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Metabolic studies in both humans and other mammals show that bis-phenol A is rapidly eliminatedfrom the body (< 24 h). Following uptake from the GI tract, the compound is conjugated (Phase II/trapp in g) in the liver with glucuronic acid (a sugar derivative). The water-soluble glucuronide is ex creted in the urine. Metabolism follows a slightly different pathway in the rat, in which the glucuronideadduct is transported to the bile and re-enters the digestive system. Enterohepatic recycling results ina longer whole-body half-life and the higher proportion of excretion in the feces, compared with thehuman. There is a need for epidemiological and dose-response studies to assess properly the human healthimplications of exposure to bis-phenol A. The Canadian government’s response in 2008 was basedon the so-called “precautionary principle” which states that new substances should not be introducedinto the marketplace until they have been proved to be safe. As previously noted, it is never possible to prove a negative – that no toxic outcomes will result fromexposure to any substance. Instead, one can only make statements along the lines of “the likelihoodof an adverse condition will be no more than (say) one in 106.” This question will be addressed morefully in the section of the course on Regulatory Toxicology.
1-49PNCO2HHOHOHOCH2OCO2HOHPiOCO2HOHCO2HPiOOH1.6.8HERBICIDEsIn case these notes leave the impression that toxicology is exclusively a mammalian concern, we willfinish this section by examining the mechanism of action of a group of herbicides. Many herbicidestarget aspects of the photosynthetic apparatus, and therefore have low animal toxicity.GlyphosateGlyphosate, N-(phosphonylmethyl)glycine (marketed as the isopropylammonium salt by Monsantounder the name Roundup) is a broad spectrum herbicide that kills plants following foliar uptake.Glyphosate has very low mammalian toxicity (LD50> 1 g/kg in all species tested) and only slighttoxicity to aquatic animals (LC50> 100 mg/L in all species tested except trout (11 mg/L). It also haszero to low potency in terms of carcinogenicity, neurotoxicty and teratogenicity in mammals, making itnon-hazardous to (animal) non-target organisms. In soil, glyphosate is made biologically unavailableby binding to clay, and is inactivated by microorganisms. In most soils this occurs within days,accounting for the attractive feature of glyphosate to farmers: weeds can be destroyed and a cropplant ed almost immediately afterwards.Glyphosate is absorbed by foliar uptake and rapidly distributed systemically. Its mechanism of actionis well understood; it inhibits the enzyme 5-enolpyruvyl shikimic acid-3-phosphate synthase. Thisenzyme catalyzes a critical step in the synthesis of aromatic aminoacids (phenylalanine, tyrosine,tryptophan). When the enzyme is inhibited, these cannot form; protein synthesis ceases as the plants stores of these aminoacids are used up, and the plant dies (although this process can be reversedif the aromatic aminoacids are supplied exogenously). This mechanism of action explains why thedie-off of the plants occurs over a period of 7-14 days.