Document evmEeY7o92p9ROYRe6zD1dNOp

P X l4 3 & 73 MONSANTO BIOHAZARDS COMMITTEE Minutes of a Meeting November 17, 1982 Dr. Timothy Long, a new t o x ic o lo g y s t a f f member, then reviewed the data on the t o x i c o l o g y o f d i o x i n s . He p o i n t i n g out t h a t the d i o x i n r i n g system can take up one to e i g h t c h io rin e -a to m s/ m o le cu le which can r e s u l t i n s e v e n t y - f i v e p o sition al isomers. These isomers are of widely va ryin g t o x ic it y in d iffe re n t animal s p e c ie s . The most potent i s 2 , 3 , 7 , 8 - t e t r a c h l o r o d i b e n z o - p - d i o x i n , some tim es d e sig n a t e d as TCDD, even though there are s i x t e e n iso m e rs o f the t e t r a c h lo r o d e r i v a t i v e . The t o x i c i t y o f t h i s f a m ily o f compounds depends upon the dose, the degree of ch lo rin a tio n , the p o sition al isomer, the length o f time of exposure and the sp e c ie s. Species vary g r e a t ly in s e n s i t i v i t y to acute t o x i c i t y o f d i o x i n s . F o r example, a guinea p ig has a LD50 o f 0.6 microgram per k ilo g r a m whereas the hamster r e q u ir e s 10,000 tim es more f o r i t s LD50 o r 6,000 micrograra per k ilo g r a m . Other common rod e n ts l i k e r a t s and r a b b i t s have LD5o ' s in the range o f 10-100 microgram per k ilo g ra m . No one 1s s u re where man sta n d s in t h i s spectrum o f animal s e n s i t i v i t y . Acute e xp o su re to d i o x i n s in some a n im a ls , I n c l u d i n g man, cau se s c h lo ra c n e to appear w i t h i n a few weeks. __I t has been re p o rt e d in man, w ith o u t d i r e c t e v id e n c e o f ca u se and e f f e c t , t h a t neurom uscular c h a n g e s , p o rp h yria and hy p e r t rlg ly c e rld e rc n a t o il o w acute expo~sur? to dioxins. It i s generally believed that d ioxins, lik e other halogenated Tiydrocarbons produce a h y p e r p la s ia o f h e p a to c y te s, hepatom egaly, and, in some a n im a ls , h e p a t ic n e c r o s i s . The cause o f death from the a c u t e t o x i c i t y o f d i o x i n s , however, i s no t known. In c h r o n ic t o x i c i t y s t u d i e s a t lower d o ses o f TCDD f a i l u r e o f r e p r o d u c t io n and c a r c i n o g e n e s i s have been observed. TCDD a t d o ses o f the o r d e r o f 0.1 microgram per kilo g ra m per day 1s a teratogen in female mice and r a t s . D io x in s, including 2,3,7,8-tetrachlorodibenzo-p-dioxin, are probably not mutagens. In general the s h o r t - t e r m g e n o to xic t e s t s ( l i k e the Ames t e s t ) are n e g a t iv e , the in viv o dominant le th a l t e s t i s negative and te s t s o f chromosomal a lt e r a t io n are equivocal. C arcin oge nicity te sts in two-year life tim e stu d ie s in ra ts and mice have shown t h a t tumors o f the lu n g , l i v e r , tongue and nasal p a ssa g e s can occur with doses o f about 0.1 microgram per k ilo g ra m per day w ith a no e f f e c t level at 1 nanogram per kilogram per day. M ixtures of hexachlorodibenzo-p d io x in s are a ls o ca rcin oge n ic in male and female mice and in female r a t s . S tu d ie s by P it o t and h is colleagues (Cancer Research 40, 3616-3620, 1980) have shown t h a t the t e t r a c h l o r o d i b e n z o - p - d i o x i n Kars promoter a c t i v i t y f o r dimethyT~nT tro sa m m e induced hepatomas in r a t s . Tl UD m ight oe a p a r t i c u l a r l y e f f e c t i v e promoter Decause i t appears to r e a c t w ith the e s t r o g e n r e c e p t o r and th u s be targeted T o the nucleus where i t can exert i t s "c h lo rin a te d hydrocarbon" e ffe c t at a specific locus.