Phenoxy toxicity

Conversion of a nontoxic molecule to one that is toxic, or a molecule with low potency to one that is more potent. Examples include the formation of the phenoxy herbicide 2,4-D from the corresponding butyrate, formation of nitrosamines, and methylation of arsenicals to trimethylarsine. 

Commercial PCB mixtures frequently contain impurities that may contribute to the 2,3,7,8-TCDD toxic equivalency factor. These impurities may include other PCBs, dioxins, dibenzofurans, naphthalenes, diphenyl ethers and toluenes, phenoxy and biphenyl anisoles, xanthenes, xanthones, anthracenes, and fluorenes (Jones etal. 1993). PCB concentrations in avian tissues sometimes correlate positively with DDE concentrations (Mora et al. 1993). Eggs of peregrine falcons (Falco peregrinus) from California, for example, contained measurable quantities of various organochlorine compounds, including dioxins, dibenzofurans, mirex, hexachlorobenzene, and / ,//-DDE at 7.1 to 26.0 mg/kg FW PCB 126 accounted for 83% of the 2,3,7,8-TCDD equivalents, but its interaction with other detectable organochlorine compounds is largely unknown (Jarman et al. 1993). 

In contrast to the broad-spectrum herbicides, others are more selective. The phenoxy herbicides, which include chemicals such as 2,4-D, 2,4,5-T, and MCPA, are toxic to broad-leaf plants but do not affect narrow-leaf plants such as grasses. 

The phenoxy herbicides inexpensiveness, selectivity, nonpersistency and low toxicity to animals are difficult to beat. Application is usually accomplished by spraying on the leaves. The herbicides cannot themselves be applied to the soil because they are washed away or decomposed by microorganisms in a few weeks. They can be applied by this method using a sulfonic acid derivative that, after hydrolysis in the soil and oxidation by bacteria, can form 2,4-D in the plant. 2,4-D is still the main herbicide used on wheat. 

Phenoxy pesticides, liquid, flammable, toxic, n.o.s., flash point less than 23 degrees C 2766... 

The presence of TCDD in 2,4,5-T is believed to be largely responsible for other human toxicities associated with the herbicide. There is epidemiologic evidence indicating an association between occupational exposure to the phenoxy herbicides and an excess incidence of non-Flodgkin s lymphoma. The TCDD contaminant in these herbicides seems to play a role in a number of cancers such as soft tissue sarcomas, lung cancer, Flodgkin s lymphomas, and others. 

Polychlorinated Dibenzo-(p)-Dioxins and Dibenzo-Furans. Another group of compounds that we need to specifically address are the polychlorinated dibenzo-p-dioxins (PCDDs) and dibenzo-furans (PCDFs) (Fig. 2.15). The PCDDs and PCDFs are not intentionally produced but are released into the environment from various combustion processes and as a result of their occurrence as unwanted byproducts in various chlorinated chemical formulations (e.g., chlorinated phenols, chlorinated phenoxy herbicides see Alcock and Jones, 1996). Because some of the PCDD and PCDF congeners are very toxic (e.g., 2,3,7,8-tetrachloro dibenzo-p-dioxin, see margin), there have been and still are considerable efforts to assess their sources, distribution, and fate in the environment. Similarly to the PCBs or DDT (see above), the PCDDs and PCDFs are highly hydrophobic and very persistent in the environment. It is therefore not surprising that they have also been detected everywhere on earth (Brzuzy and Hites, 1996 Lohmann and Jones, 1998 Vallack et al., 1998). Finally, we should note that polybrominated diphenylethers (PBDEs, see margin) that, like the PBBs (see above), are used as flame retardants, are of increasing environmental concern (de Boer et al., 2000). 

Since the same effects occurred with the non-herbicidal (2,6-dichloro-phenoxy) acetic acid as with toxic compounds, glucose metabolic changes are not the important singular effects of auxin herbicides. 

The acute toxicity of phenoxy-acid herbicides to humans and aquatic organisms is relatively low [87]. The USEPA maximum residue level for 2,4-D in drinking water is 70 000 ng/L, and the National Academy of Sciences has recommended a maximum concentration in water for protection of aquatic life of 3000 ng/L [78]. No Canadian guidelines for the protection of aquatic life and drinking water were exceeded (Table 8). 

The extent to which exposure to pesticides may be hazardous to applicators depends upon exposure levels and the toxicity of the compounds. The phenoxy herbicides have been used for nearly 40 years, and no injury to workers properly using these herbicides has been clearly established. 

In spite of their record of producing no detectable harm to humans, the phenoxy herbicides 2,4-dichlorophenoxy acetic acid (2,4-D) and 2,4,5-trichlorophenoxy acetic acid (2,4,5-T) have acquired a less than desirable reputation. This reputation has been the result of their association with low levels of impurities. They have commonly been used as a mixture, which contains trace amounts of highly toxic 2,3,7,8-tetrachlorodibenzo-jj-dioxin, a minor product in the manufacturing of 2,4,5-T. In early production of 2,4,5-T a low level of dioxin was retained. Today s manufacturing process produces 2,4,5-T with no more than 0.1 ppm of the 2,3,7,8 tetrachlorodibenzo-]D-dioxin. This association with toxic dioxin and confusion of the public and the media regarding these issues have led to public distrust in the safety of using phenoxys and to the need to establish clearly the extent of human exposure to these compounds as well as the resulting effects of this exposure. 

Due to our awareness that extraneous exposure can occur, we have taken measures to limit these types of pre-exposure in our most recent studies. The data we have collected supply adequate evidence that extraneous means of exposure are common. If it occurs in these phenoxy studies, it is likely that it occurs for workers applying more toxic pesticides. 

Including this extraneous exposure, the degree of safety that we calculated for forest workers using phenoxy herbicides was such that even the most highly exposed crewmembers received exposure which was several orders of magnitude below the noobservable-effect-level. Decreases in the level of exposure with the use of protective measures, however, may be of real consequence to workers applying more toxic materials. 

A brief summary of the toxicity of the forest herbicide 2,4-D can be presented as follows. Table IV shows the acute LD-50 values of most of the phenoxy herbicices. These range from 300 mg/kg for 2,4,5-T and 375 mg/kg for 2,4-D up to 6400 mg/kg for Bifenox. It is useful to set the acute oral toxicity for 2,4-D in the context of other phenoxy herbicides and in relation to other pesticides so the public can gain a perception of where 2,4-D fits on a scale of relative values with regard to... 

The tetrahydropyridine l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) 288 is a well-known neurotoxin that induces symptoms like those for Parkinson s disease. The toxic effects of this compound have been attributed to its oxidation by monoamine oxidase (MAO) to form the pyridine MPP+ 289. MPP+ migrates into the mitochondria of neural cells inhibiting the production of ATP and results in cell death <2000MI1, 2001MI1>. Numerous compounds, such as 4-phenoxy- 290<1997BMC1519> and 4-pyrrole-tetrahydropyridines 291 <2002BMC3031>, have been modelled on MPTP in an attempt to inhibit MAO without exhibiting neurotoxic effects. 

However, controlled or specific environmental degradation sometimes is necessary for herbicidal action. For example, the phenoxy herbicide sesone (sodium 2,4-dichlorophenoxyethyl sulfate) has no effect on plants until it can be oxidized to 2,4-D by a specific soil microorganism, Bacillus cereus (38). The growth regulator ethophon (Ethrel) relies upon slow environmental conversion into ethylene for its activity (39). And metham (Vapam) depends upon hydrolysis in soil to release toxic methyl isothiocyanate (40). 

The benzene metabolites hydroquinone and muconic dialdehyde can produce hematotoxic effects (Eastmond et al. 1987 Gad-El Karim et al. 1985 Latriano et al. 1986). The co-administration of phenol (75 mg/kg/day) and hydroquinone (25-75 mg/kg/day) twice daily for 12 days to B6C3Fj mice produced myelotoxicity similar to that induced by benzene (Eastmond et al. 1987). The proposed mechanism suggested that selective accumulation of hydroquinone occurred in the bone marrow after the initial hepatic conversion of benzene to phenol and hydroquinone. Additionally, phenol is thought to stimulate the enzymatic activity of myeloperoxidase, which uses phenol as an electron donor, thus producing phenoxy radicals. These radicals further react with hydroquinone to form 1,4-benzoquinone, a toxic intermediate that inhibits critical cellular processes (Eastmond et al. 1987). 

A completely different modification of the clofibrate structure was obtained by synthesis of the phenoxy-methylphenoxyisobutyric acids. The 4 -bromo 36 and the 4 -chloro compound 35 were found to be considerably more active than the reference compound clofibrate. But whether definite advantages of these compounds over clofibrate can be demonstrated will be shown only by the current investigations on the mode of action, of side effects and toxicity. 

Certain phenoxy herbicides adversely affect sensitive crops (7) such as cotton, grapes, and tomatoes at distances of as much as 15 miles from the site of application. With this type of herbicide, not only are the physical state, particle size, and extent of the area treated important, but also the vapor phase of the toxicant. Highly volatile herbicides have been known to adversely affect sensitive crops some distance away for a duration of several weeks. 

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