Toxaphene congeners differ from toxaphene mixtures in their dysmorphogenic effects on cultured rat embryos
Introduction
Toxaphene is a complex mixture of polychlorinated bornanes with a broad spectrum of pesticidal activity. It was introduced in 1945 and reached maximum world consumption in 1976, when it started to replace DDT. Before its ban in 1982 it was the most heavily used insecticide in the United States and many parts of the world (Saleh, 1991). Despite its global distribution similar to DDT and PCBs, toxaphene is still used in South America, Africa and Mexico (Saleh, 1991). Toxaphene can be transported through the atmosphere from the sites of application due to its high vapour pressure and spread in the environment (Ribick et al., 1981). It is persistent in soils and lakes sediments (Bidleman et al., 1988) and has been found in fish (Stern et al., 1992), marine mammals (Bidleman et al., 1993), terrestrial mammals (Zhu and Norstrom, 1993) and human milk (Bidleman et al., 1988).
Recently, the toxicology of toxaphene is receiving renewed attention because it is the most prevalent organochlorine compound in Great Lakes fish (Glassmeyer et al., 1997). Moreover, in the Arctic where consumption of fish and marine mammals is common, a high percentage of the people had dietary exposure levels exceeding the tolerable daily intake level (TDI) of 0.2 μg/kg body weight/day established by the Health Protection Branch of Health Canada (Chan et al., 1997).
Relatively little is known about the mode of action of toxaphene, partly because of its complicated mixture nature. The toxaphene technical mixture was, however, shown to be acutely (Gaines, 1960) and chronically (Ohsawa et al., 1975) toxic to aquatic life and poses a carcinogenic risk to humans. Effects of toxaphene technical mixture on different enzyme systems and biochemical processes have also been described (Chu et al., 1988).
Astrong relationship has been found between embryo-fetal mortality and maternal toxicity in rodents upon toxaphene exposure (Kavlock et al., 1982). Chernoff et al. (1990)found that rat litters of dams treated with toxaphene had elevated incidences of supernumerary ribs. However, in a one generation two litter reproduction study in rats, toxaphene technical mixture treatment of up to 290–380 μg/kg per day given orally had no effects on litter size, pup weight, fertility, or gestation and survival indices (Chu et al., 1988). Teratogenicity of toxaphene was also demonstrated in a teleost (Fundulus heteroclitus) embryo culture model (Crawford and Guriano, 1985). Results of epidemiological studies have shown that the developing embryos are the most susceptible target organ for organochlorine toxicity (Jacobson and Jacobson, 1996). Information on the toxicity and teratogenicity of toxaphene, however, are based on studies using the toxaphene technical mixture containing over 800 congeners. The toxicity of toxaphene residues in biological or food samples may differ from that of the technical mixture; only two major congeners, 2-exo,3-endo,5-exo,6-endo,8,8,10,10-octachlorobornane (T2) and 2-exo,3-endo,5-exo,6-endo,8,8,9,10,10-nonachlorobornane (T12), were found in the Canadian Arctic traditional food system and in the milk of indigenous women (Stern et al., 1992). Therefore, it is important to verify the relative toxicity of these two environmentally prevalent congeners.
In this study, the dysmorphogenic effects of the toxaphene technical mixture and T2 and T12 were studied using the rodent embryo culture model to test the hypothesis that there are differences in the dysmorphogenic potency between the toxaphene technical mixture and the environmentally prevalent toxaphene congeners. The embryo culture model was used because it offered the advantage that the exposure concentrations on the embryo could be more accurately controlled and the effects of mixtures of the chemical could be easily studied. A mammalian system was chosen to provide a more physiologically relevant system with respect to implications on human health.
Section snippets
Animals maintenance and mating procedure
Virgin female Sprague–Dawley rats (180–200 g) (Charles River Canada, St. Constant, PQ) were used in all experiments. Upon arrival, the females were housed in a temperature-controlled room (20°C) with a 14L–10D reversed light cycle (lights on at 16:00 h). The animals were kept in plastic shoe box cages with Beta-Chip bedding (Beta-Chip, Northeastern Products, Warrenburg, NY). Purina Rat Chow (Ren’s Feed and Supply, Oakville, Ontario, Canada) and tap water were fed ad libitum. Females were housed
Results
After the 48 h culture period, control embryos exhibited normal growth and development. The embryos underwent rotation to assume fetal position, the neural tube closure was completed and brain vesicle formation occurred. Cardiac looping and a rapid uninterrupted heartbeat were established. Optic and otic vesicles were formed, visceral arches 1, 2 and 3 became apparent and yolk-sac circulation was initiated. The forelimb and hindlimb buds showed development characteristic of GD 12.
The effects of
Discussion
The most remarkable finding of this study was the differential toxicity of the toxaphene congeners versus the technical mixture. Although all treatments had a significant adverse concentration-response effect on total morphological score, the toxicity of toxaphene technical mixture or the T2+T12 mixture was different from that of the congeners. Exposure of embryos to treatment with either T2 and T12 alone had a lesser effect on growth than did the toxaphene technical mixture or the T2+T12
Acknowledgements
Grant support from the Natural Sciences and Engineering Research Council of Canada to H.M. Chan and S. Kubow are gratefully acknowledged. The research is also partially funded by the Canadian Chlorine Coordinating Committee.
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