Endosulfan

Endosulfan is a neurotoxic organochlorine insecticide of the cyclodiene family of pesticides. It is highly toxic and an endocrine disruptor, and it is banned in the European Union, the Philippines, Cambodia, and several countries. It is still used extensively in many countries including the US and India. It is made by Bayer CropScience, Makhteshim-Agan, and Drexel Company among other, and sold under the tradenames Thionex, Thiodan, Phaser, and Benzoepin. Because of its high toxicity and high potential for bioaccumulation and environmental contamination, a global ban on the use and manufacture of endosulfan is being considered under the Stockholm Convention.

Uses
Endosulfan is used in agriculture around the world to control insect pests including aphids, leafhoppers, Colorado potato beetles, cabbage worms, and other pests. It has also seen use in tse-tse fly control, in wood preservation, and in home gardening. The World Health Organization estimated world wide annual production to be about 20 million lbs in the early 1980s. In India, more endosulfan is produced than any other pesticide except mancozeb and monocrotophos, with almost 180 million lbs manufactured in 1999-2000.

In the US, endosulfan is registered only for agricultural use, where it is used extensively on cotton, potatoes, and apples according to the Environmental Protection Agency (EPA). The EPA estimates that 1.38 million lbs of endosulfan were used annually from 1987 to 1997. In California, annual use of endosulfan dropped from 230,000 lbs in 1995 to just 83,000 lbs in 2005.

History

 * Early 1950s Endosulfan developed.
 * 1954 Hoechst AG registers endosulfan with the EPA, and US farmers begin using it. (Hoechst AG became Aventis after its merger with Rhône-Poulenc S.A. in 1999. In 2002, Aventis CropScience was acquired by Bayer AG, forming Bayer CropScience).
 * 2000 Home and garden uses are terminated by agreement with the EPA.
 * 2002 The EPA determines that for young children, age 1-6, the risk of acute toxicity from endosulfan in food exceeds the agency's level of concern. The agency therefore imposes more restrictions on endosulfan's agricultural uses. To mitigate its concerns over drinking water contamination and worker exposure, the EPA proposes additional label amendments.
 * 2007 The UN takes steps to restrict the international trade of endosulfan. The Chemical Review Committee of the Rotterdam Convention on Prior Informed Consent recommends endosulfan for inclusion in the Convention.
 * 2007 In July, the European Commission proposes to add endosulfan to the list of chemicals banned under the Stockholm Convention on Persistent Organic Pollutants. If approved, all use and manufacture of endosulfan would be banned globally.

Health Effects
Endosulfan is one of the more toxic pesticides on the market today, responsible for many fatal pesticide poisoning incidents around the world. Endosulfan is also a xenoestrogen—a synthetic substance that imitates or enhances the effect of estrogens—and it can act as an endocrine disruptor, causing reproductive and developmental damage in both animals and humans. Whether endosulfan can cause cancer is debated.

Toxicity
Endosulfan is acutely neurotoxic to both insects and mammals, including humans. The US EPA classifies it as Category I: "Highly Acutely Toxic" based on a LD50 value of 30 mg/kg for female rats, while the World Health Organization classifies it as Class II "Moderately Hazardous" based on a rat LD50 of 80 mg/kg. It is a GABA-gated chloride channel antagonist, and a Ca2+, Mg2+ ATPase inhibitor. Both of these enzymes are involved in the transfer of nerve impulses. Symptoms of acute poisoning include include hyperactivity, tremors, convulsions, lack of coordination, staggering, difficulty breathing, nausea/vomiting, diarrhea, and in severe cases, unconsciousness. Doses as low as 35mg/kg have been documented to cause death in humans, and many cases of sub-lethal poisoning have resulted in permanent brain damage. Farm workers with chronic endosulfan exposure are at risk of rashes and skin irritation.

EPA's acute reference dose for dietary exposure to endosulfan is 0.015 mg/kg for adults and 0.0015 mg/kg for children. For chronic dietary expsoure, the EPA references doses are 0.006 mg/kg-day and 0.0006 mg/kg-day for adults and children, respectively.

Endocrine Disruption, and Reproductive and Developmental Effects
Theo Colborn, an expert on endocrine disruption, lists endosulfan as a known endocrine disruptor, and both the EPA and the Agency for Toxic Substances and Disease Registry consider endosulfan to be a potential endocrine disruptor based numerous in vitro studies documenting its estrogenic activity and animal studies demonstrating its reproductive and developmental toxicity especially among males. It is not known whether endosulfan is a human teratogen (an agent that causes birth defects), though it has significant teratogenic effects in laboratory rats.

Several studies have documented that endosulfan can also effect human development. Researchers studying children from an isolated village in Kerala, India have linked endosulfan exposure to delays in sexual maturity among boys. Endosulfan was the only pesticide applied to cashew plantations in the hills above the village for 20 years and had contaminated the village environment. The researchers compared the villagers to a control group of boys from a demographically similar village that lacked a history of endosulfan pollution. Relative to the control group, the exposed boys had high levels of endosulfan in their bodies, lower levels of testosterone, and delays in reaching sexual maturity. Birth defects of the male reproductive system including cryptorchidism were also more prevalent in the study group. The researchers concluded that "our study results suggest that endosulfan exposure in male children may delay sexual maturity and interfere with sex hormone synthesis." Increased incidences of cryptorchidism have been observed in other studies of endosulfan exposed populations.

A 2007 study by the California Department of Public Health found that women in the first eight weeks of pregnancy who live near farm fields sprayed with endosulfan and the related organochloride pesticide dicofol are several times more likely to give birth to children with autism. These results are highly preliminary due to the small number of women and children involved and lack of evidence from other studies.

Endosulfan and Cancer
Endosulfan is not listed as known, probable, or possible carcinegon by the EPA, IARC, or other agencies. There are no epidemiological studies linking exposure to endosulfan specifically to cancer in humans, but in vitro assays have shown that endosulfan can promote proliferation of human breast cancer cells. Evidence of cancinogenicity in animals is mixed.

Endosulfan in the Environment
According to the EPA endosulfan breaks down in to endosulfan sulfate and endosulfan diol, both of which have "structures similar to the parent compound and are also of toxicological concern…The estimated half-lives for the combined toxic residues (endosulfan plus endosulfan sulfate) [range] from roughly 9 months to 6 years." The EPA concluded that, "[b]ased on environmental fate laboratory studies, terrestrial field dissipation studies, available models, monitoring studies, and published literature, it can be concluded that endosulfan is a very persistent chemical which may stay in the environment for lengthy periods of time, particularly in acid media." The EPA also concluded that "[e]ndosulfan has relatively high potential to bioaccumulate in fish."

The EPA recommends not more than 74 ppb (part per billion) in lakes, streams, or rivers, and not more than 0.1 – 2 ppm (parts per million) on surfaces of agricultural products (except dried tea, <24 ppm). Consumers are advised to wash agricultural products before their consumption.

In 2001, in Kerala, India, endosulfan spraying became suspect when linked to a series of abnormalities noted in local  children. Initially endosulfan was banned, yet under pressure from the pesticide industry this ban was largely revoked. Achyuthan A studied the effects of the spraying. The situation there has been called "next in magnitude only to the Bhopal gas tragedy."

Chemistry
Endosulfan is produced from the addition of hexachlorocyclopentadiene to cis-butene-1,4-diol and subsequent reaction of the Diels-Alder product with thionyl chloride. Technical endosulfan is a mixture of steroisomers, designated "α" and "β," in a 7:3 ratio. The technical material may also contain small amounts endosulfan sulfate and related chemicals. α- and β-endosulfan are conformational isomers, and can be interconverted without breaking bonds. α-Endosulfan is the more thermodynamically stable of the two, and β-endosulfan slowly and irreversibly converts to the α form over time.