Lindane

Lindane is a synthetic chemical that was initially developed as an agricultural insecticide and then formulated for medical use due to its antiparasitic efficacy against scabies and lice.

Lindane is the gamma isomer of hexachlorocyclohexane (“gamma-HCH”), formerly known as benzene hexachloride or BHC, and more broadly belongs to the organochlorine class of compounds. Its mechanism of action is by interfering with the GABA neurotransmitter function of parasites, specifically by interacting with the GABAA receptor-chloride channel complex at the picrotoxin binding site. In animal models, lindane has a reported oral LD50 of 88 mg/kg and a dermal LD50 of 1000 mg/kg. In humans, health effects have been described for oral, respiratory and dermal routes of lindane exposure, with varied clinical outcomes depending on the situation, setting and use application.

Agricultural vs. Healthcare Applications
Lindane (i.e., gamma-HCH) has been available for use in the U.S. for more than 60 years, with applications in both healthcare and agriculture. In the 1940s, lindane was registered with the U.S. Department of Agriculture (USDA), and in 1951 it was approved by the U.S. Food and Drug Administration (FDA) for medical use in the treatment of scabies, head lice and pubic lice (crabs). During this time, the vast majority of lindane use―more than 99%―has been for agricultural purposes and much of the safety and environmental concerns have related to this application. This is not unlike other medications where the active ingredient has other non-healthcare applications. For example, warfarin is used as a rodenticide to poison mice and rats (e.g., Kaput™, D-Con™) but is also formulated for medical use as an oral anticoagulant or "blood thinner" to treat patients with heart attacks, strokes and other clot-related disorders (e.g., Coumadin®).

In 2006, the U.S. Environmental Protection Agency (EPA) called for the voluntary cancellation of all agricultural uses of lindane, limited in recent years to pre-planting seed treatments. (see also Regulatory Status) The FDA, however, continues to support the use of lindane prescription medications, noting that “The risk of occupational/environmental exposure should be assessed separately and independent of the risk related to the therapeutic use of a medication to treat a medical condition where there is direct benefit to the patient.” (see also Regulatory History) Repeatedly, the FDA has concluded that lindane medications provide public health benefits at an acceptably low level of risk—a factor for all medications.

In 1995, lindane medications were designated second-line and are now reserved for patients who are unable to tolerate or have failed first-line treatments—--a growing problem in the U.S. and elsewhere due to increased rates of resistance. The U.S. Centers for Disease Control and Prevention also includes lindane medications in their Sexually Transmitted Disease Treatment Guidelines as viable treatment alternatives for the management of scabies and pubic lice, consistent with the approved prescription labeling for these products. (see also Pharmaceutical Uses) Other countries, like Canada, similarly approve of pharmaceutical applications for lindane but no longer permit its broader use agriculturally. (see also Regulatory Status)

Pharmaceutical Uses
In the U.S., lindane medications are regulated and approved for clinical use in humans by the FDA. Lindane Lotion is approved for the treatment of scabies. Lindane Shampoo is approved for the treatment of pubic lice (crabs) and head lice. Both medications contain 1% purified pharmaceutical-grade gamma-HCH and are formulated to the standards of the United States Pharmacopeia (USP)—the official public authority that sets quality standards for drugs manufactured and sold in the U.S. They are available as prescription-only medications and are indicated second line, meaning they are prescribed when first-line therapies have failed, cannot be tolerated or are otherwise contraindicated.

Lindane lotion and lindane shampoo have been used clinically for more than 50 years in tens of millions of patients, if not more, and have been reviewed for safety on numerous occasions by experts working with the FDA who have consistently confirmed the safety and tolerability of these medicines when used properly. Although serious side effects have been reported (e.g. seizures), they are rare and have almost always resulted from improper use and oral ingestion.

Adverse Reactions
The most common side effects associated with topical use of lindane medications are nonserious reactions of the skin, including burning, itching, dryness and rash. Central nervous system stimulation ranging from dizziness to seizures, has also been reported; however, serious effects, like seizures, have almost always resulted from oral ingestion or misuse of medication (e.g., repeated treatments or prolonged applications). Only rarely have seizures and even more rarely fatal reactions been reported when lindane medications were used (presumably) according to directions.

In 2003, the FDA published a safety analysis of adverse events reported in association with the use of lindane medications received through its adverse event monitoring system (“AERS” database) between from 1974 through 2002. The vast majority (85%) of these reports―488 total―were classified as nonserious, while serious events most often resulted from product misuse (80% of serious cases). The most common reports to the FDA were "drug ineffective," followed by convulsions, dermatitis and dizziness. (Note: These events represent the most common reported to the FDA and do not represent the most common events associated with the use of lindane lotion and lindane shampoo overall).

A review of the most serious cases described 15 deaths of which two were confirmed related to lindane misuse including a suicidal ingestion. The direct causes of death for the other cases were attributed to reasons other than lindane. In addition, there were 46 hospitalizations, and seven life-threatening outcomes—five from the same household. Six cases of congenital anomaly were also described–five for infants "possibly" exposed to lindane in utero and one paternal exposure—but no characteristic pattern of effect was noted.

In all age groups, reported adverse events occurred mainly in patients with contraindications to the use of lindane or in those who appeared to have misapplied or orally ingested medication

Based on these findings, lindane lotion and lindane shampoo were limited to small unit-dose bottles in 2003 by the FDA to mitigate the risk of misuse and further enhance product safety. At the same time, a boxed warning was added to the prescription label to highlight to healthcare providers appropriate use criteria and rare treatment risks. A medication guide, written in plain English, was also developed and is now required by law to be dispensed with every lindane prescription dispensed in the U.S. to better educate patients and caregivers on safe application technique. When used properly, lindane medications are safe and effective for the diseases they are approved. The most common side effects are nonserious reactions of the skin (e.g., burning, itching, dryness and rash).

The current FDA-approved product labeling emphasizes that lindane medications are contraindicated for use in premature infants and individuals with known uncontrolled seizure disorders and should be used with caution in infants, children, the elderly, and individuals with other skin conditions (e.g., atopic dermatitis, psoriasis) and in those who weigh less than 110 lbs (50 kg) as they may be at risk of serious neurotoxicity. It also notes that careful consideration should be given before prescribing lindane medications to patients with conditions that may increase the risk of seizure, such as HIV infection, history of head trauma or a prior seizure, CNS tumor, the presence of severe hepatic cirrhosis, excessive use of alcohol, abrupt withdrawal from alcohol or sedatives, as well as concomitant use of medications known to lower seizure threshold. Additional information on the benefits and risks of pharmaceutical lindane, including full prescribing information and patient medication guides for lindane lotion and lindane shampoo, can be found on the FDA’s website at: http://www.fda.gov/cder/drug/infopage/lindane/default.htm.

In the U.S., lindane medications are exclusively manufactured and distributed by Morton Grove Pharmaceuticals, Inc. The company’s promotion agreement with Alliant Pharmaceuticals, which commenced in 2005, was terminated May 2007.

Human Health Effects
While adverse reactions can occur with use of low-dose topical pharmaceutical formulations, serious effects are rare and have most often resulted from the misuse of medication. (see also Pharmaceutical Uses) Indeed, most of the adverse human health effects reported for lindane have related to agricultural uses and chronic, occupational exposure of seed treatment workers to agricultural-grade lindane. (see also Agricultural vs. Healthcare Applications)

Exposure to large amounts of lindane can negatively affect the nervous system, producing a range of symptoms from headache and dizziness to seizures, convulsions and more rarely death. Adverse hematologic effects have also been reported with chronic occupational exposures and excessive dermal applications; however, a direct cause and effect has not been established. Vomiting and nausea are usual symptoms associated with oral ingestions of lindane but serious neurologic effects can occur, albeit less frequently. The most common side effects with topical use of lindane medications are nonserious reactions of the skin, including burning, itching, dryness and rash. (see also Pharmaceutical Uses) Lindane has not been shown to alter immunocompetence in humans and is not considered to be genotoxic.

Studies of the carcinogenic effects of lindane have been inconclusive and often limited by study design; however, no major carcinogenic effects have been noted in human trials to date. For example, a meta-analysis of studies looking at the association between occupational exposure to agricultural lindane and non-Hodgkin’s lymphona among U.S. farmers found that lindane was not a primary factor in the development of the disease. The majority of studies of the general population have also shown no association between serum or breast tissue levels of lindane and breast cancer. Similarly, no increased cancer risk was noted in a large epidemiologic study of lindane medications involving a 143,594-patient database with up to 21 years of follow up, which concluded that “There is still no persuasive evidence from studies of humans that lindane, as ordinarily used clinically, is carcinogenic in humans.”

In 1987, the International Agency for Research on Cancer (IARC) classified lindane as a possible human carcinogen. However, more recent evaluations by subject matter experts do not support this rating. In 2001, the Environmental Protection Agency’s Cancer Assessment Review Committee for lindane downgraded the carcinogenic classification of lindane from “possible” to “suggestive evidence,” concluding that the data did not support the need for further study of the carcinogenic risks in humans. The Joint Committee on Pesticide Residues (JMPR) of The World Health Organization and Food and Agricultural Organization of the United Nations similarly concluded in 2004 that “In the absence of genotoxicity and on the basis of the weight of the evidence from the studies of carcinogenicity, JMPR has concluded that lindane is not likely to pose a carcinogenic risk to humans.”

Environmental Contamination
The issue of environmental contamination has largely revolved around extensive agricultural uses of lindane and chemical manufacturing, which have declined significantly in the last 20 years. Indeed, trend analyses show a significant reduction in lindane levels in the U.S. from 1986 through 2003, consistent with decreasing agricultural usage patterns.

In the U.S., more than 99% of lindane has been in the form of agricultural-grade products; less than 1% has been used for medicinal purposes. (see also Agricultural vs. Healthcare Applications) Lindane is released into the environment during and after agricultural application through volatilization into the atmosphere (estimated at 12-30%), where it has long-range transport potential and can be deposited by rainfall. Lindane in soil can leach to surface and even ground water, although the potential is low, and can bioaccumulate in the food chain. In fact, the most widespread exposure of the general population to lindane results from agricultural uses and the intake of contaminated foods, such as produce, meats and milk. Over time, lindane is broken down in soil, sediment and water into less harmful substances by algae, fungi and bacteria; however, the process is relatively slow and dependent on ambient environmental conditions. The ecological impact of lindane’s environmental persistence continues to be debated.

Lindane has not been shown to be a drinking water contaminant of concern in the U.S. In 2003, the EPA reported on the results of large-scale water contaminant testing of 16,000 water systems serving 100 million people across the U.S. and found that none contained lindane levels above the maximum contaminant level standard considered safe. Similar findings were noted by U.S. Geologic Survey teams in 1999 and 2000. More specifically, the EPA conducted “down-the-drain” estimates of the amount of lindane reaching public water supplies from the use of lindane medications using data from California water treatment facilities, concluding that lindane levels from pharmaceutical sources were “extremely low” and not of concern. Again, lindane medications have accounted for only a small fraction of the total amount of lindane used in the U.S.

The current water safety standard, or maximum contaminant level (“MCL”) for the amount of lindane allowed in public drinking water reservoirs—established by the EPA in 1991—is 0.2 parts per billion (“ppb”).25 In 2003, the Agency found scientific justification to raise the MCL for lindane to 1.0 ppb based on new data of the health effects of lindane; however, this change was never implemented because states had no apparently difficulty in maintaining levels below the MCL standard previously set as noted above.

Non-Gamma Isomers
Larger than the issue of lindane toxicity are concerns related to the non-gamma isomers of HCH, namely alpha-HCH and beta-HCH, which are notably more toxic than lindane. Alpha- and beta-HCH were used agriculturally in the U.S. in the form of technical-grade HCH until 1976 and are also produced as manufacturing by-products but are void of insecticidal properties and have little to no use. In the 1940s and 1950s lindane producers stockpiled these isomers in open heaps, which led to ground and water contamination. The International HCH and Pesticide Forum has since been established to bring together experts to address the clean-up and containment of these sites. Modern manufacturing standards for lindane involve the treatment and conversion of waste isomers to less toxic industrial chemicals, a process known as “cracking.” Today, only a few production plants remain active worldwide to accommodate public health uses of lindane and declining agricultural needs. Lindane has not been manufactured in the U.S. since the mid-1970s but continues to be imported and formulated for restricted use.

Regulatory Status
Lindane is registered for use in 50 countries, with restricted-use status in 33 of these countries. The latter includes the U.S. and Canada, which support public health uses of pharmaceutical lindane but no longer allow agricultural applications. The US FDA continues to maintain that lindane medications have necessary health benefits that outweigh potential risks and should remain available for patients with head lice, scabies and pubic lice (crabs) who have few treatment alternatives. These infectious diseases, two of which are sexually transmitted, affect tens of millions of Americans and hundreds of millions of people worldwide every year. In the U.S., petitions to ban the use of pharmaceutical lindane have been rejected by the FDA and determined to be without merit by experts working with this regulatory agency. Worldwide, effective treatment options for the control of scabies and lice are relatively limited.

Canada’s Pest Management Regulatory Agency phased out of all agricultural uses of lindane between 2000 and 2005 due to concerns of chronic occupational exposure and risks to workers during seed treatment and planting. However, lindane medications remain available in Canada for public health purposes as non-prescription therapies. In 2002, the EPA concluded that lindane agricultural products were eligible for re-registration given industry compliance with certain data and labeling requirements to mitigate occupational risks to workers. However, in 2006, the Agency published an addendum to its initial decision and called for the voluntary cancellation of all agricultural uses by registered manufacturers (effective July 2007), citing a significant change in the costs and benefits of agricultural uses due to the recent introduction of seed-treatment alternatives to lindane. The EPA has approved the use of lindane stockpiles through 2009. Lindane medications remain available for public health purposes in the U.S. but, unlike Canada, are prescription-only therapies.

Lindane is banned in 52 countries, including some European and developing countries, and is under review for addition to the Stockholm Convention On Persistent Organic Pollutants. Mexico has committed to a structured, voluntary phase out of lindane through the North American Regional Action Plan (NARAP) but currently authorizes agricultural, veterinary and healthcare uses. California passed legislation banning pharmaceutical uses of lindane (effective 2002) and there is a bill in the New York State Assembly and Senate to ban its use in head lice products and limit its use on scabies, which had not passed as of September 2007. However, the FDA continues to support the use of lindane medications for the diseases they are indicated and approved.

Morton Grove Lawsuit
In the face of negative publicity concerning lindane pharmaceutical products, the U.S. manufacturer, Morton Grove Pharmaceuticals, filed a legal complaint on February 6, 2007 in the U.S. District Court in Chicago, Illinois against the National Pediculosis Association, the Ecology Center, Inc., and two physicians for statements made and disseminated to healthcare providers and consumers using the internet and through a series of printed literature. As noted by the U.S. District Court, the case pleads that “[d]efendants swap agricultural and pharmaceutical research selectively quoting and/or misstating findings from studies relating to the agricultural use of lindane, and widely disseminate false, misleading, and defamatory statements about the safety profile and effectiveness of lindane.” On June 18, 2007, Judge Elaine Bucklo issued a written decision denying defendant’s motion to dismiss and further held that Morton Grove had properly pled a case suitable for trial on the following counts: defamation, false advertising under the Federal Lanham Act, trade disparagement and violation of the Illinois Uniform Deceptive Trade Practice Act. The company seeks damages and injunctive relief against all of the defendants.

In response to Morton Grove's complaint, the Ecology Center defendents moved to dismiss the case based on an alleged lack of personal jurisdiction. However, Morton Grove presented new facts supporting its case for jurisdiction in Illinois and the Court held that Morton Grove's "Second Amended Complaint would provide specific jurisdiction over the Center and Weil." (June 8, 2007 order)