Pesticides in the Environment

Characteristics

Pesticide Transport and Fate

Monitoring in the Environment

Methods for Measuring Human Exposure to the Agent

Exposure Pathways

Strategies for Preventing and Controlling Pesticides


Harmful Effects of Alachlor

Dose Response of Alachlor

Absorption, Distribution and Metabolism

Sites of Toxicity

Biomarkers of Disease and Molecular Mechanisms of Action

Risk Assessment

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Biomarkers of Disease and Molecular Mechanisms of Action

Biomarkers are used for a variety of reasons when assessing the toxicity of alachlor. There are three types of biomarkers, each measuring different types of effects. They include biomarkers of exposure, response, and susceptibility. One of the main concerns of alachlor is that it is a probable carcinogen. The biomarkers show what molecular changes are occurring and how these changes influence the progression of disease.

Biomarkers of exposure

Exposure biomarkers are used to determine what the actual level of exposure is. In toxicity tests for alachlor the doses are assumed to be the actual level of exposure. This is fairly accurate, but it should not be presumed that 100% of the chemical has been absorbed by the subject. For this reason blood tests are conducted to achieve a more exact estimate. This level is usually similar to amounts dispersed to organs. The absorption rate of alachlor depends upon the route of exposure. Alachlor generally has a high absorption rate through ingestion and inhalation routes. However, absorption varies more through the dermal route. When alachlor was applied to the skin of rats at a low dose (14 mg/kg) nearly 75% was absorbed, while monkeys only absorbed 8 to 10% through the skin.

When assessing the exposures of a chemical in the blood, it is important to take into consideration the metabolites of the substance. One prevalent metabolite of alachlor is ethane sulfonic acid (ESA). It is formed when a chlorine atom is displaced by a sulfonic acid moiety. Toxicity tests have concluded that alachlor’s metabolite, ESA is less toxic than its parent. For example, the acute, oral LD50 in one study was 900 mg/kg for alachlor and >6000 mg/kg for alachlor ESA. In a study on metabolism alachlor was present in the blood after 24 hours and after five days. Conversely, the ESA metabolite was poorly absorbed and readily excreted (71% to 82% in one day). It was reasoned that since the metabolite was highly polar and sulfonated, its absorption rate in the body is low and if it does get absorbed it is efficiently excreted. Also, Alachlor ESA is also doubtfully a carcinogen. Metabolites of alachlor generally are not as toxic as the parent chemical.

Biomarkers of response

Biomarkers of response are consequences of the exposure. An area of great concern for alachlor is its effects on genes which may be the basis for carcinogenesis. Alachlor is thought to be a probable carcinogen. The development of stomach, thyroid, and nasal tumors has occurred in rats given high doses of alachlor. Carcinogenesis causes an uncontrolled proliferation of cells in tissues and organs. Many cancers are caused from mutated somatic cells which disturb the genetic control. However, studies have shown that alachlor does not appear to be mutagenic. Reactions to alachlor are invoked by threshold sensitive mechanisms. Carcinogenic reactions only occur at high levels of exposure. Pharmacokinetic studies have shown that alachlor and its metabolites are transformed into a diethyl quinoneimine (DEIQ) metabolite. The presence of DEIQ produces protein adducts. It leads to cytotoxicity which ultimately produces cell proliferation and tumor formation. Exposure to high levels of alachlor also increases circulating TSH levels. Acute exposures cause upregulation of metalloproteinases (MMP) and other genes related to extracellular homeostasis. These increased emissions cause follicular cell hyperplasia and neoplasia. This process can produce malignant tumors as were seen in the rats. However, scientists are unsure of the exact carcinogenic effects of alachlor.

Biomarkers of susceptibility

They can be seen in variations across species. Studies across different species have shown why alachlor may be more likely to be a carcinogen in certain animal species versus humans. For instance, rats are able to convert the secondary sulfide metabolite of alachlor to 2,6 – DEA, the precursor to DEIQ greater than 30 times that of monkeys and 751 time greater than humans. Variations in individual, human susceptibility may also be a result of differences in metabolism, expression of tumor suppressor genes, and nutritional variations. Differences in metabolic phenotype, as detected in enzymes, may cause variances in required metabolic activation. Environmental carcinogen susceptibility may also have to do with phenotypes for detoxifying enzymes.

References

The Role of Individual Susceptibility in Cancer Burden Related to Environmental Exposure

Summary of Toxicology Studies on Alachlor

Genomic Analysis of Alachlor Induced Oncogenesis

EPA, Alachlor Reregistration Eligibility Decision, 1997

Assessing Health Risks from Pesticide

Consumer Factsheet on Alachlor