereas c h e m i c a l selection i n G e n e - T o x database is m o r e r a n d o m (based o n i n d i v i d u a l authors' interests), a n d t h e protocols are v a r i e d . H o w e v e r , i n t h e case o f the Salmonella assay, t h e most l i k e l y reason for the r e p o r t e d differences i n sensitivity, specificity, p r e d i c t i v e ability, a n d concordance is p r o b a b l y r e l a t e d to c h e m i c a l class d i s t r i b u t i o n o f the agents tested. T h e G e n e - T o x c h e m i c a l classification s c h e m e is based o n selected o r ganic functional groups, r i n g systems, b i o l o g i c a l origins, a n d organic c o m position. C a r c i n o g e n s that have b e e n tested i n t h e Salmonella assay are m o r e apt to b e classified as halides, epoxides, sulfur c o m p o u n d s , mustards, xanthenes, n i t r o a n d nitroso c o m p o u n d s , nitrosamines, metals, p o l y c y c l i c aromatic hydrocarbons ( P A H s ) , steroids, a n d b e n z e n e rings t h a n w o u l d b e expected i f the c h e m i c a l s a m p l i n g w e r e r a n d o m . Noncarcinogens i n the G e n e - T o x Salmonella database are p r i m a r i l y h a l ides (class 2), aromatic amines (class 8), carbamates a n d ureas (class 11), n i t r o c o m p o u n d s (class 18), P A H s (class 22), a n d b e n z e n e r i n g c o m p o u n d s (class 25).

Usefulness of Mutagenicity Assays. O n t h e basis o f this analysis, it appears that the Salmonella assay c a n b e a useful tool for i d e n t i f y i n g r o d e n t carcinogens, as l o n g as attention is p a i d to t h e i m p o r t a n c e o f c h e m i c a l class w h e n results are i n t e r p r e t e d . Public Availability.

T h e G e n e - T o x database is n o w p u b l i c l y available

t h r o u g h t h e T O X N E T system o f the N L M . T h e T O X N E T u n i t r e c o r d for the G e n e - T o x database is s h o w n i n L i s t 2. T h i s is t h e structure o f the r e c o r d as u s e d b y the N L M ; i t shows the a b b r e v i a t e d f i e l d names u s e d i n storing


8.

C i M l N O A&D XfA&titA List 2.

the Gene-Tox Program T O X N E T Gene-Tox Unit Record: F i e l d Names and Descriptions

0.


1.

2.

97

GTN DATE RLEN UPDT ID NAME RN SY CCAT MSTU GENB

GENA

** Administrative information Gene-Tox number (sequential order) last revision date record length update history ** Substance identification name of substance C A S Registry Number synonyms chemical classification category ** Mutagenicity studies Gene-Tox evaluation B (post-1980) [species/cell type] [sex] [assay type] [assay code] [results] [activation] [dose response] [reference] [panel report] Gene-Tox evaluation a (pre-1980) [species/cell type] [sex] [assay type] [assay code] [results] [activation] [dose response] [reference] [panel report]

a n d searching for data a n d an e x p a n d e d explanation of the contents of that field. A n example of the data, a small p o r t i o n of the u n i t r e c o r d for f o r m a l d e h y d e , is s h o w n i n L i s t 3. I n the f u t u r e , u p d a t i n g the o n - l i n e database w i l l p r i m a r i l y b e the r e sponsibility of the E P A w i t h the assistance of E M I C . T h e update w i l l c o n t i n u e to m a k e use of the p e e r r e v i e w system i n a slightly m o d i f i e d f o r m . C h e m i c a l s to be a d d e d to the database w i l l c o n t i n u e to b e p u b l i s h e d i n Mutation Research: Reviews in Genetic Toxicology; w h e n the m a n u s c r i p t is s u b m i t t e d , the data w i l l s i m u l t a n e o u s l y b e a d d e d to the T O X N E T file. P r e s ently, this file contains a l l of the c h e m i c a l s e v a l u a t e d i n Phase I p l u s the results of the Phase I I I updates for the C H O - h y p o x a n t h i n e - g u a n i n e p h o s phoribosyltrarisferase, M c r o r i u c l e u s a n d see assays.


98

ENVIRONMENTAL EPIDEMIOLOGY List 3.

Gene-Tox Unit Record: Sample (Partial Record of Formaldehyde)


GTN UPDT RLEN NAME RN GENB

-

14 Complete update on 11/21/90, 6 fields added/edited/deleted 1593 formaldehyde 50-00-0

Species/cell type Assay type Assay code Results Reference Panel report

Chinese hamster ovary ( C H O ) cells gene mutation at the H G P R T locus CHOT no conclusion EMIC/53976; / . Toxicol Environ. Health 1983, 12; 27-38 EMIC/71517; Mutat. Res. 1988, 196, 17-36

Species/cell type Assay Assay code Results Reference Panel report

mammalian polychromatic erythrocytes, all species micronucleus test MNTT no conclusion EMIC/41641; Mutat. Res. 1981, 90, 91-109 EMIC/77345; Mutat. Res. 1990, 239, 29-80

Species/cell type Assay type Assay code Results Panel report

Neurospora crassa reverse mutation NER + positive EMIC/52327; Mutat. Res. 1984, J33, 87-134

GENB

GENA

Acknowledgments T h e E P A acknowledges the m a n y m e m b e r s o f the genetic toxicology c o m m u n i t y w h o have so g e n e r o u s l y g i v e n their t i m e a n d talent to c o n t r i b u t e to the success o f the p r o g r a m . W e are also grateful to J o h n W a s s o m a n d the staff o f the E M I C ,

a n d to D o r o t h y S t r o u p a n d t h e staff o f N L M for t h e i r

unfailing s u p p o r t , w i t h o u t w h o m this p r o g r a m w o u l d not b e possible.

References 1. Nesnow, S.; Argus, M.; Bergman, H.; C h u , K.; Frith, C.; Helmes, T.; M c Gaughy, R.; Ray, V.; Slaga, T. J.; Tennant, R.; Weisburger, E. Mutat. Res. 1987, 185, 1-195. 2. Ray, V. A.; Kier, L . D.; Kannan, K. L.; Haas, R. T.; Auletta, A . E.; Wassom, J . S.; Nesnow, S.; Waters, M . D . Mutat. Res. 1987, 185, 197-241. 3. Russell, L . B.; Aaron, C . S.; de Serres, F.; Generoso, W. M.; Kannan, K. L.; Shelby, M.; Springer, J.; Voytek, P. Mutat. Res. 1984, 134, 143-157. 4. Brusick, D.; Auletta, A . Mutat. Res. 1985, 153, 1-10. 5. Zeiger, E.; Haseman, J . K.; Shelby, M . D.; Margolin, B. H.; Tennant, R. W . Environ. Mol. Mutagen. 1990, 16(Suppl. 18), 1-14.


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99

Appendix L i s t o f P u b l i c a t i o n s o f the G e n e - T o x P r o g r a m o f the U.S. E P A


1

Introductory Papers 1. G r e e n , S.; A u l e t t a , A. "Editorial I n t r o d u c t i o n to the Reports of ' T h e G e n e - T o x P r o g r a m ' . A n E v a l u a t i o n o f Bioassays i n G e n e t i c Toxicology". Mutat. Res. 1980, 76, 165-168. 2. Waters, M. D.; A u l e t t a , A . " T h e G e n e - T o x P r o g r a m : G e netic A c t i v i t y E v a l u a t i o n " . J Chem. Inf. Comp. Sci. 1981, 21, 3 5 - 3 8 . Phase I Panel Reports 3. B r u s i c k , D. J.; S i m m o n , V . F.; R o s e n k r a n z , H. S.; Ray, V . A.; Stafford, R . S. " A n E v a l u a t i o n o f Escherichia coli W P 2 and W P 2 uvrA Reverse M u t a t i o n A s s a y " . Mutat. Res. 1980, 76, 169-190. 4. G e n e r o s o , W. M.; B i s h o p , J. B.; G o s s l e e , D. G.; N e w e l l , G. W.; S h e u , C.-J.; V o n H a l l e , E. " H e r i t a b l e Translocation Test i n Mice". Mutat. Res. 1980, 76, 191-215. 5. H s i e , A. W.; Casciano, D. A.; C o u c h , D. B.; K r a h n , D. F.; O'Neill, J. P.; W h i t f i e l d , B . L. " T h e U s e o f C h i n e s e H a m s t e r O v a r y C e l l s To Q u a n t i f y Specific L o c u s M u t a t i o n a n d T o Determine M u t a g e n i c i t y o f C h e m i c a l s . A R e p o r t o f the G e n e Tox P r o g r a m " . Mutat. Res. 1981, 86, 193-214. 6. R u s s e l l , L. B.; Selby, P. B.; V o n Halle, B.; S h e r i d a n , W.; Valcovic, L. " T h e M o u s e S p e c i f i c - L o c u s Test w i t h A g e n t s O t h e r T h a n Radiations. I n t e r p r e t a t i o n o f D a t a a n d R e c o m mendations for F u t u r e W o r k " . Mutat. Res. 1981, 86, 329354. 7. R u s s e l l , L. B.; Selby, P. B.; V o n Halle, E.; S h e r i d a n , W.; Valcovic, L. " U s e o f the M o u s e Spot Test i n C h e m i c a l M u tagenesis: Interpretaions o f Past D a t a a n d R e c o m m e n d a t i o n s for F u t u r e W o r k " . Mutat. Res. 1981, 86, 3 5 5 - 3 7 9 . 8. L a t t , S. A.; Allen, J.; B l o o m , S. E.; C a r r a n o , A.; F a l k e , E.; K r a m , D.; Schneider, E.; Schreck, R.; T i c e , R.; W h i t f i e l d , B.; Wolff, S. " S i s t e r - C h r o m a t i d E x c h a n g e s : A R e p o r t o f the G e n e - T o x P r o g r a m " . Mutat. Res. 1981, 87, 1 7 - 6 2 . 9. Bradley, M. O.; Bhuyan, B.; Francis, M. C.; Langenbach, R.; Peterson, A.; Huberman, E. "Mutagenesis by Chemical Agents i n V 7 9 C h i n e s e H a m s t e r C e l l s : A R e v i e w a n d A n a l 1

Reprints still available may be obtained from John S. Wassom, Environmental Mutagen

Information Center, Oak Ridge National Laboratory, Building 2001 Mail Stop 6050, P.O. Box 2008, Oak Ridge, T N 37831.


ENVIRONMENTAL EPIDEMIOLOGY ysis of the Literature. A R e p o r t of the G e n e - T o x P r o g r a m " . Mutat. Res. 1981, 87, 81-142.


10. P r e s t o n , R. J.; Au, W.; B e n d e r , M. A.; B r e w e n , J. G.; C a r rano, A. V.; H e d d l e , J. A.; M e F e e , A. F.; Wolff, S.; W a s s o m , J. S. " M a m m a l i a n I n V i v o a n d I n V i t r o C y t o g e n e t i c Assays: A report of the U.S. EPAs Gene-Tox Program". Mutat. Res.

lus

1981, 87, 143-188. 11. L e i f e r , Z.; K a d a , T.; M a n d e l , M.; Zeiger, E.; Stafford, R.; R o s e n k r a n z , H. S. "An E v a l u a t i o n of Tests U s i n g DNA R e p a i r - D e f i c i e n t B a c t e r i a for P r e d i c t i n g G e n o t o x i c i t y a n d Carcinogenicity. A R e p o r t of the U.S. EPAs Gene-Tox Program". Mutat. Res. 1981, 87, 2 1 1 - 2 9 7 . 12. Kafer, E.; Scott, B. R.; D o r n , G. L.; Stafford, R. "Aspergilnidulans: Systems a n d Results of Tests for C h e m i c a l Induction of M i t o t i c Segregation a n d M u t a t i o n . I. Diploid a n d D u p l i c a t i o n Assay Systems. A R e p o r t of the U.S. EPA GeneTox P r o g r a m " . Mutat. Res. 1982, 98, 1-48.

13. Scott, B. R.; D o r n , G. L.; Kafer, E.; Stafford, R . "Aspergilnidulans: Systems a n d Results of Tests for I n d u c t i o n of M i t o t i c Segregation a n d M u t a t i o n . I I . H a p l o i d Assay S y s tems a n d O v e r a l l Response of A l l Systems. A R e p o r t of the U.S. EPA Gene-Tox Program". Mutat. Res. 1982, 98, 49-94. 14. L a r s e n , K. H.; B r a s h , D.; C l e a v e r , J. E.; H a r t , R . W.; M a h e r , V. M.; Painter, R. B.; Sega, G. A. "DNA Repair Assays as Tests for Environmental Mutagens. A Report of the U.S. EPA Gene-Tox Program". Mutat. Res. 1982, 98, 287318. lus

15. Legator, M. S.; B u e d i n g , E.; B a t z i n g e r , R.; C o n n e r , T. H.; Eisenstadt, E.; F a r r o w , M. G.; F i s c o r , G.; H s i e , A.; S e e d , J.; Stafford, R. S. "An Evaluation of the Host-Mediated Assay and Body Fluid Analysis. A Report of the U.S. Environmental Protection Agency Gene-Tox Program". Mutat. Res. 1982, 98, 319-374. 16. C o n s t a n t i n , M. J.; O w e n s , E. T. " I n t r o d u c t i o n a n d P e r s p e c tives of Plant G e n e t i c a n d C y t o g e n e t i c Assays. A R e p o r t of the U.S. E n v i r o n m e n t a l P r o t e c t i o n A g e n c y G e n e - T o x P r o g r a m " . Mutat. Res. 1982, 99, 1-12. 17. C o n s t a n t i n , M. J.; Nilan, R. A. " C h r o m o s o m e A b e r r a t i o n Assays i n B a r l e y (Hordeum vulgare). A R e p o r t of the U.S. E n v i r o n m e n t a l P r o t e c t i o n A g e n c y G e n e - T o x P r o g r a m " . Mutat. Res. 1982, 99, 13-36. 18. C o n s t a n t i n , M. J.; N i l a n , R. A. " T h e C h l o r o p h y l l - D e f i c i e n t M u t a n t Assay i n B a r l e y (Hordeum vulgare). A R e p o r t of the


CIMINO AND AULETTA The Gene-Tox Program

U.S. E n v i r o n m e n t a l P r o t e c t i o n A g e n c y G e n e - T o x P r o g r a m " . Mutat. Res. 1982, 99, 3 6 - 4 9 . 19. R e d e i , G . P. " M u t a g e n Assay i n A r a b i d o p s i s . A R e p o r t of the U . S . Environmental Protection Agency Gene-Tox Program". Mutat. Res. 1982, 99, 243-255. Ma, T.-H. "Vicia Cytogenetic Tests for Environmental Mutagens. A Report of the U.S. Environmental Protection Agency Gene-Tox Program". Mutat. Res. 1982, 99, 257-271. 21. G r a n t , W . F. " C h r o m o s o m e A b e r r a t i o n Assays in Allium. A R e p o r t of the U.S. E n v i r o n m e n t a l P r o t e c t i o n A g e n c y G e n e Tox P r o g r a m . Mutat. Res. 1982, 99, 2 7 3 - 2 9 1 . 22. Ma, T.-H. "Tradescantia Cytogenetic Tests (Root-Tip Mitosis, P o l l e n M i t o s i s , P o l l e n M o t h e r C ell Meiosis). A R e p o r t of the U.S. E n v i r o n m e n t a l P r o t e c t i o n A g e n c y G e n e - T o x P r o g r a m " . Mutat. Res. 1982, 99, 2 9 3 - 3 0 2 . Downloaded by UNIV OF CALIFORNIA SAN DIEGO on August 24, 2015 | http://pubs.acs.org Publication Date: May 5, 1994 | doi: 10.1021/ba-1994-0241.ch008

20.

23. Van't H o f , J.; Schairer, L. A . "Tradescantia Assay System for Gaseous M u t a g e n s . A R e p o r t of the U . S . E n v i r o n m e n t a l P r o t e c t i o n A g e n c y G e n e - T o x P r o g r a m " . Mutat. Res. 1982, 99, 303-315.

formation

24. Plewa, M. J. " S p e c i f i c - L o c u s M u t a t i o n Assays i n Zea mays. A R e p o r t of the U . S . E n v i r o n m e n t a l P r o t e c t i o n A g e n c y G e n e - T o x P r o g r a m " . Mutat. Res. 1982, 99, 3 1 7 - 3 3 7 . 25. V i g , B . K . " S o y b e a n (Glycine max [ L . ] m e r r i l l ) as a S h o r t T e r m Assay for the S t u d y of E n v i r o n m e n t a l M u t a g e n s . A R e port of the U.S. E n v i r o n m e n t a l P r o t e c t i o n A g e n c y G e n e - T o x P r o g r a m " . Mutat. Res. 1982, 99, 3 3 9 - 3 4 7 . 26. H e i d e l b e r g e r , C.; F r e e m a n , A. E.; P i e n t a , R . J.; Sivak, A.; B e r t r a m , J. S.; Casto, B. C.; D u n k e l , V. C.; F r a n c i s , M. W.; K a k u n a g a , T.; Little, J. B.; S c h e c h t m a n , L. M. "Cell Transby Chemical Agents—A Review and Analysis of the L i t e r a t u r e . A R e p o r t of the U.S. E n v i r o n m e n t a l P r o t e c tion A g e n c y G e n e - T o x P r o g r a m " . Mutat. Res. 1983, 114, 283-385.

27. W y r o b e k , A. J.; G o r d o n , L. A.; B u r k h a r t , J. G.; F r a n c i s , M. W.; K a p p , R. W., Jr.; L e t z , G.; M a l l i n g , H. V.; T o p h a m , J. C.; W h o r t o n , M. D . "An Evaluation of the Mouse Sperm Morphology Test and Other Sperm Tests in Nonhuman Mammals. A Report of the U.S. Environmental Protection Agency Gene-Tox Program". Mutat. Res. 1983, 115, 1-72.0 28. W y r o b e k , A. J.; G o r d o n , L. A.; B u r k h a r t , J. G.; F r a n c i s , M. W.; K a p p , R. W., Jr.; Letz, G.; M a l l i n g , H. V.; T o p h a m , J . C.; W h o r t o n , M. D . " A n E v a l u a t i o n of H u m a n S p e r m as Indicators of C h e m i c a l l y I n d u c e d A l t e r a t i o n s of S p e r m a t o -




genie F u n c t i o n . A R e p o r t of the U.S. E n v i r o n m e n t a l P r o t e c tion A g e n c y G e n e - T o x P r o g r a m " . Mutat. Res. 1983, 115, 73148. 29. L o p r i e n o , N.; B a r a l e , R.; V o n H a l l e , E. S.; v o n B o r s t e l , R. C . " T e s t i n g of C h e m i c a l s for M u t a g e n i c A c t i v i t y w ith Schizosaccharomyces pombe. A R e p o r t of the U.S. E n v i r o n m e n tal P r o t e c t i o n A g e n c y G e n e - T o x P r o g r a m " . Mutat. Res. 1983, 115, 2 1 5 - 2 2 3 . 30. C l i v e , D.; M c C u e n , R.; Spector, J . F. S. P i p e r , C.; M a v o u r n i n , K . H. "Specific G e n e M u t a t i o n s i n L 5 1 7 8 Y C e l l s i n C u l t u r e . A R e p o r t of the U . S . E n v i r o n m e n t a l P r o t e c t i o n A g e n c y G e n e - T o x P r o g r a m " . Mutat Res. 1983, 115, 2 2 5 251. ;

31. H e d d l e , J. A.; H i t e , M.; Kirkhart, B.; M a v o u r n i n , K.; M a c G r e g o r , J. T.; N e w e l l , G. W.; Salamone, M. F. " T h e I n d u c t i o n of M i c r o n u c l e i as a M e a s u r e of Genotoxicity. A R e p o r t of the U.S. E n v i r o n m e n t a l P r o t e c t i o n A g e n c y G e n e - T o x P r o g r a m " . Mutat. Res. 1983, 123, 6 1 - 1 1 8 . 32. L e e , W . R.; A b r a h a m s o n , S.; V a l e n c i a , R.; V o n H a l l e , E. S.; W u r g l e r , F. E.; Z i m m e r i n g , S. " T h e S e x - L i n k e d Recessive L e t h a l Test for Mutagenesis i n Drosophila melanogaster. A R e p o r t of the U.S. E n v i r o n m e n t a l P r o t e c t i o n A g e n c y G e n e Tox P r o g r a m " . Mutat. Res. 1983, 123, 183-279.

33. M i t c h e l l , A. D.; Casciano, D. A.; Meltz, M. L.; R o b i n s o n , D. E. San, R. H. C.; W i l l i a m s , e n e - T o x P r o g r a m " . Mutat. Res. 1983, 123, 3 6 3 - 4 1 0 . 34. B r o c k m a n , H. E.; de Serres, F. J.; Ong, T.-m.; DeMarini, D. M.; K a t z . A . J,; G r i f f i t h s , A. J. F.; Stafford, R. S. " M utation Tests i n Neurospora crassa. A R e p o r t of the U.S. Environmental Protection Agency Gene-Tox Program". Mutat. Res. 1984, 133, 87-134. ;

35. Z i m m e r n m a n , F. K.; v o n B o r s t e l , R. C.; V o n H a l l e , E. S.; Parry, J. M.; S i e b e r t , D.; Z e t t e r b e r g , G.; B a r a l e , R.; Loprieno, N. " T e s t i n g of C h e m i c a l s for G e n e t i c A c t i v i t y w i t h Saccharomyces cerevisiae: A R e p o r t of the U.S. Environmental Protection Agency Gene-Tox Program". Mutat. Res. 1984, 133, 199-244. 36. V a l e n c i a , R. A b r a h a m s o n , S.; L e e , W. R.; V o n H a l l e , E. S.; Woodruff, R. C.; W u r g l e r , F. E.; Z i m m e r i n g , S. " C h r o m o some M u t a t i o n Tests for M u t a g e n e s i s in Dronosophila melanogaster. A Report of the U.S. Environmental Protection Agency Gene-Tox Program". Mutat. Res. 1984, 134, 61-88. ;



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37. G r e e n , S.; A u l e t t a , A.; F a b r i c a n t , J.; K a p p , R.; M a n a n d h a r , M.; S h e u , C.-j.; Springer, J.; Whitfield, B . " C u r r e n t Status of Bioassays i n G e n e t i c T o x i c o l o g y — T h e D o m i n a n t L e t h a l Assay. A R e p o r t of the U.S. E n v i r o n m e n t a l P r o t e c t i o n A g e n c y G e n e - T o x P r o g r a m " . Mutat. Res. 1985, 154, 4 9 67. 38. K i e r , L. D.; B r u s i c k , D. J.; A u l e t t a , A. E.; V o n H a l l e , E. S.; B r o w n , M. M.; S i m m o n , V. F.; D u n k e l , V.; M c C a n n , J.; M o r t l e m a n s , K.; P r i v a l , M.; Rao, T. K.; Ray, V. " T h e Salmonella t y p h i m u r i u m / M a m m a l i a n M i c r o s o m a l Assay. A R e port of the U.S. E n v i r o n m e n t a l P r o t e c t i o n A g e n c y G e n e - T o x P r o g r a m " . Mutat. Res. 1986, 168, 6 9 - 2 4 0 . 39. N e s n o w , S.; A r g u s , M.; B e r g m a n , H.; Chu, K.; Frith, C; H e l m e s , T.; M c G a u g h y , R.; Ray, V.; Slaga, T. J.; T e n n a n t , R.; W e i s b u r g e r , E. " C h e m i c a l C a r c i n o g e n s : A R e v i e w a n d Analysis of the L i t e r a t u r e of Selected C h e m i c a l s a n d the Establishment of the Gene-Tox Carcinogen Data Base". Mutat. Res. 1 9 8 7 , 1 8 5 , 1-195. P h a s e I I Assessment P a n e l R e p o r t s 40. R u s s e l l , L. B.; A a r o n , C. S.; de Serres, F.; G e n e r o s o , W. M.; K a n n a n , K. L.; Shelby, M.; Springer, J.; V o y t e k , P. " A R e p o r t of the U.S. E n v i r o n m e n t a l P r o t e c t i o n A g e n c y G e n e Tox P r o g r a m . E v a l u a t i o n of M u t a g e n i c i t y Assays for P u r poses of G e n e t i c R i s k Assessment". Mutat. Res. 1984, 134, 143-157. 41. B r u s i c k , D.; A u l e t t a , A. " D e v e l o p m e n t a l Status of Bioassays i n G e n e t i c Toxicology. A R e p o r t of Phase II of the U.S. Environmental Protection Agency Gene-Tox Program". Mutat. Res. 1985, 153, 1-10. 42. Ray, V. A.; K i e r , L. D.; K a n n a n , K. L.; H a a s , R. T.; A u l e t t a , A. E.; W a s s o m , J. S.; N e s n o w , S.; W a t e r s , M. D. "An Approach To Identifying Specialized Batteries of Bioassays for Specific Classes of Chemicals: Class Analysis Using Mutagenicity a n d C a r c i n o g e n i c i t y Relationships a n d P h y l o g e n e t i c C o n c o r d a n c e a n d D i s c o r d a n c e Patterns. 1. C o m p o s i t i o n a n d Analysis of the O v e r a l l D a t a Base. A R e p o r t of Phase II of the U.S. E n v i r o n m e n t a l P r o t e c t i o n A g e n c y G e n e - T o x P r o g r a m " . Mutat. Res. 1987, 185, 197-241. Phase I II Panel Reports 43. Li, A. P.; G u p t a , R. S.; H e f l i c h , R. H.; W a s s o m , J. S. " A R e v i e w a n d A n a l y s i s of the C h i n e s e H a m s t e r O v a r y / H y p o xanthine G u a n i n e P h o s p h o r i b o s y l Transferase Assay T o D e t e r m i n e the M u t a g e n i c i t y of C h e m i c a l A g e n t s . A R e p o r t of



104


Phase I I I of the U.S. E n v i r o n m e n t a l P r o t e c t i o n A g e n c y G e n e - T o x P r o g r a m " . Mutat. Res. 1988, 196, 1 7 - 3 6 . 44. M a v o u r n i n , K. H.; Blakey, D. H.; C i m i n o , M. C.; Salam o n e , M. R; H e d d l e , J. A. " T h e I n V i v o M i e r o n u e l e u s Assay i n M a m m a l i a n B o n e M a r r o w a n d P e r i p h e r a l B l o o d . A R e p o r t of the U.S. E n v i r o n m e n t a l P r o t e c t i o n A g e n c y G e n e Tox P r o g r a m " . Mutat. Res. 1990, 239, 2 9 - 8 0 . 45. Tucker, J. D.; A u l e t t a , A.; C i m i n o , M. C.; D e a r f l e l d , K. L.; J a c o b s o n - K r a m , D.; T i c e , R. R.; C a r a n n o , A. V. " S i s t e r C h r o m a t i d E x c h a n g e : S e c o n d R e p o r t of the G e n e - T o x P r o g r a m " . Mutat. Res. 1993, 2 7 9 , 101-180. RECEIVED

for

review

September

3,

1992.

ACCEPTED

revised

February 17, 1993.


manuscript

The Gene-Tox Program - Advances in Chemistry (ACS Publications)

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