Herbicides mammalian toxicity

Herbicides constitute a large and diverse class of pesticides that, with a few exceptions, have very low mammalian toxicity and have received relatively little attention as environmental pollutants. Much of the work in the held of ecotoxicology and much environmental risk assessment has focused on animals, especially vertebrate animals. There has perhaps been a tendency to overlook the importance of plants in the natural world. Most plants belong to the lowest trophic levels of ecosystems, and animals in higher trophic levels are absolutely dependent on them for their survival. 

Trigard 75 WP is a new insecticide with a unique mode of action and a unique triazine structure. It is a solid formulated as a wettable powder and is packaged in water-soluble bags. The active ingredient in Trigard has the common name cyromazine. Cyromazine is a triazine, but, unlike the well-known triazine herbicides, this compound has insecticidal properties and no herbicidal activity. Cyromazine has low mammalian toxicity and low vapor pressure. It is hydrophilic, so dermal penetration is expected to be... 

In summary, the sulfonylureas are new herbicides which exhibit activity at extremely low rates of application and show very low mammalian toxicity. Exceptionally high activity is shown by compounds containing a benzene ring substituted in the ortho position, an unsubstituted sulfonylurea bridge, and a pyrimidine or triazine heterocycle substituted with methyl or methoxy groups. 

Herbicides are designed to kill plants, not animals, and in general have lower mammalian toxicity than insecticides. Most herbicides interfere with plant hormones or enzymes that do not have any direct counterpart in animals. The most serious human health concerns have been related to contaminants of the primary chemical herbicide. There is an enormous amount of animal and some human toxicity data on 2,4-D and 2,4,5-T, but it now appears that much of this toxicity is caused by the contaminant TCDD. Military personnel exposed to Agent Orange, often contaminated with TCDD, reported birth defects, cancers, liver disease, and other illness. These concerns led to improvement in the manufacturing process to reduce TCDD contamination and ultimately to a reduction in use of 2,4-D herbicides. There is also concern that some herbicides may affect wildlife. For example, atrazine, a persistent herbicide, may adversely affect frogs. Persistence of herbicides may also... 

Herbicidal activity generally consists of interference with plant-specific biochemical reactions. Thus, mammalian toxicity is generally low and not predictable from the mechanism of herbicidal action. In contrast, rodenticide target selectivity is not based on differences in biochemistry between humans and rodents but rather on differences in physiology or behavior, especially feeding behavior. For example, an emetic may be included in a rodenticide formulation to promote vomiting in humans who accidentally consume the product rodents do not have a vomit reflex. 

Sulfamoyl-2-chloroadenosine (121) from a strain of Streptomyces alhus possesses potent herbicidal activity on broad leaf weeds in post-emergent application (80 percent control on Sinapis alba, Stellaria media, Veronica persica, and Xanthium spinosum at <24 g/acre). Unfortunately, this compound also exhibits strong mammalian toxicity (LCso in mouse fibroblasts 0.013 pg/ml). Nucleocidin glucoside (122), a fluoronucleoside from a Streptomyces strain, is a weak herbicide [97]. 

The tnicroencapsululion of pesticides (qv) and herbicides active area of development that has produced several commercial products. The function of the microcapsules is to prolong activity while reducing mammalian toxicity, volatilization losses, phytotoxicity. environmental degradation, and movement in the soil. Ideally, encapsulation would also reduce the amount of agrochemical needed. 

The organophosphosphates represent another extremely important class of organic insecticides. They were developed during World War II as chemical warfare agents. Early examples included the powerful insecticide schradan, a systemic insecticide, and the contact insecticide parathion. Unfortunately, both of these compounds are highly poisonous to mammals and subsequent research in this field has been directed toward the development of more selective and less poisonous insecticides. In 1950, malathion, the first example of a wide-specUnm organophosphorus insecticide combined with very low mammalian toxicity, was developed. And at about the same time the phenoxyacetic acid herbicides were discovered. These systemic compounds ate extremely valuable for the selective control of broad-leaved weeds in cereal crops. These compounds have a relatively low toxicity to mammals and are therefore relatively safe to use. 

The majority of phenols, especially those containing chlorine, are toxic to microorganisms. However, the majority of phenols are too phytotoxic to permit their use as agricultural fungicides. They are widely used as industrial fungicides. Dinocap, a mixture of several compounds, was first introduced in 1946 as a non-systemic aphidde and contact fungicide. Dinocap is used to control powdery mildew on major horticultural crops. Unlike the herbicide DNOC and other chlorinated phenols, dinocap has relatively low mammalian toxicity. 

Chlorophenoxy herbicides exhibit low mammalian toxicity. The acute oral LD50 for 2,4-D in rats is > 300 mg kg Dogs are more susceptible to 2,4-D... 

Herbicide resistance is currently less of a problem than with the other pesticide groups, although, once it occurs, the effects are profound. Instead, the major interest centres around the control of off-target drift (i.e. application issues), specificity and the use (and side-effects) of certain herbicides with genetically modified crops. The examples listed in Table 8.1 indicate the continuing importance of pre-1980 molecules. For instance, glyphosate has become the most important herbicide, with its recent fall in price, broad spectrum of efficacy, low mammalian toxicity and (where GM crops are acceptable) its compatibility with Roundup ready crops. 

The first synthetic herbicide12 was 2,4-dichlorophenoxy-acetic acid (11.7). The one used in largest volume today is atrazine, which is typical of a group of triazine herbicides. Glyphosate (very low mammalian toxicity) is used extensively to kill vegetation nonselectively.13 Alachlor is a typ-... 

Two newer classes of herbicides are active at much lower dosages. The sulfonylureas (11.8)15 are used at 2-4 g/ha. The sulfonylureas have low mammalian toxicity. Only 1.4 oz/acre of the imidazolinones (see 11.8) 16 is needed. 

The ultimate success of this discovery is demonstrated by the fact that there are fourteen commercialized and advanced candidate sulfonylurea herbicides. These compounds are useful in crops such as cereals, soybeans, rice, com, and canola as well as for noncrop use. TTieir low use rates favorable soil half-lives and low mammalian toxicity make them ideal products environmentally. These factors arc discussed in more detail by Brown and Kearney in the following chapter. 

To minimize the potential for mammalian or non pest toxicity the target should be present in plants, but not mammals. However, toxicity of xenobiotics is difficult to predict since it is often due to effects that are unrelated to inhibition of the target site. Most herbicidal inhibitors of glutamine synthetase (glufosinate) and acetyl-CoA carboxylase (diclofop and sethoxydim) have very low mammalian toxicity (2), yet both enzymes are found in animal tissues. 

The ceramide synthase pathway is clearly a viable site for herbicides, provided an inhibitor can be found that is plant specific. We have been unsuccessfiil in finding a ceramide synthase inhibitor with high phytotoxicity, but low mammalian toxicity (e.g., 11). Even inhibitors widi little structural similarity to the fumonisins, such as australifungin 12), have relatively little difference between mammalian and plant toxicity. This topic is considered in more detail in a recent review 13). 

A basic requirement for a safe herbicide is that it exhibit strong phytotoxicity and weak or no mammalian toxicity. The demonstration that FBi is a tumor promoter eliminates it from direct consideration as a herbicide. However, the finding that FBi is phytotoxic by a different mechanism than any commercially used herbicide makes it worthwhile to search for analogs with low mammalian toxicity and high phytotoxicity. 

---