83
Mutation Research, 65 ( 1 9 7 9 ) 8 3 - - 1 1 9 © E l s e v i e r / N o r t h - H o l l a n d B i o m e d i c a l Press
THE GENOTOXIC EFFECTS OF 2,4,5-T
W I L L I A M F. G R A N T
Genetics Laboratory, McGill University, Macdonald Campus, Ste. Anne de Bellevue, Québec H 9 X 1 C 0 (Canada) (Received 20 S e p t e m b e r 1978) (Revision received 16 J a n u a r y 1979) ( A c c e p t e d 21 J a n u a r y 1979)
Contents Introduction ................................................. Chemistry ................................................... Molecular activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Toxicology .................................................. M o r p h o l o g i c a l and cytological e f f e c t s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A. P r i m a r y and physiological e f f e c t s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. S e c o n d a r y and s t r u c t u r a l e f f e c t s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . M u t a g e n i e i t y o f 2,4,5-T . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C a r c i n o g e n i e i t y o f 2,4,5-T . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . T e r a t o g e n i c i t y o f 2,4,5-T . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements ............................................. Referenees ..................................................
84 87 88 89 90 90 95 103 106 107 112 114 114
Summary 2,4,5-T (2,4,5-trichlorophenoxyacetic acid) is a herbicide that is used primarily for brush and weed control on rangelands and pastures, and rights-of-way. Commercial formulations contain up to 0.1 ppm of the c o n t a m i n a n t dioxin (TCDD) which has been shown to cause birth defects and tumors in animals when administered in concentrations below 100 ppt. In m a n y studies (especiaUy in literature prior to 1970) it is not clear whether the reported genotoxic effects are the result of the 2,4,5-T per se, the TCDD contaminant, or a combination of both. The possible harmful effects of 2,4,5-T to humans and wildlife came into prominence during the Vietnam war when the American A r m y used Agent Orange (equal parts of 2,4-D and 2,4,5-T) for defoliation purposes. The reported increases in the incidence of congenital malformations and certain types of cancer in defoliant-treated regions led to the Bionetics Research
84
Laboratory study in which 2,4,5-T was reported to cause developmental abnormalities in rats. Subsequent research showed that 2,4,5-T is a clastogen producing chromosome aberrations including bridges and micronuclei in a variety of animal and plant species. In addition, 2,4,5-T induces cell enlargement, lengthens the duration of the mitotic cycle, extends DNA synthesis, induces mitosis and causes chromosome contraction, stickiness, and sticky bridges, all at low concentrations. C-Mitoses, multinucleate cells, polyploidy, reduced fertility, and species resistance have also been reported. In vivo production of chromosome aberrations in humans is inconclusive. The emulsifiers and solvents in commercial preparations o f 2,4,5-T have also been shown to induce chromosome aberrations. 2,4,5-T is only weakly mutagenic with positive reports recorded in only 2 of 4 sex-linked lethal tests in Drosophila and in one of two studies on Saccharom y c e s cerevisiae. Only two studies on carcinogenicity from 2,4,5-T are reported with contradictory results. While the data on teratogenicity are n o t clear-cut, the number of positive reports suggest that 2,4,5-T is definitely teratogenic both with and without TCDD and that 2,4,5-T and TCDD may potentiate teratogenic activity. Further studies, including epidemiological investigations of human groups exposed to 2,4,5-T, are required to supplement insufficient data and to resolve contradictory evidence.
Introduction
The herbicide 2,4,5-T (2,4,54richlorophenoxyacetic acid) is a chlorinated phenoxylalkanecarboxylic acid (Fig. 1) with physiological properties simflar to the natural plant growth h o r m o n e indoleacetic acid. As a result it is classified as a hormonic herbicide. Its acute oral toxicity (LDs0) is specific and reported from 1 0 0 to 1200 mg/kg (Table 1). 2,4,5-T is somewhat more toxic than 2,4-D (2,4
Mutation Research, 65 ( 1 9 7 9 ) 8 3 - - 1 1 9 © E l s e v i e r / N o r t h - H o l l a n d B i o m e d i c a l Press
THE GENOTOXIC EFFECTS OF 2,4,5-T
W I L L I A M F. G R A N T
Genetics Laboratory, McGill University, Macdonald Campus, Ste. Anne de Bellevue, Québec H 9 X 1 C 0 (Canada) (Received 20 S e p t e m b e r 1978) (Revision received 16 J a n u a r y 1979) ( A c c e p t e d 21 J a n u a r y 1979)
Contents Introduction ................................................. Chemistry ................................................... Molecular activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Toxicology .................................................. M o r p h o l o g i c a l and cytological e f f e c t s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A. P r i m a r y and physiological e f f e c t s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. S e c o n d a r y and s t r u c t u r a l e f f e c t s . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . M u t a g e n i e i t y o f 2,4,5-T . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C a r c i n o g e n i e i t y o f 2,4,5-T . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . T e r a t o g e n i c i t y o f 2,4,5-T . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements ............................................. Referenees ..................................................
84 87 88 89 90 90 95 103 106 107 112 114 114
Summary 2,4,5-T (2,4,5-trichlorophenoxyacetic acid) is a herbicide that is used primarily for brush and weed control on rangelands and pastures, and rights-of-way. Commercial formulations contain up to 0.1 ppm of the c o n t a m i n a n t dioxin (TCDD) which has been shown to cause birth defects and tumors in animals when administered in concentrations below 100 ppt. In m a n y studies (especiaUy in literature prior to 1970) it is not clear whether the reported genotoxic effects are the result of the 2,4,5-T per se, the TCDD contaminant, or a combination of both. The possible harmful effects of 2,4,5-T to humans and wildlife came into prominence during the Vietnam war when the American A r m y used Agent Orange (equal parts of 2,4-D and 2,4,5-T) for defoliation purposes. The reported increases in the incidence of congenital malformations and certain types of cancer in defoliant-treated regions led to the Bionetics Research
84
Laboratory study in which 2,4,5-T was reported to cause developmental abnormalities in rats. Subsequent research showed that 2,4,5-T is a clastogen producing chromosome aberrations including bridges and micronuclei in a variety of animal and plant species. In addition, 2,4,5-T induces cell enlargement, lengthens the duration of the mitotic cycle, extends DNA synthesis, induces mitosis and causes chromosome contraction, stickiness, and sticky bridges, all at low concentrations. C-Mitoses, multinucleate cells, polyploidy, reduced fertility, and species resistance have also been reported. In vivo production of chromosome aberrations in humans is inconclusive. The emulsifiers and solvents in commercial preparations o f 2,4,5-T have also been shown to induce chromosome aberrations. 2,4,5-T is only weakly mutagenic with positive reports recorded in only 2 of 4 sex-linked lethal tests in Drosophila and in one of two studies on Saccharom y c e s cerevisiae. Only two studies on carcinogenicity from 2,4,5-T are reported with contradictory results. While the data on teratogenicity are n o t clear-cut, the number of positive reports suggest that 2,4,5-T is definitely teratogenic both with and without TCDD and that 2,4,5-T and TCDD may potentiate teratogenic activity. Further studies, including epidemiological investigations of human groups exposed to 2,4,5-T, are required to supplement insufficient data and to resolve contradictory evidence.
Introduction
The herbicide 2,4,5-T (2,4,54richlorophenoxyacetic acid) is a chlorinated phenoxylalkanecarboxylic acid (Fig. 1) with physiological properties simflar to the natural plant growth h o r m o n e indoleacetic acid. As a result it is classified as a hormonic herbicide. Its acute oral toxicity (LDs0) is specific and reported from 1 0 0 to 1200 mg/kg (Table 1). 2,4,5-T is somewhat more toxic than 2,4-D (2,4
