Document 1464925

NATIONAL TOXICOLOGY PROGRAM BOARD OF S C I E N T I F I C COUNSELORS August 16-17, 1984 SUMMARY M I MUTES
Nat ional Toxicology Program
Board o f S c i e n t i f i c Counselors' Meeting
August 16-17, 1984 '
SUMMARY MINUTES
Paqe Numbers
Contents I. Peer Review and P r i o r i t y Ranking o f Chemicals Nominated f o r NTP Testing REV1EW OF NIEHS/NTP SYSTEMIC TOXICOLOGY
BRANCH PROGRAMS
11.
111.
Overview
Chemical D i s p o s i t i o n Section
A. Studies by Dr. Y. M. Ioannou
B. Studies by D r . B. I. Ghanayem
C. Studies by O r . ~ i n d aS. Birnbaum
D. Studies by O r . L. T. Burka
E. Extramural Program
5 . Fatz7e F ; z i s
IV.
V. Biochemical Toxicology Section
Immunological Toxicology Section
Extramural Program
B. Intramural Program
C. Future Plans
A. VI.
Concept Reviews:
Effect of the Ah Locus on Lifespan and Pathology o f Congenic Mice B. Development o f Ovari an Toxic i ty Screening Methods: Studies on tihe C l a s s i f i c a t i o n o f Ovarian F o l l ic:les as an I n d i c a t i o n o f Ovarian T o x i c i t y A. VII.
VIII.
Report o f the D i r e c t o r
-
NTP
F i n a l Report o f the -Ad Hoc Panel on Chemical Carcinogenesis Testing and Evaluation Attachments 1
-
11
N a t i o n a l ToxicoTogy Program Board o f S c i e n t i f i c Counselors * Meeting August 16 and 17, 1984 Summary M i nut e s
The N a t i o n a l T o x i c o l o g y Program (NTP) Board o f S c i e n t i f i c Counselors met on
August 16 and 17, 1984, i n t h e Conference Center, B u i l d i n g 101, South Campus',
N a t i o n a l I n s t i t u t e of Environmental H e a l t h Sciences, Research T r i a n g l e Park,
N o r t h C a r o l i n a (Attachment 1: Federal R e g i s t e r Meeting Announcement; Attactment
2: Agenda and Roster o f Members and E x p e r t C o n s u l t a n t s ) . Members o f t h e Belard a r e Drs Mortimer Mendelsohn (Chairperson 1, Norman Breslow, L e i 1a Diamond, C u r t i s Harper, J e r r y Hook, Jeanne Manson, Henry P i t o t , and James Swenberg. Dr. P i t o t was unable t o a t t e n d t h e meeting. .
The minutes o f t h e Board o f S c i e n t i f i c Counselors' meeting of March 27 and 28,
1984, were approved unanimously.
1. Peer Review and P r i o r i t y Ranking o f Chemicals Nominated f o r NTP T e s t i s :
(Attachment 3 ) There were 27 chemical nominations t o be considered by t h e
Board. A l l had been reviewed p r e v i o u s l y by t h e NTP Chemical E v a l u a t i o n
Cornmi t t e e (CEC). Dr. Mendelsohn c h a i r e d t h e r e v i e w and Drs. Dorothy Canter,
NIEHS, B a r r y Johnson, NIOSH, and M a r i l y n Wind, CPSC, members of t h e CEC, as w e l l
as O r . V i c t o r Funq, NTP Chemical S e l e c t i o n Coordinator, served as resource oerSGGS. Cad-, Guoi-4 iiio~ibc't iiad beeti dsked i u h e r ve a's p r i n c i p a l r e v i e w e r f o r t h r e e
o r f o u r chemicals except Dr. Swenberg who was asked t o l e a d t h e r e v i e w of s i x
n i t r o p y r e n e s . F o l l o w i n g o r a l p r e s e n t a t i o n o f each r e v i e w and d i s c u s s i o n , a
m o t i o n was made and voted on by t h e Board members.
The group of s i x n i t r o p y r e n e compounds, reviewed by t h e CEC on November 17,
1982, had been reviewed by t h e Board on September 27, 1983, and d e f e r r e d f o r
f u t u r e c o n s i d e r a t i o n so t h a t i n f o r m a t i o n c o u l d be p r o v i d e d on ongoing and
completed s t u d i e s by o t h e r o r g a n i z a t i o n s . Ms. A l i c e Freund, AFL-CIO, gave a
p r e s e n t a t i o n i n which she commented on t h e g r e a t l y increased uses of d i e s e l
engines and t h e broad groups o f workers b e i n g exposed t o n i t r o p y r e n e s . She
t h e r e had been l i t t l e animal t e s t i n g done although t h e need f o r s t u d i e s was
p o r t e d by t h e f i n d i n g o f p o t e n t e f f e c t s by some d t r o p y r e n e s on unscheduled
s y n t h e s i s . Dr. Jane Warren, H e a l t h E f f e c t s I n s t i t u t e (HEI), then addressed
Panel about s t u d i e s t h e HE1 was s u p p o r t i n g on b i o l o g i c a l e f f e c t s of n i t r o p y
i n s e v e r a l u n i v e r s i t y and p r i v a t e l a b o r a t o r i e s . The s t u d i e s were funded ha
t h e € and h a l f by t h e automotive i n d u s t r y and focused p r i m a r i l y on c a r c i n o g e n i c and mutabenic e f f e c t s e i t h e r i n -- t r o i n a v a r i e t y o f systems o r i n
v i v o by t h e i n h a l a t i o n r o u t e o f exposure. D r . Steven Nesnow, EPA, d i s c u s s e d t h a t agency's f i n d i n g s , n o t i n g t h a t most completed s t u d i e s had been done w i t h
complex m i x t u r e s such as d i e s e l exhaust. More s t u d i e s needed t o be done w i t h
i n d i v i d u a l n i t r o p y r e n e s . He supported e v a l u a t i o n o f t h e n i t r o p y r e n e s i n a bin:t e r y of s h o r t term t e s t s and c h r o n i c t e s t i n g ' o f 1 - n i t r o p y r e n e and
1 , 8 - d i n i t r o p y r e n e i n r-odeits by t h e gavage r o u t e . D r . Swenberg, as p r i n c i p a '
r e v i e w e r , agreed w i t h D r . Nesnow's recommendations and added t h a t r e p r o d u c t ve
and general t o x i c i t y s t u d i e s a l s o were needed. F u r t h e r , s i n c e s h o r t - t e r m t e s t s
were b e i n g o r had been performed by o t h e r s i n c l u d i n g H E I , a l l c l a s s members
would n o t need t o be evaluated i n a complete t e s t b a t t e r y .
vi
O f t h e remaining 2 1 chemical nominations t o be evaluated, 11 had been reviewed
w h i l e 10, i n c l u d i n g a group
by t h e CEC on May 31, 1983 (Attachment 3, Table I),
o f substances ( b l a c k n e w s p r i n t i n k s ) , had been reviewed by t h e CEC on Novemaer 8,
1983 (Attachment 3, Table 11). From t h i s l a t t e r group of nominations, t h e 3oard
made t e s t i n g recommendations on f i v e nominations. However, t h e Board recommended unanimously t h a t a c t i o n be d e f e r r e d u n t i l t h e n e x t meeting on f i v e
azo and n i t r o dyes (C.I.
D i r e c t Yellow 4, C.I. D i s p e r s e Brown 1, C.I. Basic Red
A c i d Yellow 151, and C.I. Direct, Red 80) t o a l l o w f o r a p r e s e n t a t i o n
18, C.I.
on t h e r a t i o n a l e f o r t h e nomination o f these dyes as r e p r e s e n t a t i v e o f t h e i z o
and n i t r o dyes c l a s s .
The Board's recommendations, p r i o r i t y f o r t e s t i n g , and a d d i t i o n a l remarks
and/or caveats f o r t h e twenty-seven nominations a r e summarized i n Attachmen: 4 .
REVIEW OF NIEHS/NTP SYSTEMIC TOXICOLOGY BR,ANCH PROGRAMS
11. Overview: (Attachments 5 and 6) D r . Bernard Schwetz, Branch Chief,
d e s c r i b e d t h e o r g a n i z a t i o n a l s t r u c t u r e o f t h e T o x i c o l o g y Research and T e s t i n g
Program (TRTP), t h e NIEHS component o f t h e NTP, and t h e o r g a n i z a t i o n o f t h e
Systemic T o x i c o l o g y Branch (ST61 which i s composed of f i v e s e c t i o n s :
biochemical t o x i c o l o g y , chemical d i s p o s i t i o n , imrnunotoxicology, f e r t i l i t y and
r e p r o d u c t i o n , and i n h a l a t i o n t o x i c o l o g y . Dr. Schwetz e x p l a i n e d how t h e pro(1rams
t o be reviewed f i t i n t o t h e t o x i c o l o g y e v a l u a t i o n process. He s a i d t h e major
s c i e n t i f i c o b j e c t i v e s o f t h e STB were t o h e l p improve methods f o r toxicological
e v a l u a t i o n , and t o b e t t e r understand mechanisms o f t o x i c i t y o f s e l e c t e d cheflii 1..
u
a.
a " ~L ~ U I I w a ~ O C ~OnS appiied ;-=it;clt"~-h
arid i i ~ e t i l u dd~e v e i ~ ~ l < ~ edln dL
v a l i d a t i o n along w i t h some b a s i c research on mechanisms, STB s t a f f serve as chemi c a l managers, as members o f t h e T o x i c o l o y Design Committee, as c o n s u l t a n t s t o
o t h e r l n s t i t u t e programs and t h e i n t e r a g e n c y Chemical Eva1 u a t i o n Committee, and
a c t i v e l y c o l l a b o r a t e w i t h p r o f e s s i o n a l s t a f f i n t h e i n t r a m u r a l r e s e a r c h procram,
o t h e r programs i n TRTP, and where a p p r o p r i a t e , w i t h o t h e r government agencies.
Dr. Schwetz handed o u t i n f o r m a t i o n on t h e r e s e a r c h and development c o n t r a c t s and
d i v i s i o n of s t a f f t i m e among research and a d m i n i s t r a t i v e o r s u p p o r t a c t i v i t i e s
f o r t h e t h r e e Branch programs t o be reviewed (Attachment 6 ) . He noted t h a t t i m e
would n o t a l l o w d e s c r i p t i o n o f a l l a c t i v i t i e s , j u s t s e l e c t e d ones.
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9
111. Chemical D i s p o s i t i o n Section: (Attachment 7) Dr. H.B. Matthews, S e c t i o n
Head, described t h e growth o f h i s program since i t s f o r m a t i o n i n 1979 and t h e
S e c t i o n ' s l a s t r e v i e w by t h e Board i n 1981. He s a i d t h e e a r l y o b j e c t i v e s of t h e
Sect i o n were focused on c h a r a c t . e r i z i n g t h e chemical d i s p o s i t i o n and pharm a c o k i n e t i c s o f chemicals w i t h s t r o n g p o t e n t i a l f o r bioaccumutation. More
r e c e n t l y emphasis has been placed on s u p p o r t i n g NTP experimental designs f o r
most chemicals through measuring r a t e s of a b s o r p t i o n , metabolism, clearance and
d o s e - r e l a t e d e f f e c t ? p r i o r t o i n i t i a t i o n of long-term t o x i c o l o g y and c a r c i n o g e n e s i s s t u d i e s . There i s a l s o increased p a r t - i c i p a t i o n i n more i n - d e p t h
t o x i c o l o g i c a l c h a r a c t e r i z a t i o n s t u d i e s as r e q u i r e d by t h e r e s u l t s o f long-term
t e s t s . The long-term o b j e c t i v e s o f t.he S e c t i o n are t o i n v e s t i g a t e s t r u c t u r e a c t i v i t y r ' e l a t i o n s h i p s , determine mechanismsof t o x i c i t y as r e l a t e d t o chemical
d i s p o s i t i o n , and develop d a t a which can be used i n cross-species e x t r a p o l a t i o n .
D r . Matthews commented t h a t n o t a l l chemicals coming i n t o the program a r e
s t u d i e d , e s p e c i a l l y when adequate s t u d i e s have been done by o t h e r s o r t h e y are
endogenous chemicals o r complex m i x t u r e s . However, t h e d i s p o s i t i o n o f over 100
chemicals has been evaluated s i n c e 1979 (Attachment 7, Table 1) w i t h 1 7 of these
chemicals e v a l u a t e d t o address s p e c i f i c q u e s t i o n s raised i n the l o n g - t e r m s t ~ d y .
-+
Emphasis has been g i v e n where p o s s i b l e t o examining s t r u c t u r e - a c t i v i t y r e l a - ,
t i o n s h i p s (chemical c l a s s s t u d i e s 1. He 1is t e d t h e personnel resources o f t h e
s e c t i o n and t h e e x t r a m u r a l support, c u r r e n t l y t h r e e c o n t r a c t s and one i n t e r - ,
agency agreement (Attachments 5 and 6).
He a l s o p o i n t e d o u t t h a t t h e j u n i o r
s t a f f members devote most o f t h e i r t i m e t o r e s e a r c h w h i l e t h e s e n i o r s t a f f d i v i d e s
t h e i r t i m e among research, c o n t r a c t m o n i t o r i n g , chemical management and s u p p o r t
activities.
Dr. Matthews discussed h i s own research p r o j e c t s o v e r t h e l a s t t h r e e years,
i n c l u d i n g : (1) t h e d i s p o s i t i o n o f f o u r a n i l i n e d e r i v a t i v e s ; ( 2 ) b l o o d t r a n s p o r t
of halogenated biphenyls; ( 3 ) d i s p o s i t i o n o f f u r a n i n response t o h e p a t o t o x i c i t y
a r i s i n g d u r i n g t e s t i n g ; ( 4 ) d i s p o s i t i o n o f benzyl a c e t a t e t o assess t h e r e l t t i o n s h i p between t o x i c i t y observed i n two-year s t u d i e s and d i s p o s i t i o n ( r o u t e
and dose dependency) ; and ( 5 ) d i s p o s i t i o n o f 2,3-di bromopropanol b y dermal t nd
o r a l r o u t e s . The l a t t e r s t u d y l e d t o a d e t a i l e d i n v e s t i g a t i o n o f how v a r i o i s
f a c t o r s i n chemical dosing can a f f e c t t h e degree o f chemical a b s o r p t i o n and
toxicity.
Discussion: D r . Lech asked whether a chemical d i s p o s i t i o n s t u d y performed c f t e r
c h r o n i c t e s t i n g has been completed may p r o v i d e answers which make r e p e a t o f t h e
c h r o n i c s t u d y unnecessary. Dr. Matthews s a i d t h i s was so c i t i n g t h e s t u d y k i t h
benzyl acetate.
A. S t u d i e s by Or. Y. M. Ioannou: A l l y 1 i s o t h i o c y a n a t e (AITC) was shewn
i n an NTP c h r o n i c s t u d y t o produce t r a n s i t i o n a l c e l l tumors o f t h e u r i n a r y
bidddei- hi tiidle I tits Liui nut i n l e i ~ i a l er a t 5 o r mice o f e i t h e r sex. O r . ioannou
d e s c r i b e d experiments on t h e m e t a b o l i c f a t e o f AITC i n b o t h sexes/species. These
s t u d i e s showed d i f f e r e n c e s i n metabolism between r a t s and mice, and sex d i f ferences i n r a t s . These r e s u l t s i n d i c a t e t h a t t o x i c i t y may have been due t c
s m a l l e r u r i n e volumes and decreased u r i n a r - y frequency i n male r a t s r e s u l t i n g i n
g r e a t e r a s s o c i a t i o n o f AITC and m e t a b o l i t e s w i t h b l a d d e r t i s s u e thereby
r e s u l t i n g i n g r e a t e r c h r o n i c s t i m u l a t i o n and tumor f o r m a t i o n . Other d i s p o s i t i o n
s t u d i e s by D r . Ioannou are d e s c r i b e d i n Attachment 7.
Discussion: I n response t o D r . Swenberg, D r . Ioannou s a i d t h e m e t a b o l i t e s h e r e
c a r r i e d i n t h e u r i n e and n o t formed i n t h e b l a d d e r
se. O r . Hook s t a t e d t h e
sex d i f f e r e n c e s i n u r i n a r y volumes were an i m p o r t a n t o b s e r v a t i o n i n a good
study. He cautioned a g a i n s t r e f e r e n c e t o t i s s u e l e v e l s o f a chemical as
r e s u l t i n g from increased b i n d i n g a f f i n i t y w i t h o u t f u r t h e r evidence f o r such a
mechanism.
6. S tudies by D r . B. I. Ghanayem: The b a s i s f o r t h i s research was the
o b s e r v a t i o n t h a t t h e r e were increased incidences o f forestomach tumors i n
s e v e r a l long-term r o d e n t t e s t s where a r e a c t i v e chemical was g i v e n by gavage.
Dr. Ghanayem described r e s u l t s obtained w i t h one such chemical, e t h y l a c r y l a t e ,
and s t r u c t u r a l analogs, methyl and n - b u t y l a c r y l a t e s , u s i n g o i l and water gavage
as w e l l as d i f f e r i n g c o n c e n t r a t i o n s o f chemical i n t h e v e h i c l e . The p r i n c i p a l
acute e f f e c t seen was edema o f t h e forestomach which progressed w i t h t i m e t o
s c a r r i n g and h y p e r k e r a t o s i s . T h i s s t u d y showed t h e t o x i c e f f e c t s o f e t h y l a z r y l a t e t o be dose, time, and c o n c e n t r a t i o n dependent. F u r t h e r , s t r u c t u r e - a c t i v i t y
s t u d i e s demonstrated t h a t acute t o x i c i t y decreased w i t h i n c r e a s i n g c h a i n l e n g t h
of t h e a l c o h o l moiety ( m e t h y l > e t h y l > b u t y l a c r y l a t e ) .
Discussion:
-
D r . Swenberg commented t h a t the r e s u l t s o f this study show the Jsef u l n e s s o f u s i n g t h i s t y p e o f study i n dose l e v e l and dose c o n c e n t r a t i o n s e t t i n g
f o r a l o n g - t e r m bioassay.
-
C.
S t u d i e s by Dr. L i n d a S . Birnbaum: Her research programs focus on c h ~ i m i c a l d i s p o s i t i o n , p a r t i c u l a r l y o f halogenatzed aromatic chemicals, mechanisms o f
t o x i c i t y as r e l a t e d t o chemical d i s p o s i t i o n , and aging as a m o d i f y i n g f a c t o - i n
chemical d i s p o s i t i o n and t o x i c i t y . S p e c i f i c p r o j e c t s d e s c r i b e d included: [ l )
i n v e s t i g a t i o n of species, s t r a i n and sex d i f f e r e n c e s i n t o x i c i t y o f
2,3,7,8-tetrachlorodibenzofuran (TCDF) and 2,3,7,8-tetrachlorodibenzo-p-diocin
(TCDD) as affected by metabolism, body f a t content, and d i f f e r e n c e s a t t h e ,\h
locus. Body f a t c o m p o s i t i o n seemed t o be t h e most i m p o r t a n t determinant o f
t o x i c i t y ; (2) a s t u d y o f t h e d i s p o s i t i o n o f Santonox (4,4' -thio-bisC6-t-but.f1m
- - c r e s o l l ) which showed t h a t delayed a b s o r p t i o n a f t e r o r a l d o s i n g was due t o
i n c r e a s e d r e t e n t i o n i n t h e stomach and severe i r r i t a t i o n b y t h e chemical.
L i n e a r a b s o r p t i o n occurred i n t h e small i n t e s t i n e f o l lowed b y h e p a t i c metabill ism
p r i m a r i l y t o a g l u c u r o n i d e conjugate; ( 3 ) d i s p o s i t i o n o f benzo(f ) q u i n o l i n e w i t h
r a p i d metabolism i n t h e r a t and about equal e x c r e t i o n i n u r i n e and feces; and
( 4 ) s t u d i e s on t h e mechanisms o f n e p h r o t o x i c i t y and l i v e r enlargement causeil b y
o-benzyl-p-chlorophenol which focused on tihe e f f e c t s of t h e chemical on changes
i n x e n o b i o t i c m e t a b o l i z i n g enzyme systems i n l i v e r and kidneys.
Dr. Birnbaum discussed h e r l a b o r a t o r i e s 1 i n v e s t i g a t i o n s o f t h e e f f e c t s of ailing
on chemical metabolism, d i s p o s i t i o n and/or t o x i c i t y i n r a t s , i n c l u d i n g : (11s t u d i e s o f t h e d i s p o s i t i o n o f two hexachlorobiphecyls (HCB) suggesting increased
body f a t i n o l d e r animals as a major f a c t o r i n decreased metabolism and excret i o n of chemicals; ( 2 ) s t u d i e s of a g e - r e l a t e d changes i n i n t e s t i n a l absorpt on
of chemicals u s i n g glucose analogs. These s t u d i e s suggest p a s s i v e a b s o r p t i o n i s
much l e s s a f f e c t e d b y senescence then a c t i v e t r a n s p o r t ; and ( 3 ) s t u d i e s nn -:he
L o i a i i ~ ebetween y l u ~ u unyi
r
L r dtihfer-ebe anu D - g l ucuron iuase enzymes ana now .ne
balance i n l i v e r and k i d n e y i s a f f e c t e d by aging. She r e p o r t e d on s t u d i e s
l o o k i n g a t i n t e r a c t i v e e f f e c t s o f TCDD and TCDF (which were o n l y a d d i t i v e ) ,tnd
o f TCDO and a p l a n a r HCB (which were s y n e r g i s t i c ) i n i n d u c t i o n o f c l e f t p a l i i t e ,
and a l s o o f i n t e r a c t i v e s t u d i e s w i t h t h y r o i d hormones. F i n a l l y , Dr. Birnbanm
d e s c r i b e d s t u d i e s o f t h e chemical d i s p o s i t i o n and t o x i c i t y o f two isomers 01'
hexabromonaphthalene b o t h contaminants o f t h e polybromi nated b i p h e n y l m i x t u r e ,
F i r e m a s t e r BP-6, i n v o l v e d i n t h e major environmental c o n t a m i n a t i o n episodes i n
Michigan.
Discussion: D r . Lech asked whether t h e y had s t u d i e d t h e r e l a t i o n s h i p between
changes i n body f a t l e v e l s and t h e area under t h e plasma l e v e l curve i n c h r o n i c
f e e d i n g s t u d i e s . Dr. Birnbaum agreed t h i s was i m p o r t a n t t o do b u t had n o t tieen
done i n her s t u d i e s a l t h o u g h o t h e r s had examined t h i s r e l a t i o n s h i p w i t h more
water s o l u b l e chemicals.
D.
Studies by D r . L. T. Burka: His niajor research i n t e r e s t s are i n (1' t h e
metabolism of x e n o b i o t i c s i n c l u d i n q i d e n t i f i c a t i o n o f m e t a b o l i t e s and products
o f t h e r e a c t i o n o f p a r e n t compounds o r m e t a b o l i t e s w i t h t i s s u e components, i ~ n d
( 2 ) i n v e s t i g a t i n g t h e chemical mechanisms o f m i xed f u n c t i o n oxidase metabol sm.
He commented on t h e use of p h y s i c a l o r g a n i c c h e m i s t r y techniques t o evaluate.'
changes i n r a t e s o f metabolism from d i f f e r e n t s u b s t i t u e n t s on t h e molecule. He
d e s c r i b e d s t u d i e s , u s i n g these techniques t o i n v e s t i g a t e t h e mechanisms of
cytochrome P-450 c a t a l y z e d h y d r o x y l a t i o n o f monohalobenzenes and d e m e t h y l a t o n of
p - s u b s t i t u t e d d i m e t h y l a n i 1 ities. He observed t h a t the problem f o r t h e f u t u r e 1ay
i n how t o expand r e s u l t s o b t a i n e d -in v i t r o t o t h e more complex environment 1ound
i n b i o l o g i c a l systems.
D r . Burka r e p o r t e d on t h e i d e n t i f i c a t i o n o f m e t a b o l ' t e s
f o r s e v e r a l chemicals c a r r i e d o u t i n c o l l a b o r a t i o n w i t h o t h e r members of the
section.
E. Extramural Proqram - Research C o n t r a c t s and I n t e r a g e n c y Agreements:
Dr. Matthews s a i d t h e c u r r e n t s h o r t and lona-term o b j e c t i v e s o f t h e extramuriil
program para1 l e l e d those f o r t h e i n t r a m u r a l 1 He b r i e f l y discussed t h e
accomplishments o f two v e r y p r o d u c t i v e c o n t r a c t s which have expired. One a t t h e
U n i v e r s i t y of Oregon was p r i m a r i l y concerned w i t h d e t a i l e d d i s p o s i t i o n s t u d i e s
o f b e n z i d i n e and b e n z i d i n e congener based dyes. The second e x p i r e d c o n t r a c t a t
t h e U n i v e r s i t y o f Arizona examined t h e d i s p o s i t i o n o f a number o f d i v e r s e chcmic a l s which have been o r are c u r r e n t l y i n NTP long-term t o x i c o l o g y and c a r c i nogenesi s s t u d i e s . These s t u d i e s addressled more than 20 chemical s, i n c l ud ing
i n v i t r o metabolism s t u d i e s of
dermal a b s o r p t i o n o f a number o f p h t h a l ates and -p o l y c h l o r i n a t e d b i p h e n y l s . The l a t t e r s t u d i e s were c a r r i e d o u t t o p r o v i d e
cross-species comparisons w i t h human, monkey and dog l i v e r microsomes.
New c o n t r a c t s i n c l u d e one a t t h e Research T r i a n g l e I n s t i t u t e through which wit
a r e s t u d y i n g t h e d i s p o s i t i o n o f a v a r i e t y o f chemicals i n c l u d i n g those t h a t i r e
v o l a t i l e (cyclohexane), s p a r i n g l y s o l u b l e i n b i o l o g i c a l media
( 1 - m i no-2,4-d ibromoanthraqui none, C I Vat Blue 1) and r e a c t i v e ( e t h y l a c r y l a :e,
t o l u e n e 2,6-diisocyanate, crotonaldehyde, and t - b u t y l perbenzoate). A seconil
c o n t r a c t a t Southern Research I n s t i t u t e b r i n g s a s t r e n g t h i n development of i n a l y t i c a l methodology u s e f u l i n d e s i g n i n g s e n s i t i v e assays f o r use w i t h nonr a d i o l a b e l l e d compounds and i n measuring g a s t r o i n t e s t i n a l a b s o r p t i o n o f
s p a r i n g l y s o l u b l e chemicals. T h i r d , t h e c o n t r a c t a t t h e U n i v e r s i t y o f Arizona
was r e i n i t i a t e d w i t h the focus b e i n g placed on s t u d y i n g chemical d i s p o s i t i o n o f
b i n a r y combinations o f e i g h t Superfund chemicals i n an e f f o r t t o d e t e c t addi:ive
or synerqistic toxicity.
Dr. Birnbaum described t h e a c t i v i t i e s a t t h e Lovelace Biomedical and
Environmental Research I n s t i t u t e under an i nteragency agreement w i t h the
Department of Energy. The major s t r e n g t h o f t h i s agreement i s t h a t the c a p a l i 1it y e x i s t s f o r d o i n g d i s p o s i t i o n s t u d i e s u s i n g i n h a l a t i o n exposure. Aims a - e
t o determine f o r a chemical by t h e i n h a l a t i ~ o nr o u t e h a l f l i v e s t o steady s t a t e ,
equi 1 ib r i u m concentrat.ions i n t a r g e t t i s s u e s , and major r o u t e s of e x c r e t i o n .
Data w i 11 be compared w i t h t h a t obtained by o t h e r r o u t e s such as i n t r a p e r i t o neal, o r a l o r i n t r a t r a c h e a l . Dr. Birnbaum discussed d i s p o s i t i o n s t u d i e s w i t i
2,3-dichloropropene and methyl bromide. Methodology has been developed w i t h azodicarbonamide f o r i t s a d m i n i s t r a t i o n as a d u s t and d i s p o s i t i o n o f the chemical
a f t e r i n h a l a t i o n exposure i s b e i n g compared w i t h t h a t by o r a l and i n t r a t r a c h s a l
a d m i n i s t r a t i o n . The agreement was expanded t o a l l o w repeated dose s t u d i e s i i
more than one species w i t h 1,3-butadiene and benzene, b o t h t o i n c l u d e
DNA-binding assays and the l a t t e r t o i n c l u d e v a r i o u s measures o f genetic t o x i city.
Discussion: D r . Harper i n q u i r e d whether t h e r e were s i g n i f i c a n t s t r e s s e f f e c t s
on the animals from use o f nose-only exposures. D r . Birnbaum r e p l i e d t h a t t h e r e
d i d n o t seem t o be.
The u l t i m a t e goal o f most s t u d i e s i n t o x i c o l o g y i s t o p r o v i d e i n f o r m a t i o n which
w i l l f a c i l i t a t e e x t r a p o l a t i o n o f l a b o r a t o r y d a t a t o humans. Dr. 3urka r e p o r t e d
t h a t NTP was s o l i c i t i n g proposals f o r up t o t h r e e c o n t r a c t s t o develop methodology which w i l l a l l o w comparison o f the metabolism o f f o r e i g n chemicals by human
t i s s u e s t o metabolism by l a b o r a t o r y species. I t i s expected t h a t most of the
methods w i l l u s e l i v e r t i s s u e b u t one c o n t r a c t may focus on e x t r a h e p a t i c
-.
t i s s u e s , e.g. kidney. Standard substances w i l l be used t o develop a d a t a bcse
and e v a l u a t e i n t e r s p e c i e s v a r i a b i l i t y .
Discussion: Dr. Lech asked whether t h e r e would be a p r o v i s i o n f o r s t u d y i n g t h e
t i m e course f o r s t a b i l i t y o f i s o l a t e d t i s s u e s . Dr. Matthews s a i d t h i s was an
i m p o r t a n t aspect of methods development.
F. F u t u r e Plans: Dr. Matthews s a i d t h a t i n a d d i t i o n t o c o n t i n u i n g p r i m a r y
s u p p o r t o f t h e t o x i c i t y t e s t i n g process from b e g i n n i n g t o end, a t t e n t i o n would
be g i v e n t o chemical d i s p o s i t i o n s mechanisms and t h e i r r e l a t i o n s h i p t o t o x i c i t y ,
development o f pharmacoki n e t i c models f o r d a t a f r o m NTP c h r o n i c studies, d i spos i t i o n s t u d i e s o f metals and m e t a l l i c complexes, and use o f -i n v i t r o systems.
I V . Biochemical Toxicology Section: (Attachment 8) Dr. Joyce Goldstein,
S e c t i o n Head, noted t h a t her r e s p o n s i b i l i t i e s as a Chemical Manager and as a
member of t h e Toxicology Design Committee r e q u i r e d about 40% o f her time. She
s a i d t h e p r i m a r y o b j e c t i v e o f h e r l a b o r a t o r y work over t h e p a s t f o u r y e a r s had
been t o examine t h e r e g u l a t i o n o f h e p a t i c cytochrome P-450 i n t h e r a t , t o
c o n t r i b u t e t o understanding o f t h e r o l e t h i s microsomal enzyme system p l a y s i n
a c t i v a t i o n and d e a c t i v a t i o n o f chemicals, and t o examine how t h i s system
responds t o i n f l u e n c e s such as age, sex and a d m i n i s t r a t i o n of f o r e i g n chemicals.
Dr. G o l d s t e i n proceeded t o d e s c r i b e several of t h e major p r o j e c t s completed a r
i n progress i n her l a b o r a t o r y .
(1) Recent emphasis has been on i s o l a t i n g a
.5'-HCB 1.
major isozyme o f P-450 induced b y a hexachlorobiohenyl (3.4.5.3\4'
~ ; i * - ~ i t t : ' < - l ~i -t lst ~aubsLr
~
d i e ; > p e1~ii o i i.y drni comparing i c w i t n o t h e r induced
isozymes. ( 2 ) A radioimmunoassay ( R I A ) u s i n g r a b b i t a n t i s e r a was developed i n
c o l l a b o r a t i o n w i t h Dr. Michael L u s t e r , STB, t o d e t e c t the P-450 isozymes -P-448MC,
P-448-HCB, and P-450-PB.
The procedure i s much more s e n s i t i v e t h a i
o t h e r techniques, such as r a d i a l immunodiffusion ( R I D ) , used i n t h e p a s t t o
measure P-450 isozymes. ( 3 ) The a b i l i t y o f t h e P-450 isozymes t o generate m ~ t a genic m e t a b o l i t e s from prernutagens was measured u s i n g a Salmonella assay. T i e
P-448-MC isozyme was shown t o be more e f f e c t i v e than t h e P-448-HCB form i n o n v e r t i n g benzo(a)pyrene and i t s 7,8-dihydrodiol t o mutagenic m e t a b o l i t e s , whi l e
t h e P-448-HCB was more e f f e c t i v e i n producing t h e N-hydroxylated m e t a b o l i t e ~f
2-acet.ylaminof1uorene (2-AAF).
( 4 ) An i n d e p t h study was done on t h e metabolism
i n v i t r o l i v e r systems o f 2-AAF t o b o t h t h e r i n g h y d r o x y l a t e d form ( i n a c t i v e
by -m e t a b o l i t e ) and the N-nydroxylated form b e l i e v e d t o be a s t e p i n a c t i v a t i o n :o
t h e mutagemc m e t a b o l i t e . Anti bodies t o t h e i sozymes were made and used t o
assess t h e c o n t r i b u t i o n o f the isozymes i n metabolism o f 2-AAF. The P-448-HGB
(5) The i n d u c t i o n by
form was again more a c t i v e i n N - h y d r o x y l a t i o n '
2,3,7,8-tetrach~orodibenzc-p-dioxin (TCDD) o f P-448-MC and P-448-HCB i n extrsihep a t i c t i s s u e s was studied. The P-448-MC was induced i n a l l t i s s u e s s t u d i e d
w h i l e P-448-HCB was induced o n l y i n l i v e r . (6) A study was done t o determine
whether cytochromes P-448-MC and P-448-HCB were induced c o o r d i n a t e l y i n l i v e r .
The d a t a obtained suggested t h a t the two isozymes are induced c o o r d i n a t e l y , jirob a b l y v i a a common mechanism.
O r . G o l d s t e i n discussed some o f the s p e c i f i c NTP chemicals t h a t the S e c t i o n had
worked w i t h over the past few years i n c l u d i n g t h e PCBs. An o b j e c t i v e i s t o
e x p l o r e e f f e c t s of exposure t o v a r i o u s chemicals o r c l a s s e s of chemicals on
P-450 isozyme r e g u l a t i o n i n t h e r a t and d e f i n e t h e consequence of changes
observed. Chemicals are n o t b e i n g screened e r se b u t are looked a t as pro1.0types and are examined f o r t h e i r a b i l i t y t o i n u G t h e P-450 isozymes i n h e p a t i c
and e x t r a h e p a t i c t i s s u e s . S p e c i f i c a l l y , she discussed i n d u c t i o n o f isozyme! and
f o r m a t i o n o f a n t i b o d i e s w i t h c l o f i b r a t e and d i e t h y l h e x y l p h t h a l a t e .
5
Dr. G o l d s t e i n discussed s t u d i e s b e i n g done b y o t h e r workers i n t h e Section. Dr.
Heather Yeowel 1 i s i n v e s t i g a t i n g metabol ism o f p r o s t a g l a n d i n s b y t h e P-450 i sozymes and t r y i n g t o r e l a t e t o x i c i t y t o changes i n metabolism, and i n c o l l a b o r a t i o n
w i t h Dr. E r n e s t Hodgson a t North C a r o l i n a S t a t e U n i v e r s i t y , she i s s t u d y i n g
i n t e r a c t i o n s of c e r t a i n methylene d i oxyphenyl compounds and 3-MC i n i n h i b i t i o n
of isozyme i n d u c t i o n . With Ms. P a t r i c i a McClel land-Green, Dr. G o l d s t e i n has
begun i s o l a t i n g and c h a r a c t e r i z i n g v a r i o u s c o n s t i t u t i v e isozymes o f P-450.
In
h e r c o n c l u d i n g remarks, Dr. G o l d s t e i n s t a t e d t h a t her l a b o r a t o r y c o u l d f u r t h e r
c o n t r i b u t e t o NTP programs b y p r e p a r i n g monoclonal a n t i b o d i e s t o t h e various
isozymes, and from t h e i r experience w i t h p r o t o t y p e chemicals, t h e y c o u l d
c l a s s i f y and c h a r a c t e r i z e NTP chemicals as t o t h e i r p o t e n t i a l f o r i n d u c t i o n of
chemical m e t a b o l i z i n g enzymes.
Discussion: Dr. Gasiewicz i n q u i r e d as t o whether t h e r e was cross r e a c t i v i t y of
t h e a n t i b o d i e s f o r r a t isozymes w i t h those f o r o t h e r species. D r . G o l d s t e i n
s a i d t h e r e was wide c r o s s species homology w i t h t h e e x c e p t i o n o f the chicken and
t h e y would be examining human t i s s u e ( s k i n c e l l s ) . Dr. Swenberg asked how these
s t u d i e s w i t h i s o l a t e d systems a p p l i e d t o t h e whole animal. Dr. G o l d s t e i n
i n v i v o and s a i d t h e y hoped t o do snmp
acknowledged t h e much g r e a t e r c o m p l e x i t y -'In
viva
adduct
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t
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d
i
e
s
a
i
d
would
ir.y
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i a L e auduci. f o r m a t i o n t o isozyme
7-
induction.
V.
Immunological Toxicology Section: (Attachment 9 ) D r . Michael Luster,
S e c t i o n Head, described t h e background, h i s t o r y and need f o r t h e program i n
immunotoxicology. He noted t h a t he and D r . Jack Dean had organized a consensus
conference in 1979, sponsored by t h e NTP, b r i n g i n g t o g e t h e r p r i m a r i l y immuno:og i s t s and t o x i c o l o g i s t s t o d e f i n e t h e c r i t i c a l issues i n t h i s s c i e n t i f i c area.
A t t h e conference, t h e types of assays needed t o measure immunotoxicity were
defined and given a p r i o r i t y order.
A. Extramural Proqram: Dr. L u s t e r s a i d t h e NTP immunotoxicology e f f s r t s
were c a r r i e d o u t through t h e in-house research groups and two research and d'velopment c o n t r a c t s . I n d e s c r i b i n g t h e extramural e f f o r t s , he noted t h r e e p r i m a r y
o b j e c t i v e s o f t h e c o n t r a c t s : (1) t o develop methodology f o r measuring h o s t
r e s i s t a n c e t o i n f e c t i o u s agents and t r a n s p l a n t a b l e tumor c e l l s ; ( 2 ) t o e s t a b l i s h
a standard s e t o f immunologic assays; and ( 3 ) t o i n t e g r a t e and v a l i d a t e t h e s ?
assays u s i n g chemicals o f i n t e r e s t t o the NTP. The f i r s t two phases have b e ~ ? n
completed. Chemicals t h a t were used i n t h e developmental and v a l i d a t i o n phases
i n c l u d e d known immunosuppressants -- cyclophosphamide, d i e t h y l s t i l b e s t r o l ,
d i m e t h y l n i t r o s a m i n e , and cadm'um.
A 1 1 chemicals examined f o l l o w i n g the v a l i l i a t i o n phase have been from those t e s t e d i n NTP p r e c h r o n i c and long-term toxic1)l o g y and carcinogenesis s t u d i e s . D r . L u s t e r reviewed t h e assays comprising t h e
immunological and h o s t r e s i s t a n c e screening panel. I n c l u d e d are measures o f
immunooathology, h o s t r e s i s t a n c e , c e l l - m e d i a t e d and humora'i immunity, and
macrophage f u n c t i o n . Most r e c e n t l y added was h y p e r s e n s i t i v i t y s k i n t e s t i n g n
..
mice as many i n d u s t r i a l chemicals and NTP chemicals a r e a1 lergens. Dr. L u s t e r
d e s c r i b e d i n more d e t a i l s e v e r a l o f these assays, t h e types o f d a t a t h a t can be
obtained, and t h e i r b i o l o g i c a l relevance. Dr. L u s t e r noted t h a t t h e dose l e v e l s
used i n these s t u d i e s were comparable t o those used i n t h e 14-day repeat o r ;woy e a r c h r o n i c s t u d i e s . He discussed some o f t h e i n f e c t i v i t y models chosen wi:h a
f o c u s on t h e tumor s u s c e p t i b i 1 it y and mouse m a l a r i a models. The primary e f f o r t
r e m a i n i n g on t h e two c o n t r a c t s i s completion o f t h e t e s t i n g phase f o l l o w e d b:f
d a t a r e d u c t i o n and a n a l y s i s .
/-
L
Discussion: Dr. Swenberg asked whether t h e r e was an a d a p t i v e response o f t h e
immune system t o chemical e f f e c t s a f t e r c h r o n i c a d m i n i s t r a t i o n . Dr. L u s t e r s a i d
t h a t s t u d i e s w i t h tetrahydrocannabinol and cadmium c h l o r i d e u s i n g d i f f e r e n t
dosing regimens a r e p r e s e n t l y b e i n g performed t o s t a r t answering such questions
.
B. I n t r a m u r a l Program: To i n t r o d u c e d i s c u s s i o n o f t h e in-house progr'ims,
Dr. L u s t e r reviewed t h e genesis o f t h e d i f f e r e n t c e l l types comprising t h e
immune system and t h e f u n c t i o n s o f each type. He l i s t e d known o r p o t e n t i a l
immunotoxins o f NTP i n t e r e s t i n c l u d i n g estrogens, p o l y c y c l i c aromatics, p o l y l i a l ogenated aromatics, t h i a z o l e s , and mycotoxins. Selected chemicals examined i n
depth in-house over t h e p a s t t h r e e years i n c l u d e benzidine, diphenylhydantoin,
d i e t h y l s t i l b e s t r o l and TCDD.
Dr. Anne Tucker described s t u d i e s w i t h d i p h e n y l h y d a n t o i n (DPH). Up t o 60%
o f humans t a k i n g DPH e x h i b i t c l i n i c a l s i g n s c h a r a c t e r i s t i c o f humoral immunolleficiency.
I n mice, i n d i c a t o r s o f humoral immunity were depressed as was hos".
i c a <atdiiLiC :1 1-1 r1 t- i-~Ai:t n-.-- ~wi i i t d PId~ifiudiuiiip e l i i . me mobi. sensi Live b i Le was Lne
-.
bone marrow where t h e r e was l o s s o f t h e m u l t i p o t e n t stem c e l l s a f t e r one weec.
Concurrent a d m i n i s t r a t i o n o f f o l i c a c i d p r o t e c t e d a g a i n s t t h e loss, i n d i c a t i i g
t h a t DPH operates v i a an a n t i f o l a t e mechanism t o a l t e r stem c e l l k i n e t i c s i n t h e
mouse.
Dr. Tucker discussed s t u d i e s w i t h b e n z i d i n e as a p r o t o t y p e aromatic amine. She
summarized immune system e f f e c t s o f t h e chemical as b e i n g depressions o f
lymphocyte a c t i v a t i o n , c e l l - m e d i a t e d immunity, and h o s t r e s i s t a n c e . Experiments
were performed t o determine whether b i o t r a n s f o r m a t i o n o f benzi d i ne was in v o l i e d
i n U s immunosuppressive e f f e c t s . A c e t y l ated o r h y d r o x y l ated metabol it e s fo-med
i n t h e l i v e r were shown n o t t o be a c t i v e . However, b e n z i d i n e o r methylated
d e r i v a t i v e s serve as a c o - o x i d a t i o n s u b s t r a t e f o r arachadonic a c i d metabolism.
She s a i d they p o s t u l a t e d t h a t t h e b e n z i d i n e e f f e c t s were mediated by t h e h i g i
l e v e l s of hydroxy f a t t y acids generated through t h e lipoxygenase pathway.
D r . L u s t e r described s t u d i e s on t h e e f f e c t s o f TCDD on the immune system. H z
c o n t r a s t e d the long- l a s t i n g suppression of T - c e l l f u n c t i o n i n animals exposej
p e r i n a t a l l y vs. exposure o f a d u l t animals which produces suppression of 0 - c e l l
and bone marrow f u n c t i o n s . He discussed the r o l e o f t h e Ah r e c e p t o r i n t h e
t o x i c e f f e c t s of TCOO and ooted t h a t mouse s t r a i n s w i t h h i g h l e v e l s of o r h i g h
a f f i n i t y of t h e TCDD r e c e p t o r showed marked immunosuppression w h i l e t h e r e was
l i t t l e suppression i n s t r a i n s w i t h low l e v e l s o r low a f f i n i t y o f the r e c e p t o r .
D e t a i l e d s t u d i e s i n which antibody development was monitored i n d i c a t e d t h a t TCDD
d i r e c t l y a f f e c t s 0 - c e l l m a t u r a t i o n by a f f e c t i n g t h e i r a b i l i t y t o respond t o
gvowth f a c t o r s . D r . L u s t e r a l s o commented on a hematopoietic stem c e l l model
f o r s t u d y i n g TCDD t o x i c i t y , i n which a l t e r e d s,tern c e l l d i f f e r e n t i a t i o n occurred
i n Ah-responsive mice. O r . L u s t e r described an Ah r e c e p t o r a n t a g o n i s t f o r TCDD,
1-ami no-3,7,8-trichlorodibenzo-p-dioxin, which i n -i n v i t r o s t u d i e s abolishes
c e r t a i n imnune suppressive e f f e c t s o f TCDD.
.
C. F u t u r e Plans: D r . L u s t e r concluded b y r e v i e w i n g t h e l e v e l s of e f f o r t
f o r v a r i o u s aspects o f t h e program over t h e l a s t f o u r y e a r s and f u t u r e plans.
He s a i d t h e t h r u s t of methods development and v a l i d a t i o n phases were completed
a l t h o u g h a small e f f o r t would c o n t i n u e t o t e s t t h e u t i l i t y o f new assays for
p o s s i b l e i n c o r p o r a t i o n i n t o t h e s c r e e n i n g panel. Screening o f NTP chemicals f o r
immunotoxic e f f e c t s w i 11 c o n t i n u e t o be a s i g n i f i c a n t e f f o r t through c o n t r a c t s
w h i l e t h e in-house e f f o r t w i l l c o n t i n u e i n examining mechanisms o f t o x i c
e f f e c t s . There w i l l be increased a c t i v i t y i n (1) d e v e l o p i n g t a r g e t organ s i t e s p e c i f i c models w i t h r e l e v a n c e t o humans, and (2) s u p p o r t i n g s t u d i e s o f exposed
human p o p u l a t i o n s and c o r r e l a t i o n s o f d a t a f r o m these s t u d i e s w i t h animal s t u d i e s . New approaches f o r d e t e c t i o n and q u a n t i f i c a t i o n o f a chemical's p o t e n t i a l
f o r p r o d u c i n g h y p e r s e n s i t i v i t y w i l l be g i v e n h i g h p r i o r i t y .
VI . NIEHS/NTP Systemic T o x i c o l o g y Branch Programs
- Concept Reviews:
A. E f f e c t o f t h e Ah Locus on L i f e s p a n and Pathology o f Congenic Mice:
(Attchment 10) Dr. Birnbaum s a i d t h e o b j e c t i v e o f t h e proposal was t o examine
t h e e f f e c t of a s i n g l e gene, t h e Ah locus, on l i f e s p a n , general health, tumor
i n c i d e n c e and non-tumor pathology i n female congenic mice which d i f f e r e i t h e r
i n h a v i n g t h e Ah r e c e p t o r (Ah r e s p o n s i v e ) o r l a c k i n g t h e r e c e p t o r (Ah nonrespons i v e ) . To c o n f i r m g e n e t i c homogeneity about 35 t o 50 o t h e r gene l o c i w i l l be
examined i n t h e d i f f e r e n t s t r a i n s o f C57BL/6J mice. The experimental design p r o posed should p r o v i d e a h i g h power o f r e s o l v i n g g e n o t y p i c d i f f e r e n c e s i n
1i f e s p a n , tumor i n c i d e n c e , and non-tumor pathology. Time p o i f i t s f o r s a c r i f i c e
w i 11 a1 low comparison t o d a t a o b t a i n e d w i t h t h e B6C3Fi mouse s t r a i n customari l y
used i n NTP long-term t o x i c o l o g y and c a r c i n n g e n ~ s i ss t u d i e s * D r . Swenberg cornmerited t h a t -if a "ioiig-term o b j e c t i v e o f t h e s t u d y i s t o p r o v i d e a d i f f e r e n t
mouse s t r a i n t o r e p l a c e o r complement t h e B6C3Fi mouse i n long-term t e s t i n g then
male mice should be i n c l u d e d i n t h e design. Dr. Birnbaum r e p l i e d t h a t t h i s
would be t o o c o s t l y i n terms o f t h e c u r r e n t o b j e c t i v e o f t h e concept, and
f u r t h e r t h e r e had been no sex d i f f e r e n c e s shown f o r t h e Ah l o c u s . Chemicals
l i k e l y t o be chosen f o r study would be members o f c l a s s e s whose metabolism i s
modulated by t h e Ah l o c u s . Dr. Lech s a i d i t was i m p o r t a n t t o examine d i f f e r e n ces i n chemical metabolism among t h e t h r e e s t r a i n s . Dr. Birnbaum agreed and
s a i d these types o f s t u d i e s would be done by i n t r a m u r a l i n v e s t i g a t o r s and n o t on
t h e c o n t r a c t . Considerable d i s c u s s i o n ensued as t o whether t h e design should
focus on background incidences o f tumor and non-tumor p a t h o l o g y and perhaps
i n c l u d e b o t h sexes o r whether t h e design should remain as presented t o i n c l u d e
t r e a t m e n t w i t h chemical carcinogens. Dr. Mendelsohn s a i d t o i n c l u d e both sexes
and carcinogen groups along w i t h s t u d i e s on i n d u c t i o n and b i n d i n g would make a
v e r y complicated design. Dr. Swenberg moved t h a t t h e concept as o r i g i n a l l y p r e sented be approved b u t w i t h t h e m o d i f i c a t i o n t h a t t h e design i n c l u d e both sexes.
D r . Harper seconded t h e motion and t h e concept proposal was approved unanimously by t h e Board. D r . R a i l p o i n t e d o u t t h a t t h e Board should understand t h a t
t h e m o d i f i c a t i o n would markedly i n c r e a s e t h e c o s t .
B. Development o f Ovarian T o x i c i t y Screening Methods: Studies on the
C l a s s i f i c a t i o n o f Ovarian F o l l i c l e s as an I n d i c a t i o n of Ovarian T o x i c i t y :
(Attachment 11) D r . James C. Lamb s a i d t h e o b j e c t i v e o f t h i s proposal was t o
e v a l u a t e o v a r i a n f o l l i c l e c l a s s i f i c a t i o n as a method o f s c r e e n i n g chemicals f o r
p o t e n t i a l o v a r i a n t o x i c i t y . I n d i s c u s s i n g c u r r e n t measurements o f r e p r o d u c t i v e
t o x i c i t y , he n o t e d there was a need f o r an e s t a b l i s h e d procedure f o r measuring
o v a r i a n t o x i c i t y which c o u l d be i n c o r p o r a t e d i n t o t h e 90-day p r e c h r o n i c s t u d i e s .
The method would be evaluated u s i n g t i s s u e s from animals i n the NTP continuous
oreeding s t u d i e s of 16 chenicals, tnus making fertility d a t a a v a i l a b l e . E x c e p t
f o r one s t u d y i n r a t s , mice w i l l be the t e s t animals as t h i s i s the species ~ s e d
-.
i n t h e continuous b r e e d i n g s t u d i e s . The d a t a generated w i l l p r o v i d e a much
needed b a s e l i n e . Dr. Manson r e p o r t e d t h a t t h e concept proposal had r e c e i v e d
r e v i e w by t h e NTP Board Subcornmi t t e e on Reproduct i ve and Developmental
Toxicology. Dr. Swenberg suggested a p p l y i n g s t e r e o l o g i c techniques t o g a i n
q u a n t i t a t i v e i n f o r m a t i o n on t h e f o l l i c l e s . Dr. Manson moved t h a t t h e concep: be
approved. Dr. Swenberg seconded t h e m o t i o n and i t was approved unanimously b y
t h e Board.
VII.
Report o f t h e D i r e c t o r , NTP: Dr. David P. R a i l r e p o r t e d t h a t :
( a ) M r . Ruckelshaus as Chairman of t h e NTP E x e c u t i v e Committee has i n i t i ated speci a1 e v a l u a t i o n s o f benzene, 1,3-butadiene, g l y c o l e t h e r s
and halogenated s o l v e n t s . He noted t h a t t h e n e x t Executive
Committtee meeting would be August 31. A t t h i s meeting, Dr. Robert
Scala was t o d i s c u s s t h e f i n a l r e p o r t of t h e NTP Ad Hoc
Panel Report on Chemical Carcinogenesis T e s t i n g and E v a l u a t i o n wh l e
Dr. Mendelsohn was t o d i s c u s s t h e r e c e n t a c t i v i t i e s of t h e NTP Boiird
o f S c i e n t i f i c Counselors;
( b ) Dr. Frank Young, former Dean of t h e Medical School a t t h e U n i v e r s t y
o f Rochester, has begun h i s tenure as Commissioner, FDA;
( c ) t h e FY 1985 NIEHS budget was s t i l l a w a i t i n g Congressional passage.
( d l upcoming meetings sponsored o r cosponsored by t h e NIEHS and t o be
h e l d i n t h e Conference Center, B u i t d i n q 101 included:
' B r a i n Tumors i n Man and ~ n i m a l s ' , ~ e ~ t e m b 5e rand 6, 1984;
'DNA Aciducts: Dosimeters t o M o n i t o r Human Exposure t o
Environmental Mutagens and Carcinogens', September 24-26, l98d; and
r r c
r
: c a i i - n L I i e ~ i - sU I A L ~ JF r e ~ i ~ i L d i i u n 'iiuveiiiber
,
i5 ami i6,
1984, which was prompted by a r e q u e s t f o r a workshop on t h e s i b j e c t from t h e A p p r o p r i a t i o n s Commi t t e e , House o f Representat iv es;
NIEHS has several onqoinq i n t e r n a t i o n a l a c t i v i t i e s . Among
these a r e e x t e n s i v e i n t e r a c t i o n s w i t h t h e World H e a l t h 0rgani z a t i o n
and i t s I n t e r n a t i o n a l Program on Chemical Safety (IPCS). An I n t e l r e g i o n a l research u n i t o f t h e IPCS headed by Dr. George Becking, a
Canadian t o x i c o l o g i s t , i s l o c a t e d a t t h e NIEHS. The NIEHS has e l e v e n
b i l a t e r a l agreements i n c l u d i n g major ones w i t h Japan (two), A u s t r i 1 ia,
and t h e USSR;
( f t h e t h i r d task f o r c e on environments"! h e a l t h and research needs
(Task Force I I I ) , composed o f d i s t i n g u i s h e d s c i e n t i s t s , met a t the
NIEHS f o r two weeks i n June. T h e i r f i n a l r e p o r t w i l l be presentee t o
t h e Congress e a r l y i n 198.5;
( g ) t h e f i r s t d r a f t o f the FY 1985 NTP Annual P l a n would be sent t o
t h e E x e c u t i v e Committee i n l a t e August f o r r e v i e w w h i l e work on t t e
FY 1985 Review of Current DHHS, DOE and EPA Research Related t o
T o x i c o l o g y was in progress;
( h ) xhe Technical Reports Review Subcommittee o f t h e Board met a t t h e
N l E H S J u l y 26 t o r e v i e w t h e c a r c i n o g e n i c i t y d a t a on D & C Red No. 33
f o r t h e FDA's Center f o r Food Safety and A p p l i e d N u t r i t i o n , and or
J u l y 27 t o r e v i e w and approve t h e t e c h n i c a l r e p o r t s f o r NTP t o x i c c l o g y
and c a r c i n o g e n e s i s s t u d i e s o f benzene, c h r y s o t i l e asbestos,
1 , 3 - d ichloropropene (Telone I I 1, 2 - c h l o r o e t h a n o l , IiC Blue No. 2, and
d i m e t h y l hydrogen phospnite. The n e x t meeting w i 11 be h e l d a t the
N I E H S on November 2; and
i t h e n e x t meeting o f the Board w i l l be on October 3 1 and November 1 a t
t h e NiEHS.
--
1 , .
- l J - 8 .
.L-
F i n al Report of
------t h e Ad Hcc Panel on Chemical Carcinoqenesis T e s t i n g and
D
r
.
John
Dou11, Panel Chairperson, gave an overview and background
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:
---VIII.
o f the Panel and i t s Subgroup's review processes and noted some cross c u t t i g issues
and recommendations. He said the f i n a l Panel r e p o r t was a reasonable f i r s t step
and recommended t h a t the Board convene i n t e r a c t i v e workshops. He concluded t h a t
the NTP was already implementing many o f the recommendations i n the report.
Dr. Swenberg ( f i11i n g i n f o r Dr. Frederica Perera, Subpanel Chairperson) su
marized some o f the recommendations o f the Subpanel on Short Term Tests. H said
the c u r r e n t NTP program was making good use o f the a v a i l a b l e assays. The
Subpanel focused i n t h e i r review on t e s t s which might be amenable t o human nd
animal t e s t i n g and comparisons. The Subpanel gave emphasis t o two areas ne ding
speci a1 e f f o r t :
(1) developing b e t t e r methods f o r d e t e c t i n g promoters, and ( 2
developing a good series o f non-carcinogens f o r t e s t v a l i d a t i o n .
O r . Andrew Sivak, Subpanel Chairperson, summarized the major issues i d e n t i f ed by
the Subpanel on Subchronic Studies and Related Issues, and recommendations
thereon. These had t o do w i t h (1) the chemical s e l e c t i o n process, ( 2 ) a su t a b i l i t y o f the F344 r a t and B6C3Fi mouse as t e s t species, and ( 3 ) factors affe t i ng
dose - range, numbers, route and vehicle.
Dr. Robert Scal a, Subpanel Chairperson, summari zed the issues and recommendations from the Subpanel on the Design o f Chronic Studies. The s p e c i f i c a
covered were: (1) general experimental design considerat ions; ( 2 ) s e l e c t i a
species and doses; ( 3 ) s e l e c t i o n o f r o u t e of administration; ( 4 ) s e l e c t i o n
dose vehicle; (5) duration o f study; ( 6 ) use o f an -i n u t e r o exposure systerr
husbandry requirements and aual i t v c o n t r o l ; (8) ~ a t h o l o o yr e a u i r ~ m p n t s ; ( 9 )
tistioal Issue3 i n ihe iiiierpreiai.ion of d a t a from NTP whole animal bioassa
(10) e r r o r s and e r r o r rates; (11) combining benign and ma1 ignant neoplasms
evaluating carcinogenicity; and (12) evidence o f carcinogenicity.
Ad Hoc Panel and t h
Dr. Mendelsohn responded f o r the Board. He praised the -them f o r an e x t r a o r d i n a r i l y important and w e l l done task. He was p a r t i c u l a
impressed by t h e enormous volume o f w r i t t e n responses from the public, and
very c o n s t r u c t i v e and i n t e r a c t i v e p u b l i c meetings t h a t were held. He said
Ad Hoc Panel process had served t o enhance an image o f openness of the NTP.
-s t a t e d there were f o u r recommendations f o r which the Board should p l a y a r e
(1) having the responsibi 1i t y t o see t h a t the process continues; ( 2 ) evalua
the f u l l data base o f short-term t e s t s - b u t not now; ( 3 ) examining the i s s
i n p u t from outside the NTP i n t o the i n t e r f a c e between prechonic and chronic
t e s t i n g ; and (4) advising on whether both r a t s and mice are needed, and, i f
which mouse s t r a i n . With regard t o the other recommendations, he said the
receives them and gives them t o the NTP w i t h the charge t h a t the NTP respon
the next meeting or two.
There was agreement t h a t the NTP should set aside time a t upcoming Board
meetings t o discuss and respond t o the recommendations i n the -Ad Hoc Panel
r e p o r t . D r . R a i l asked the Board t o set up two o r three person subcommitte
from i t s membership t o a s s i s t the NTP i n planning workshops dealing w i t h i s
r a i s e d by the r e p o r t .
Copies of the Report o f the Ad Hoc Panel on Chemical Carcinogenesis Testin
Evaluation are a v a i l a b l e without ctia?ge from: NTP Pub1 i c Information O f f i ?
62-03, Box 12233. Research T r i a n ~ l eP a r k . NC 27709. Teleokone (919) 541-39
FTS: 629-3991.
.
The meeting was adjourned.
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ATTACHMENT 1
NOTICE OF MEETING NATIONAL TOXICOLOGY PROGRAM
BOARD OF SCIENTIFIC COUNSELORS
Pursuant t o P u b l i c Law 92-463,
n o t i c e i s hereby given o f the meeting o f the
~ a t i o n a lToxicology Program (NTP) Board o f S c i e n t i f i c Counselors, U.S.
Pub1 c
Health Service, i n the Conference Center, B u i l d i n g 101, South Campus, Natio a1
I n s t i t u t e of Environmental Health Sciences, Research T r i a n g l e Park, North
Carolina, on August 16 and 17, 1984.
The meeting w i 11 be open t o the pub1i c from 8:30 a.m.
t o adjournment on Aug s t 16.
The p r e l i m i n a r y agenda w i t h approximate times are as follows:
8:30 aim,
- 11:30
a.m.
Peer Review and P r i o r i t y Ranking of Chemicals
Nominated f o r NTP Testing.
( S i x nitropyrenes
considered and deferred by t h e Board on
September 27, 1983 w i 11 be reviewed and are 1i
i n the Federal Register, Volume 48, No. 44,
pp. 9379-9380, March 4, 1983. Additional ly, 2
chemical nominations w i l l be reviewed and are
1i s t e d i n the Federal Register, Volume 4 8 , No.
pp. 3 3 7 4 7 - 3 3 7 4 8 ,
25, 1983, and Volume 49,
5, pp. 1139-1140, January 9, 1984.)
ted.
new
143,
No.
Review o f NIEHS/NTP Systemic Toxicology Branch Programs
12:30 p.m.
-
4:00 p.m.
I n t r o d u c t i o n and Review o f Chemical D i s p o s i t i c Program 4:00 p.m.
-
5:00 p.m.
NIEHS/NTP Concept Reviews:
a. Effect o f the Ah Locus on Lifespan and
Pathology of Congenic Mice
b. Development o f Ovarian T o x i c i t y Screening
Methods: Studies on the C l a s s i f i c a t i o n of
Ovarian F o l l i c l e s as an I n d i c a t i o n o f Ovar an
Toxicity
-+
The meeting on Pu g u s t 17 w i l l be open t o the p u b l i c from 8:30 a.m.
to 3
The p r e l i m i n a r y agenda w i t h approximate times are as f o l l o w s :
Review o f NIEHS/NTP Systemic Toxicology Branch Programs (continued)
8:30 a.m.
10:15 a.m.
1:00 p.m.
1:15 p.m.
- 10:OO
-
a.m.
12:15 p.m.
-
Review o f Biochemical Toxicology Program
Review o f Immunotoxicology Program
1:15 p.m.
Report o f the D i r e c t o r , NTP
3:00 p.m.
F i n a l Report t o t h e Board o f the Ad Hoc Panel
l
On Chemical Carci nogenesi s Test in g a n d ~ v auat
I n accordance w i t h the provisions s e t f o r t h i n Section 552b(c)(6) T i t l e 5 1
Code and Section 10(d) o f Public Law 92-463, the meeting w i l l be closed t o
pub1 i c on August 17 from approximately 3:00 p.m.
t o adjournment f o r f u r t h e r
r a t i o n of NIEHS/NTP programs i n che%ica1 c!i*;p"'11^in
bn
i o.r h e m i c a l toxicotoc
and immunotoxicology, i n c l u d i n g the consideration of personnel q u a l i f i c a t i c
and performance, the competence o f i n d i v i d u a l i n v e s t i g a t o r s , and simi l a r i t
t h e disclosure of which would c o n s t i t u t e a c l e a r l y unwarranted invasion of
personal privacy.
The Executive Secretary, D r . Larry G. Hart, O f f i c e o f the D i r e c t o r , Nation;
Toxicology Program, P.O.
Box 12233, Research T r i a n g l e Park, North Carol ina
27709, telephone (919) 541-3971, FTS 629-3971, w i l l f u r n i s h a r o s t e r of 80;
members and expert consultants and other program information p r i o r t o the
meeting, and summary minutes subsequent t o the meeting.
Date
David P. R a i l , M.D. Ph.0.
Director
National Toxicology Program
ATTACHMENT 2
AGENDA
Board o f S c i e n t i f i c Counselors National Toxicology Program August 16-17, 1984 Conference center, B u i l d i n g 101, South Campus National I n s t i t u t e o f Environmental Heal t h Sciences Research Triangle Park, North C a r o l i n a Thursday, Auqust 16, 1984
8:30 a.m.
- 11:30
a.m.
OPEN
Peer Review and P r i o r it y
Ranking of Chemicals
Nominated f o r NTP T e s t i n g
Board
Dr. Dorothy Canter
NIEHS
REVIEW OF NIEHS/NTP SYSTEMIC TOXICOLOGY BRANCH PROGRAMS:
12:30 p.m.
-
12:45 p.m.
- 4:00
- 5:00
4:00 ~ . m .
Introduction
Dr. Bernard Schwe
NI EHS
p.m.
Chemical D i s p o s i t i o n Program
D r . H.B. Matthews
S t a f f , NIEHS
p.m.
Concept Reviews:
~ f f e c t o f the Ah Locus on
Lifespan and Pathology o f
Congen ic Mice
Dr. LindaBirnbautq,
NIEHS
12:45 p.m.
D r . James Lamb,
Development of Ovar ian
T o x i c i t y Screeni iig Methods:
Studies on the C l a s s i f i c a t i o n
o f Ovarian F o l l i c l e s as an
I n d i c a t i o n o f Ovarian T o x i c i t y
Friday, August 17, 1984 NIJEHS
OPEN
REVIEW OF NIEHS/NTP SYSTEMIC TOXICOLOGY BRANCH PROGRAMS (Continued):
I
Biochemical Toxicology Program D r . Joyce Goldste n and
S t a f f , NIEHS
Immunological Toxicology
Program
D r . Michael Luste? and
S t a f f , NIEHS
Report o f the Direc,tor, NTP
D r . David R a i l , NIEHS
F i n a l Report o f the -Ad Hoc
Panel on Chemical Carcinogenesis Testing and Evaluation
D r . John Doull,
.Â¥
D r . Robert Scala,
D r . Andrew Sivak
CLOSED
3:00 p.m.
-
Adjournment
Evaluation o f Programs and
Personnel i n Chemical Disposit i o n . Biochemical Toxicology,
and Immunological Toxicology
Board and Consult
.
"^
NATIONAL TOXICOLOGY PROGRAM BOARD OF SCIENTIFIC COUNSELORS
D r . Norman Breslow
Professor, Department o f
B i o s t a t i s t i c s , SC-32
U n i v e r s i t y o f Washington
Seattle, WA 98195
Dr. L e i l a Diamond
Professor
Wistar I n s t i t u t e
36th S t r e e t and Spruce
Philadelphia, PA 19104
fir. Curcis narper
Assoc iate Professor
Department of Pharmacology
School o f Medicine
U n i v e r s i t y of North Carolina
Chapel H i l l , NC 27514
D r . J e r r y B. Hook
Vice President
P r e c l i n i c a l Research and Development
Smith K l i n e & French Laboratories, L60
P. 0. Box 7929
Philadelphia, PA 19101
D r . Jeanne Manson
Associ ate D i r e c t o r of Developmental
Toxicology
Prec 1in i c a l Research and Development
Smith K l i n e & French Laboratories, L60
P. 0. Box 7929
Philadelphia, PA 19101
Dr. Mortimer L. Mendelsohn
Associate D i r e c t o r
Biomedical and Environmental Research
Lawrence Livermore Laboratory
University o f California
Livermore, CA 94550
D r . Henry P i t o t
D i r e c t o r , McArdle Laboratory
Professor o f Oncology and Pathology
sconsi n
U n i v e r s i t y o f ~i
Madison, W I 53706
D r . James A. Swenberg
Chief, Pathology Department
Chemical I n d u s t r y I n s t i t u t e o f
Toxicology
P. 0. Box 121.37
Research T r i a n g l e Park, NC 27709
NATIONAL TOXICOLOGY PROGRAM BOARD OF SCIENTIFIC COUNSELORS MEETING OF AUGUST 16 and 17, 1984
EXPERT CONSULTANTS FOR REVIEW OF NI EHS/NTP SYSTEMIC TOXICOLOGY BRANCH PROGRAMS Biochemical Toxicoloqy Dr. Eric Johnson
Division of Biochemistry
BCR-7
Scri pps Cl i nic and Research Foundat ion
10666 N. Torrey Pines Road
La Jolla, California 92037
Dr. Thomas A. Gasiewicz Dept. of Radiation Biology and Biophysics University of Rochester Medical Center Rochester, New York 14642 Chemical Disposition Or. David J. Jollow
Oept of Pharmacology
Medical University of South Carolina
Charleston, South Carol ina 29425
.
Dr. John J. Lech
Dept of Pharmacology and Toxicology
Medical College of Wisconsin
P .O. Box 26509 8701 Watertown Plank Road Milwaukee, Wisconsin 53226 .
Immunological Toxicology Dr. Dolph Adams Professor, Dept. of Pathology Duke University Durham, North Carolina 27710 Dr. James Folds, Director Clinical Microbiology-Immunology Laboratories
Memorial Hospital
University of North Carolina
Chapel Hill, North Carolina 27514
NTP BOARD OF SCIENTIFIC COUNSELORS MEETING
Conference Center, Bui l d i ng 101 National I n s t i t u t e of Environmental Health Sciences Research Triangle Park, North Carolina August 16, 1984
Hart
Rail
Mendelsohn
D iamond
McConnel 1
Schwetz
Harper
Hook
Jol low
Bres low
Lech
Swenberg
Matthews
Manson
A. Norris
8. Johnso
E. Johnson
Canter
Gasiewicz
Huff Stage
I
NTP BOARD OF SCIENTIFIC COUNSELORS MEETING
Conference Center, Bui l d i ng 101 National I n s t i t u t e o f Environmental Health Sciences Research T r i a n g l e Park, North C a r o l i n a August 17, 1984
Hart
Rail
Mendel sohn
Dou 11
McConnell
Schwetz
Di amond
Hook
Harper
ares 1ow
E. Johnson
Swenberg
Gasiewi cz
Manson
Goldstein
Seal a
Luster
Sivak
Ad ams
8. Johnson
Folds
:.
J o l low
Huff
Lech Stage
-.
ATTACHMENT 3 Public Health Service
National Institutes of Health
DEPARTMENT OF HEALTH & HUMAN SERVICES
I
National Toxicology Program
Memorandum
Â
Date J u l y 30, 1984
From NTP Chemical Sel e c t i o n Coordinator
Subject Review o f Twenty-six Chemicals and One Group o f Substances
Nominated t o t h e NTP f o r Toxicological Testing
TO National Toxicology Program Board of S c i e n t i f i c Counselors
As p a r t o f the NTP chemical selection process, the Board of S c i e n t i f i c
Counselors eval uates and makes recommendations on chemicals nomi nated t o
t h e NTP for t o x i c o l o g i c a l testing. This assessment takes place followi n g review of. the chemicals by the NTP Chemical Evaluation Committee
(CEC) and subsequent p u b l i c a t i o n of t h a t Committee's recommendations
i n the Federal Register w i t h request f o r public comment.
The Board o f S c i e n t i f i c Counselors w i l l review twenty chemicals and one
group o f substances evaluated by the NTP Chemical Evaluation Committee
a t the May 31, 1983 and November 8, 1983 meetings, and s i x n i tropyrene
n e i a m A r f * w f % ~n
9mA A - 4 n - ed by the 9c2rd cz 5 c p t c ? k r 27,
.,.. uL,
..w..v,,..,.ua
-, ..ud~ r4 r l,=u wnç,
,
1983.
. .
.
On May 31, 1983, the CEC evaluated t h i r t e e n nominated chemicals. One
o f these chemicals, 8-pinene was nominated only f o r tumor promotion
studies. Another chemical, chromic acid, was nominated f o r short-term
i n vivo and i n v i t r o mechanistic studies, and consideration for a chronic
study pending the r e s u l t s o f an ongoing sodium dichromate study. The
remaining eleven compounds were nominated f o r carcinogenicity testing.
Methyl isobutyl ketone and antimony potassium t a r t r a t e were nominated
f o r other t o x i c o l o g i c a l t e s t i n g i n addition t o carcinogenicity. Two
o f the t h i r t e e n chemicals, p-chloro-a, a, a - t r i f luorotoluene and methyl
i s o b u t y l ketone, were deferred by the CEC t o obtain more information
on industry sponsored t e s t i n g from EPA, and therefore, w i l l be presented
t o the Board for review a t a subsequent meeting.
--
--
A Federal Reqister n o t i c e was published on July 25, 1983, l i s t i n g the
t h i r t e e n chemicals and the type of t e s t i n g recommended by the CEC, and
s o l i c i t i n g public input. I n response t o the Federal Re i s t e r notice,
data on methylene bis(thiocyanate), 2-(2-butoxy-ethoxy ethyl thiocyanate,
formic acid and nitromethane were submitted t o the NTP. This information
has been incorporated i n t o the revised Executive Summaries on these
compounds.
+-
Table 1 contains the chemicals, source of nomination, production, worker
exposure, NTP t e s t i n g status, and CEC recommendations and p r i o r i t y assigned.
rage 2
On November 8, 1983, the CEC evaluated twelve nominated chemicals and one
group o f substances. One of these chemicals, malathion, was nominated
o n l y f o r reproductive studies. Six chemicals were nominated f o r chemical
d i s p o s i t i o n studies, w i t h subsequent consideration f o r carcinogenicity
t e s t i n g upon completion o f these studies. The remaining f i v e chemicals
and the group o f substances were nominated for carcinogenicity testing.
C.I. D i r e c t Red 80 and picloram were nominated f o r other toxicological^
t e s t i n g i n addition t o carcinogenicity.
Two o f the chemicals, malathion and picloram, were deferred by the CEC,
pending receipt o f data from the EPA Office of Pesticides, and w i l l be
submitted t o the Board f o r review a t a subsequent meeting. D&C Yellow
No. 11 w i l l not be reviewed by the Board since i t was the FDA's F i s c a l
Year 1983 p r i o r i t y chemical f o r carcinogenicity testing. This chemical
was referred d i r e c t l y t o the NTP Executive Committee a f t e r CEC review
i n accordance w i t h the NTP p o l i c y o f r a p i d decision making f o r p r i o r i t y
chemicals o f NTP p a r t i c i p a t i n g agencies.
A Federal ~ e g i s t e rnotice was published on January 9, 1984, l i s t i n g the
twelve chemicals and one group o f substances and the type o f t e s t i n g
recommended by the CEC, and s o l i c i t i n g public input. I n response t o
the Federal Re i s t e r notice, data on C.I. Acid Ye1 low 151, C.I. Basic
Red 1
8
,
.I
i r+
ect Red 80, C.I. D i r e c t Yellow No. 4, C.I.
Disperse
Brown 1, D&C Yellow No. 11, and cinquasia red were submitted t o the
K7P - T h K infnrmaticn has bee" ncc?po?ats<i i n t o the rev?ss2 Exe;zti ;te
Summaries o f these compounds.
Table I 1 contains the chemicals, source o f nomination, production, worker
exposure, NTP t e s t i n g status and CEC recommendations and p r i o r i t y assigned.
On September 27, 1983, the Board o f S c i e n t i f i c Counselors reviewed and
deferred s i x n i tropyrenes nominated f o r testing. The Board was interested
i n recommending t e s t i n g b u t requested t h a t f u r t h e r information on ongoing
and completed studies o f other organizations be assembled and t h a t representatives of EPA and The Health E f f e c t s I n s t i t u t e be i n v i t e d t o discuss
t h e i r studies a t a f u t u r e Board meeting. On August 16, 1984, Dr. Stephen
Nesnow, EPA, and Dr. Jane Warren, The Health Effects I n s t i t u t e , w i 11 be
making presentations on the nitropyrenes t o the Board.
The Board w i l l review the 26 chemicals and one group of substances from
8:30 a.m. t o 11:30 a.m.,
on Thursday, August 16, 1984. The following
material i s enclosed i n order t o a s s i s t you i n your review of these
chemicals:
1)
Set o f 27 Executive Summaries.
2)
Two Summary Data Tables on the chemicals discussed
a t the May and November 1983 CEC meetings.
3)
July 25, 1983 and January 9, 1984 Federal Register
notices.
Page 3
As a t past meetings, each of the Board members who w i 11 be i n attendance
has been assigned chemicals t o review f o r the purpose o f leading the
Board' s discussion and presenting t e s t i n g recommendations. The 1is t o f
assignments follows:
Name -
Chemicals
Dr. Norman Breslow Cinquasia red
C.I. D i r e c t Yellow 4
C. I.O i sperse Brown 1
Dr. L e i l a Diamond Antimony potassium t a r t r a t e
2-(2-Butoxyethoxy) e t h y l t h i ocyanate
Methylene h i s ( t h i ocyanate)
-Pi nene
Dr. c u r t i s Harper Chromic acid Formic acid L i n o l e l a i d i c acid Thi ophene Dr. Jerry Hook Black newsprint inks 2,3-Dichloropropy1ene Nitromethane 1,2,4,5-Tetrachlorobenzene Dr. Jeanne Manson
Arsine Lumi no1 Stannous f l u o r i d e Dr. Mortimer Mendelsohn C.I.
C.I.
C.I.
Dr. James Swenberg Acid Yellow 151
Basic Red 18
D i r e c t Red 80
.
1 - N i tropyrene 1.3-Dinitropyrene 1,6-Dinitropyrene 1-8-Dinitropyrene 1,3,6-Trini tropyrene 1,3,6,8-Tetrani tropyrene Ifyou wish t o receive references f o r any o f the chemicals, please contact me
and we w i 11 send them by express mai 1,
-+
I f you w i l l be unable t o assume the r e s p o n s i b i l i t y f o r discussing the
assigned chemicals, please c a l l me a t (301) 496-3511 or FTS 496-3511
so t h a t other arrangements can be made.
We look forward t o seeing you on August 16-17.
Victor A. Fung, Ph.D.
Attachments
Addresses:
Or. Mortimer L. Mendel sohn, Chairman
Norman E. Breslow
L e i l a Diamond
Curtis Harper
Jerry B. Hook
Dr. Jeanne M. Manson
Dr. Henry C. P i t o t
Dr. James A. Swenberg
Dr.
Dr.
Dr.
Dr.
- -
bb.
Ul
. David znv
Dr.
Dr.
Dr.
Dr.
Ms.
Dr.
Dr.
Dr.
Eugene McConnell
Larry Hart
James Huff
Lawrence Fishbein
Florence Jordan
Bernard Schwetz
Raymond Tennant
W i 11iam Kluwe
e-
Table 1
Summary Data on Chemicals Reviewed by the NTP Chenkal Evaluation C o o i i ttee
Chemical
CAS No.
1) Antimony
Nominating
Source
NC I
potass1iim
tartrate
28300-74-5
2) 2-(2-Butoxyethoxylethyl
t h i ocyanate
112-56-1
NC I
Production
(lbsl
10~-106
3.1~105
(imports)
( 1977 l
2x106
(1983)
Uorker
Exposure
NTP Status
3,554 workers
potentially
exposed (NOHS)
88,167 workers
potentially
exposed (NOHS)
Other
on Hay 31. 1983
Testing
Reco~endation
( P r i o r it y )
Chemical
Selection
Principles
Subchronic study,
on
with -hasis
identifying target organs such
as 1iver. bladder,
and heart
(Moderate)
Sel. for
assay
u.
6
-Salç assay
TSTso perf om
Sale. assay on
o e t i b o l i t e 2(2-butoxyethoxy)
ethyl nercaptinl
-Subchronic study
Including spenn
morphology and
vaginal cytology
assays
-Short-tern i n vivo
reproductive toxi
c i t y assay
(Hoderçte
NCI
1,807 workers Sel. f o r
assay
potentially
exposed (NOHS).
Sç1ni
-Sale. assay
-Cherical disposition
study
-Subchronic study
(Moderate)
-Past usage i n U.S.
present usage i n
other countries
-Investigate i n
~
Â
i¥od~
pos-
l
s i b l e relationship between use of drug and higher r a t e of bladder cancer i n Egypt -Potmtial for exposure fro pestlctdal
use
-Reproductive effects
testing recornendad
because of struct u r a l relationship
to cellosolves
-Evaluate for carcinogenici t y testing
following receipt of
a l l data
-
3) Hethylene bis
(thiocyanate)
6317-18-6
Remarks
3
-Interest i n
structure
-Potential for
exposure
Chemical
CAS No.
4 ) p-Chloro-
Nominating
Source
NC I
a>aia-
trif luorotoluene
98-56-5
Production
(lbs)
107-5x)07
1.5~10
(imports)
( 1977
Worker
Exposure
20 workers
exposed (NOUS)
NTP Status
Neg. i n Sala.,
as *re 4chloro-3-nitroa id - t r i f l u o rotoluene and
4-chlor-3,5-,
dinitro-a .a
trif luoroto1uene
Testing
RecoÑendatio
(Priority)
Other
-Jest nated by
ITC n
! 1981
f a r considerition for
:hronic efFects, cheai
$:el fate and
11 t oconcentration testing
-PA accepted
11.i-gotd t e d
,;m;i~t~ree-
Chemical
Selection
Principles
Defer u n t i l
next CEC
aeeting
Remarks
.
Ascertain extent of
negotiated testing
undertaken by
industry as result
of designçtio by
Iateragency Testing
C o d ttee t o €
-
industry t o
include muta~ i e n i ct iy and
!irbchronic
!;i:udIes
-1'ound i n dumps
5) Chromic
acid
13530-68-2
United Auto
Workers Union
2xlo7-lo8
(1977)
85,749
.-
Comparative chemical
disposition study of
chroak acid and
sodlua dichrocate
(High)
3,4,8
-1ndus r i a l expour
-6ecau 18 of increas d incidence
of Pu m i r y cancer
i n ra s I n study of
sodiu I d i c h r o ~ t e
u l a in stared by
i n t r a heal i n s t a l
l a t i a I. useful to
conpa be chealcal
d i spa i t i o n of
two c m i c a l s
-
Chemical
CAS NO.
Nominating
Source
6) 2,3-Oichloropropylene
78-88-6
NCI
7) Formic actd
64-18-6
NC 1
Production
dbs)
6.9~107
8.2~104
( Imports
(1979)
Worker
Exposure
--
533.799 workers
potentially
exposed
NTP Status
-Set. f o r Salm.
may, o n T t
I n Dros h i 1
-~at&tur a l l y related
compound:
-1.3-dichloropropene i n
h<stopçtholog
phase of gavage
bioassay, also
pos. I n Saln.
and selected f o r
Drosophi l a testing
For~aldehydepas./
weakly pos. I n
Salm pos., f o r
chriisomal &errations and pas./
weakly pos. f o r
sister chroaatid
exchanges i n CHO
cells: on test i n Dros h i l a ' ForiSTBt'ne. i n
Other
--
--
Testing
Recoonendation
(Priority)
Chemical Selection Principles
Reaarks -Sala. assay
-Mouse Ivifhom assay
-In v i t r o cyto#enetics
-Subchronic study,
possibly f o r longer
than 90 days, t o
I d e n t i f y target organ
toxicities
- C ~ c l n o g e n i c l t y to be
p e r f o r d i n tinder
with other comercially
inportant chlorinated
alkene
(High)
3,4
-Pose i n &&.
assay
-Structure a c t i v i t y
considerations
-ExMrtne further
toxic01 i c
potent13 o f
chlorinated alkenes
-Subchronic Md
carc1nogenici t y
studies should be
p e r f o f e d by Inhalational or skin
painting routes
-SU g e ~ NTP
t
staff
select other
alkene f o r study
-1nhalational carcinogenici t y study
-Reproductive effects
study
(We-High)
3.8
-High production
-Widespread exposure
-Structural relationship to
fon~ldehyde, a
rodent carcinogen
Chemlcal
CAS No.
Nominating
Source
8) Lfnolclatdic
ac i d
506-21-8
NCI
9) Methyl
isobutyl
ketone
108-10-1
NC I
Production
(lbs)
Worker
Exposure
-
NTP Status
Structural l y
related c-ound,
l i n o l e i c acid
neg. i n
Other
--
Test ing
Recomendation
(Priority)
No testing
Chemical
Selection
Principles
--
a. 1.9~108
2.4xlo6
(imports)
(1979)
1,433,813
workers
potentially
exposed (NOUS)
-.
-Hest nated by -Defer u n t i l next
I C !or consid- CEC meting
fir etlon f o r
-Refer t o NTP
iutagenici ty,
Reproductive and
UrttogenlcUy, D e v e l ~ t a t
(.hronic effects Toxicology Program
i.nd epidemiology for evaluation of
testing by inreproductive effects
t ustry
testing needs
-[PA accepted
regotlated
testing agreement t o be
coordinated by
C MA
-Subject to TSCA
Sections 8(a)
and B(d) reporting rules
-Fund i n duaps
--
Runrks
-Refer to X I f o r
possible entry i n t o
progrw lnvestigatIng reltttonship
between n u t r i t i o n
and cancer
Ascertain progress
of industry sponsored testing of
chemical f o r gene
t o x i c i t y tubchronic
effects and t e r t tology
Chemical
CAS No.
10) Nitromethane
75-52-5
Nominating
Source
NCI
Production
(lbs)
TSCA inventory
data:
Amount claimed
as confid n t i a l ,
but >5xl0
(1977)
s
Worker
Exposure
838,491
workers
potentially
exposed (NOHS)
NTP Status
Other
Neg. I n Sale., as
were s t r u c t u r a l l y
related compounds
nitroethane, 1n i tropropane,
1-nitrobutane;
tetranitrmthane.
2-ni troprop ane
pos. i n
Tetranitrowethane
i n chronic phise
o f inhal. bioassay
=.
4.9~107
(1979}
10 x l 0
(imports)
(1977)
12) 1.2.4.5Tetrachlorobenzene
95-94-3
NC I
lo7-$.2~108
4x10
(imports)
(1977)
7.672
workers
potentially
exposed (NOHS)
Testing
Reco~~iulation
(Priority)
-Deferred i n def in1t e l y
by ITC
-Nq. in
pos. i n muse
lynphoma w i thout activation
(NCI 1
Remarks
3.4.8
-Potential f o r
widespread exposure
-Pos. I n muse
l y o h o ~s tudy
-Structurally r e l a t e d
t o the carcinogen
2-ni t r o p r o p u e
3
-Structurally re1a t 4
t o c e r t a i n tumor
promoters
-Potenti a1 f o r
exposure
m.,
,
I
--
--
-Neg. i n 1m , as
were l , Z b
tetrachlorobenzene
and 1,2,3,5-tetrachlorobenzene
-Chlorobenzene,
three dichloro
benzenes and three
trtchlorobenzenes
also neg. i n
-1.2-Dichlorobenzene
gavage bioassey
complete
-1.4-Dichlorobenzene
i n histopathology
phase of gavage
assay
Carcinogenicity
with exwrination
of thyroid f o r
possible toxic
effects
Chemical
Selection
Principles
Skin painting
tumor promotion
assay
(Low)
-Designated by -In vivo cytogenetics 3.4.8
ITC I n 1978 -Acute neurotoxicity
f o r consider- -Carcinogenici t y i n ation f o r mut- eluding sperm aorpholagenicity.
ogy and vaginal c y t o l carcinogeni
ogy assays i n prechronic
city, t e n portion of study
togenici ty,
-Short-tem i n vivo
other t o x i c
reproductive t o x i c l t y
effects. e p i - assay
deniology and
(High)
environmental
effects t e s t i n g
as p a r t o f chlorobenzenes category
-€ proposed t e s t
r u l e i n 1980
-Subject t o TSCA
Sections 8(a) and
8(d) reporting rules
-Found i n dumps
=.
-
-Found i n waste
dumps
-Potential f o r
exposure
-Structure
activity
consideration
Chemical
CAS NO.
Nominating
Source
Production
(Ibs)
Worker
Exposure
l04-~5
62,273
-Neg. i n Saln.
-Neil. 'in*.,
workers
-structurally
pis. i n mouse
potentially
related f u r u
lirf~honw
r ith
exposed (NOHS) neg. i n Saln.,
anl without
In c h r o n r
a:l:ivation
phase o f gavage (Id)
bioassay '
(Inports)
(1977)
NTP Status
Other
Testing
Reco~endçtio
(priority)Carcinogencity
(Moderate)
Chertcç
Selection
Principles
3.4
Remarks
-Interest i n
structure
-Develop
toxUological
p r o f l1e
.
Table I1
C o ~ i t t t eon November 8.. 1983
Sumary Data on Chemicals Reviewed by the NTP Chemical :valuation
Chemical
CAS No.
Nominating
Source
Production
(lbs)
1) Arsine
7784-42-1
United Auto
Workers
Union
103-1.3~104
(1977)
2) Black newsprint NIOSH
inks
--
3 ) Cinquasla red
1047-16-1
ITC/EPA
-
22.5~107
letterpress
1.0~10
off set
( 1981)
-
Morker
Exposure
-587 workers exposed (est'd)
-900.000 workers
exposed t o
arsenic
TLV: 0.05 ppm
or 0.2 mg/m3
165,000 workers
exposed (estfd)
PEL: 5 rng/m3
o i l mist
74,444 workers
exposed (est ' d l
NTP Status
--
--
-
Other
,-
Testing
RudatiOn
(Prior1ty)
Comparative study o f
chemical disposition
of arsine and arsenic
trioxide
(Low)
Chemical
Selection
Principles
3
-Skin painting c&rcino- 4.5.8
geniclty o f two types
of ink and o f t h e i r
petroleum p i t c h and
petroleum o i l vehicle
cowponents
(High)
-Cheaical analyses o f
inks and t h e i r cowponents
t o be performed p r i o r t o
I n i t i a t i o n o f carcinogenicity studies
(High)
Inhalatlonal chÑica
disposition study
(Noderate)
4
Ronarks
-Concern is an arsenic
cowound
-LOW level exposure t o
workers
-6ençrat animal data
with
f o r c-arison
flpldmlologlcal
studies
-Continuing worker
exposure
-Ascertain I f c h w i c a l
cç be &sorbed p r i o r
t o considering It f o r
other toxicological
testin
-Potentfa1 f o r worker
exposure
I-.
23
x a
<0'4
.4
Â
Chemical
CAS No.
Nominating
Source
12) Picloram
1918-02-1
Dept. of Health,
State of West
Virginia;
Ms. E. Clark,
Research
Associates, Ltd..
Exton, PA
13) Stannous
fluoride
7783-47-3
Mr. P. Mock
M'nnepeg ,
Canada
Production
(lbs)
Worker
Exposure
2036 workers
exposed (est'd)
TLV: 10 ng/d
Listed i n
public TSCA
inventory
( 1977)
1433 workers
exposed (es ' d l
TLV: 2 @/in
NTP Status
-
-Equivocal evidence
of cuxinogenici t y
i n female rats i n
feeding study i n
rats çmmice
-Neg. i n Salm.
-Nag. i n B?o? h l l a
f o r sen-&:
cessive l e t h i l
mutations
-Po$. f o r chronos o u l aberrations
and sister chromat i d exchanges I n
CHO cells
Data on related
confounds:
Stannous chloride:
-Neg. f o r carcinogenicity i n feeding
study i n rats and
mice
-Meg. i n Salmonella
Sodium fluoride:
-thronIc phase of
drinking water
study i n rats and
mice
I n Salmonella,
-hl. for mouse
44.
Other
Recwefldation
(Priority;
PSelection
rinci~les
Defer pending
receipt of data
from EPA
Re~rks
War agricultural
c w o d l t y chÑica
-Registritlon stçn
I n early 1
-Industry long-term
feeding Study underway i n rats; other
toxicology studies
also undertaken
--
No testing
-
-StaIInouS chloride
negative i n MTP
carclnogenicity
testing; sodium
fluorlde presently
under t e s t f o r
carclnogenicity by
NTP
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#49
.
Fedani Rmdftar / Vol.
48.
No. 143 / Mondav. lulv
25. 1983
(2) Modà of production, w e n t
production levels, sad occupational
axpoiwe potential.
(3) UMI and rnulting expoaura levels,
where known.
(4) Result*of toxicological stidie* for
structurally related compounds.
Pleaen submit all infomution In
writing by Augirt 24.1963. Any
aubmiuions received after the above
date will be accepted and utilized where
poaaible.
Dated: My 12.1Ñ3 OnU P.m.
Dirmtor. National ToxicologyProgram.
/ Noticci
Behavioral Studies of Child Health and
Human Development, ,piS/MH/
NICHD." r
owwm In accordmw with the
requirement* of the Privacy Act, the
Public Health Service (PHS)te
publishing notice of a propowl to
establish a new Privacy Act m t e m of
records 08-2&-0153, ~iomedi-d
Research: Records of Subjects in
Biomedical and Behavioral Studies of .
Child Health and Human Development.
HHS/NIH/NICHD." This ¥yte wilt be
d to support research on maternal
health, child health, and human
development. We are alm proposing
routine uaes for this new lytem.
PHS invitles interested penoir to
mbmit comments on the propoçe
on or before Augut 24, *,
routine
.
"
law.
The HHS' National Toxicology
Program today announces the
availability of carclnogenesis studies of
ally! icovalerate, a synthetic fragrance
and flavoring ingredient which may be
The chemicals p-chloro-a,a,afound in soap. detergents, creams.
trifluorototuene and methyl isobutyl
perfumes, non-alcoholic beverages, ice
ketone had previously been designated
cream, candy, baked good*,gelatins.
as priority chemicals by the biteragency and puddhgs.
Testtug Committee (TTC) to the
AUyl icovalerate was administered in
strator. Environmental Protection oorn nil by gevage to F344/N rates and
9-4;. fz: =-cZ:!hti3zfez
BoCSFi mice at do- of u 81. and 62
I~dustry~required
testing. p-Chloromg/kg body weight. Under the
a.a,a-triflurotoluene was deferred to
conditions of these studies, allyl
¥¥certathe extent of tenting
isovalerate was carcinogenicfor F344/N'
undertaken by industry following its
rats and B6C3F,mice. causin~increased
designation by the ITC. Methyl isobutyl
incidences of homato&etic &stern '
ketonewas deferred to determine the
neoolasms ~mononuclear-cellleukemia
progrer of industry-sponsored testing of in male ratsand lymphoma in female
the chemical for genotoxidty,
mica).
subchronic effects and temtology
, Cornnogenesis Studies of Ally1
undertaken following negotiations
hovalemte in F344/NRats and B6C3Fl
between EPA and the affected
Mice {Gavage Studies) (T.R.253) are
available without charge by writing to:
industries. Both chamicals will be reNTPPublic Information Office, MJ).B2evaluated at the next CEC meeting.
- The chemicals nitromethane, 124.5- 04, P.O. Box 12233, Research Triangle
Park. NC 27700. Telephone: (019) 541- tetrachlorobenzeneand thiophene were
3391.m:629-3301.
previously (elected by the NTP for
genotoxicity testing in the Salmonella
Dated: July 15,1983. assay. All three chemicals were
David P. Rail negative in four strains of Salmonella
Director.
both with and without activation. None
of the other ten chemicals were
previously (elected for any type of
toxicoiogical testing by the NTP.
Prtvcy Act of 1874; EtiUtahnwnt of
Interested parties are requested to
Â¥ytwof Record*
submit pertinent information.The
following types of data are of particular
MNCX
Public Health &rvice,
relevance:
Department of Health and Human
Services.
(1)Completed, ongoing and/or
planned toxicological testing in the
ACTION: Notification of e~tabliahmentof
private lector including detailed
a new Privacy Act system of records:
experiments! protocols and, in the case
09-25-0153. "Biomedical Research:
of completed atudiea, resultant data.
Recorde of Sublecta in Biomedical and
g'g
wnt a Report of New
System to the Congrem md to the Office
Management and Budget on Jane 1.1983.
The sy~temof recordi will be effective
00 days from the date submitted to 0MB
unless PHs receives comments on the
routine uses which would result Ina
contrary determination.
Aoonuc: Comments should be
addreseed to die National Institutes of
Health (NIH) Privacy Act C o d h a t o r at
the addrew listed below. Cornmento
received will be available for inspection
during office hours in Room 3B03,
Building 31, at that address.
RATE PHS has
POMFURTHERIMFOMMATIONCONTACT
Dr. Kenneth Thibodeau. NIH Privacy
.
Act Coordinator, Building 31. Room
3B07.9000 Rockville Pike. Bethesda, MD
20205. or call 301-496-4606. This is not a
toll-free number.
-MY
INFOHMATIOM:NIH
-*
proposes to establish a new system of ,
record: 09-25-0153, "Biomedical
Research: Records of Subjects in
Biomedical and Behavioral Studies of
Child Health and Human Development
HHS/ NIH/ NICHD."Thia proposed
umbrella system of records will
comprise records generated in research
projects supported by the National
Institute of Child Health and Human
Development (NICHD)in fulfilling its
congressionally mandated responsibility
for biomedical and behavioral reserach
on maternal health, child health, and
human development.
Such reseach will involve both
ecientists on the ttaff of NICHD and
other scientistt working under contracts
awarded competitively by NICHD.
NICHD may award research contracts
to hospitals end clinics, to educational
and research institution, to Federal.
-
-
.
ft
Federal Register / ~ o l 49.
. No. 5
provide an agenda and roster of
member*. Summaries of the meeting
may be obtained by contacting Carole
A. Frank. Committee Management
Office. NIADDK. National Institutes of
Health. Room 9A46. Building 31.
Bethesda. Maryland 20205. (301)4966917.
Dated: Jan4. I%#.
B.tty I. Bevridw, N I H CommitteeManqement Officer. Punuant to Pub. L 82-163. notice is
hereby given of the meeting of the
Clinical Application! and Prevention
Advitory Committee. Division of Heart
and V a d a r Diwam. National Heart,
Lung. and Blood Institute, National
Institute* of Health. March 21-22.1964.
The meeting will be held in Conference
Room Bl19. Federal Building. 7550
Wisconsin Avenue, Bethesda, Maryland
20205.
This meeting will be open to the
public on March 21 from 9SO a.m. to
recess and from 8:30 a.m. to
adjournment on March 22 to discuss
new initiative*, program policies and
issues. Attendance by the public is.
limited to mace available.
Ms. T& Bellicha. Chief. Public
Inquiry Reports Branch, National Heart.
Lung. and Blood Institute. Building 31.
Room 4A21. National Institutes of
Health. Bethesda, Maryland 20205.
phone (301)496-4236. will provide a
summary of the meeting and a roster of
committee members upon request. Dr.
William Friedewald. Executive
Secretary of the Committee. Federal
Building. Room 212 Bethesda. Maryland
20205. phone (301) 496-2533. will furnish
substantive program information.
ICatalog of Federal Domestic Assistance
Program No. 13.837. Heart and Vascular
Diseases Research. National Institutes of
lk!dlth.]
Ddled: January4,1984
Betty I. Beveridge,
."Â¥'/ICommittee Management Officer
I K Uix M-40ÃFiled 14-84 8 4 5 am1
BILLING CODE 4140-014
Biomedical Research Support
Subcommittee of the General
Research Support Review Committee;
meeting
Pursuant to Pub. L. 92463, notice is
hereby given of the meeting of the
Ij:omedical Research Support
Subcommittee of the General Research
/ Monday. January 9. 1984 / Notices
Support Review Committee. Division of
Research Resources. National Institutes
of Health. February 24.1964. Building
31C, Conference Room 8. Bethesda.
Maryland 20205. from 9:30 a.m. to
adjournment.
The meeting will be open to the public
on February 24, from 930 a.m. to
adjournment to discuss program policies
and planning for the Biomedical
Research Support Grant Program, the
Biomedical Research Support Shared
Instrumentation Grant Program and the
Minority High School Student Research
Apprentice Program. Attendance by the
public will be limited to spa,ce available.
Mr. James Augustine. Information
Officer. Division of Research Resources,
Room SB10.Building 31. National
Institute* of Health. Bethwda, Maryland
20205, (301)496-5545. will provide
summaries of the meeting and rosters of
the Committee members. Dr. Marjorie A.
Tingle, Executive Secretary. Biomedical
Research Support Subcommittee of the
General Research Support Review
Committee will furnish substantive
program information and will receive
any comments pertaining to thi8
announcement.
(Catalogue of Federal Domestic AÑistanc
Prosrun No. 13.337. Biomedical Research
'
National hutitutea of Health!
Dated: January6-ISM.
Betty 1. Bwnridsa* Committee Management Officer. ~ o n a l
Institutes of Health. IFH Doc.M-W Filed 1-4-M. U S am1 MUJMa
cooe 414o-Çl-à Pulmonary O t e e a Advtoory
~
Committee; Meeting
Pursuant to Pub. L 92-463. notice is
hereby given of the meeting of the
Pulmonary Disease! Advisory
Committee. National Heart, Lung, and
Blood Institute, on February 16-17.1984
at the National Institutes of Health.
Building 31. Conference Room 7.9000
Rockville Pike, Bethesda, Maryland
20205.
The entire meeting, from 8.30 a.m. on
February 16 to adjournment on February
17, will be open to the public. The
Committee will discuss the plans for
fiscal year 1985. Attendance by the
public will be limited to the space
available.
Ms. Terry Bellicha. Chief. Public
Inquiry Reports Branch. National Heart.
Lung, and Blood Institute. Building 31,
Room 4A-21, National Institutes of
Health. Bethesda, Maryland 20205,
phone (301) 490-4230, will provide
summaries of the meeting and rosters of
the Committee members.
1139
Dr. Suzanne S. Hurd. Acting Executive
Secretary of the Committee.Westwood
Building. Room 6A16. National Institutes
of Health. Bethesda. Maryland 20205.
phone (301)496-7208, wiU furnish
substantive program information.
(Catalog of Federal Doimstk Assistance
Program No. 13J38. Lung Diwes Research.
National Institute* of Health)
Dated: January 4.1984.
CommitteeManayment Officer.
Â¥UMMAltYOn November & 1983. the
Chemical Evaluation Committee of the
National Toxicology Program (NTP) met
to review 12 chemicals and one group of
8ubitances nominated for toxicology
testing and to recommend the types of
testing to be performed. With thia
notice, the NTP solicits public comment
on the 13 chemical* luted herein.
For Further information and
Submission on Comments, Contact: Dr.
Dorothy Canter. Assistant to the
Director, National Toxicology Program.
Room 2B55,Building 31. National
Institutes of Health, Bethesda, Maryland
20205. (301)496-3511.
Â¥UPPLEMENTAKINFOKNATION: AS part
of the chemical (election process of the
National Toxicology Program,
nominated chemicals which have been
reviewed by the NTP Chemical
Evaluation Committee (CEC)are
published with request for comment in
the Federal Register and NTP Technical
Bulletin. This encourages outside
individuals and groups to participate in
the NTP chemical evaluation process
thereby helping the NTP to make better
informed decisions as to whether to
seleci, reject or defer chemicals for
testing.
Relevant comments and data
submitted in response to this request are
reviewed and summarized by NTP
technical staff and then forwarded to
the NTP Board of Scientific Counselors
for its evaluation of the nominated
chemicals and to the NTP Executive
Committee for its decision-making about
testing The NTP chemical selection
process is summarized in the Federal
Register. April 14. 1981 (46 FR 21818).
and also in the NTP FY 1983 Annual
Plan. pages 213-215.
f
Federal Register
1140
On November B, 1983. the CEC
evaluated 12 chemicals and one group of
substances nominated to the NTP for
toxicological testing. The table below
lists the chemicals a n d the group of
.-....
........- ..-..--.-.
...-.....-..- ....
a. Onouw nd..... .--
..---..-
4. CI. Ço YÇto 151
& C.I. BUK AM 1s....
0 C.1.OndRedBO......-...--
7. CL Okwt Y f k w 4
Monday, January 9, 1984
substances. the Chemical Abstracts
Service (CAS) registry numbers, where
applicable, and the types of testing
recommended by the CEC.
..---.--.-.-- .
Notices
.-
DEPARTMENT OF HOUSING AND
URBANDEVELOPMENT
Office of the Under secretary
AGENCY: Department of Homing a n d
Urban Development. ACTION: Notice of meeting of the Advisory Committee on Contract Document Reform. i
The chemicals malathion and
p i c h m were previously tested by the
NTP in various toxicology teat systems.
Malathion was negative for
carcinogenicity in feeding studies in
male and female rats and mice. The
chemical wax also negative in the
Salmonella nticnnomal assay when
tested in four strains of the bacteria
b&Ql with SRG wi-JIi~!i netnhiii.
activation. Mrfethion w m positive for
both chromosomal aberrations and
sister chromatid exchange* when tested
in cultured Chinese hamster ovary cells.
in an NCIINTP feeding study of
picloram in male and female rats and
mice. an increased incidence of
neoplastic nodules of the liver in female
rats was associated with treatment with
picloram. No tumors were observed in
male or female mice or male ra-ts at
incidence* that could be significantly
associated with-treatment. On the basis
of these results, it was judged that there
is equivocal evidence of carcinogenicity
for picloram. The chemical wà negative
in the Salmonella assay in all four
strains tested both with and without
metabolic activation. Picloram did not
induce d i n k e d recessive lethal
mutations when tested in Drosophila. It
currently is being tested in cultured
Chinese hamster ovary cells for its
ability to induce chromosomal
aberrations and sister chromatid
exchanges.
Although stannous fluoride has not
previously been selected for leafing by
the NTP, two related compounds.
namely stannous chloride and sodium
fluoride, have been. There wae no
evidence of carcino~enesiswhen
etannous ch!oridr was tested in a feed
eludy in male and female rats and mice.
/
Advisory Committeeon Contract
Documont Reform; Meeting
^
I. C I Own* 9iwn 1.. ........ ..--..-..... @ . M C Y - m M o . 11
1 Vol. 49. No. 5 /
The chemical waa also negative hi the
Salmonella w a y in aH four atraina
tested with and without activation.
Sodium fluoride H currently being
administered in the water to rats and
mice in a carcinogenesis stidy. It was
negative in all four strain* tested in the
Salmonella assay but yielded positive
results in the U178Y ~aouselymphoma
GçÃ
È'
None of the other chemicals evaluated
for testing at the November 8,1983
meeting have previously been selected
by the NTP for any type of toxicological
testing.
Interested parties are requested to
submit pertinent information. The
following types of data are of particular
relevance:
(1)Completed, ongoing and/or
planned toxicological testing in the
private sector including detailed
experimental protocols and, in the case
of completed studies, cesultant data.
(2) Modes of production, present
production level*, and occupational
exposure potential.
(3) Uses and resulting exposure levels,
where known.
(4) Results of toxicological studies of
structurally related compounds.
Please submit all information in
writing by (thirty daye after date of
publication). Any submissions received
after the above date will be accepted
and utilized where possible.
Dated: January 3.1064
David P. RaL
M.D.,
Ph. D..Director. National Toxicology
Program.
~2%eeecondmeetingoTthe Committee on Contract Document Reform will be held on January 31.1984 at @:SOa.m. in the Under Secretary's Conference Room {I01061 at ihe Department of Homing and'Urban Development. 451 7th Street. SW.. Washington. HC.20410. The purpose of the meeting u to
discuss Ole Committee members' written
comments on the contract documm'ts
mod in collection with the
Department's insured housing program*.
This meeting ia open t o the public.
Any interested persons may attend.
appear bef0re.e~file ¥totemen widi the Committee. Oralstatements m a y be
made at the meeting at the time and is
4J.. .....=-- w"..-....i15y
..-- +.:
'L. .4
===:--
FOR FURTHER INPOfdU-nOM CONTACT:
Joseph R. Lupica, Special h i s t a n t to
the Secretary, Department of Housing
and Urban Development, m 7 t h Street.
SW.. Washington. D.C. 20410.
Telephone: (202) 755-5719. (This is not a
toll-free number.]
Dated: December 30.1983.
Philip Abrams.
Under Secretary. Departmentof Housing usd
Urban Development.
DEPARTMENT OF THE INTERIOR
Bureau of Indian Affairs
Big Sandy Rancheria, CaNfomta;
Distribution Plan
December 30, 1983.
This notice is published pursuant to
the order issued June 13.1983, in Son
foaquin or Big Sandy Band of Indians, el
a!. v. Wait.et 01.. Civil No. C-80-3787MHP, by the United States District Court
for the Northern District of California.
Plaintiffs and class members in that
lawsuit retain their t~tstusas Indians
under the laws of the United States. The
Distribution Plan for the Big Sandy
Rancheria which was approved
'
ATTACHMENT 4 TESTING RECOMMENDATIONS FOR CHEMICALS REVIEWED BY THE
NTP BOARD OF SCIENTIFIC COUNSELORS
ON AUGUST 16, 1984
Chemical
(CAS No.)
Recommendati o n
(Priority)
1. Antimony potassium
Subchronic study
( Low
.
tartate
( 28300-74-5)
Remarks
-Past usage i n U.S.
-Current usage i n
.
o t h e r countries.
- S t r u c t u r a l interest.
2. Arsine
( 7784-42-1)
Comparative study of
Low occupational
chemical d i s p o s i t i o n of
exposure
arsine and arsenic t r i o x i d e
(Low)
3. Black newsprint inks
(No CAS Number)
Skin p a i n t i n g carcinogen- -Increased level o f
i c i t y studies on cornbuccal and pharangeal
p o s i t e samples o f each o f cancer among newsprint
the two types o f ink,
pressroom workers.
namely o f f s e t and l e t t e r - -Determine appropriate
press inks.
' t 1~
V,=G i- ,:,-in i'; (High)
.-(I
4. 2-( 2-Butoxyethoxy) e t h y l thiocyanate
( 112-56-1)
- P o t e n t i a l f o r exposure
-Salmonella assay
-Subchronic studies
-Structural interest
i n c l u d i n g sperm morphol- -Evaluate f o r carcinoogy and vaginal c y t o l o g y
g e n i c i t y t e s t i n g upon
evaluation
completion o f short-Short-term -i n vivo
term studies
reproductive t o x i c i t y assay
(Moderate )
5. Chromic a c i d
( 13530-68-2)
Comparative chemical
d i s p o s i t i o n study o f
chromic a c i d and sodium
d i chromate
(Moderate )
6. Cinquasia red
( 1047-16-1)
I n h a l a t i o n chemical
d i s p o s i t i o n studies
(Moderate)
-0ccupat i o n a l exposure
-Increased incidence
o f pulmonary cancer i n
r a t s i n sodium dichromate i n t r a t r a c h e a l
i n s t i l l a t i o n study
P o t e n t i a l f o r worker
exposure.
r
+
Page 2
Chemical
(CAS No.
Recommendation (Priority)
7. C. I. Acid Ye1 low 151
Deferred.
(
(
(
(
(
(
(
(
(
Deferred (Further information
(requested on r a t i o n a l e
( f o r nomination o f the
( f i v e dyes as representa( t i v e s o f azo and n i t r o
(dyes class.
( 12715-61-6)
8.
*
C.I. Basic Red 18
( 14097-03-1)
9. C. I. D i r e c t Red 80
( 2610-10-8)
Deferred
10. C. I. D i r e c t Yellow 4
( 3051-11-4)
Deferred
11. C. I.Disperse Brown 1
( 23355-64-8) Deferred
14. L i n o l e l a i d i c a c i d
( 506-21-8)
(
(
(
(
f
-Salmonel l a assay
-Mouse lymphoma, i n v i t r o
cytogenetics assays.
-Subchronic study
-Carcinogenicity t o be
performed i n tandem w i t h
another commerci a1 l y
important alkene
(Moderate 1
13. Formic a c i d
( 64-18-6)
Remarks -Positive results i n
Salmonella assay
-Structure a c t i v i t y
considerations
-1nhalational carcinogeni- -High production and
c i t y study
widespread expo-Reproductive e f f e c t s study sure.
(Moderate -Structural r e l a t i o n s h i p t o formaldehyde
No t e s t i n g
Refer t o N C I f o r
consideration of
research on r e l a t i o n ship between n u t r i t i o n
and cancer.
Page 3
Chemical
(CAS No.)
Recommendati o n (Priority) Remarks
15. Luminol
(521-31-3)
-Salmonel l a assay
(Moderate 1
-Lack o f t o x i c i t y
data
-Structural interest
-Low exposure
16. Methylene b i s
(thiocyanate
(6317-18-6)
-Salmonel 1a assay
-Chemical d i s p o s i t i o n
study
-Subchronic study
(Moderate 1
-Structural interest
-Potential f o r human
exposure
17. N i tromethane
( 75-52-51
-Carcinogenicity
(Moderate)
-Interest i n nitroalkanes
Two-stage promot i o n study. (Moderate 1 IQ. S t m n ~ u sf
lu~ride
- S t r u c t u r a l 1y r e l a t e d
compounds are tumor
promoters
- P o t e n t i a l f o r human
exposure.
.
- G e n o t ~ x j c i t yt e s t s
-Short-term i n vivo
reproductive t o x i c i t y
assay.
(Moderate
-Human exposure
due t o use i n
dental products
20. 1,2,4,5-Tetrachlorobenzene
( 95-94-3 1
- I n v i v o cytogenetics
-Acute n e u r o t o x i c i t y
-Carcinogenicity
i n c l u d i n g sperm morphology and vaginal c y t o l o g y
assays i n prechronic
p o r t i o n of study
-Short term i n v i v o
reproductive t o x i c i t y
assay.
(High)
-Potential f o r exposure
-Possible s u b s t i t u t e f o r
PCBs
-Potential f o r b i o accumulation
-Environment a 1
occurrence
21. Thiopfiene
( 110-02-1)
-Subchronic study
(Moderate 1
-Carcinogenicity
(Low)
-Structural interest
-Develop t o x i c o l o g i cal p r o f i l e .
( 1183-47-3)
w
.--.