2. HEALTH EFFECTS

2.1 INTRODUCTION

2.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE

2.2.1 Inhalation Exposure

2.2.1.1 Death

2.2.1.2 Systemic Effects

2.2.1.3 Immunological Effects

2.2.1.4 Neurological Effects

2.2.1.5 Reproductive Effects

2.2.1.6 Developmental Effects

2.2.1.7 Genotoxic Effects

2.2.1.8 Cancer

2.2.2.2 Systemic Effects

Absorption of the various HCH isomers following inhalation, oral, or dermal exposure has been inferred from humans who have become ill or who have increased serum levels of the various isomers following exposure by these routes. No animal data are available from the inhalation route, and there are no data to quantify the extent or rate of absorption from inhalation exposure. Technical-grade HCH has been shown to be well absorbed in the gastrointestinal tract of animals. The distribution of HCH isomers in humans and animals is primarily to the adipose tissue but also to the brain, kidney, muscle, blood, and other organs. P-HCH accumulates to a greater extent than g -HCH. The excretion of HCH isomers is primarily through the urine. The isomers have also been detected in milk and semen. The primary urinary metabolites are chlorophenols and an epoxide. The conversion occurs mainly by hepatic enzymes.

2.3.1 Absorption

Evidence exists that humans absorb g -HCH vapor or dusts via inhalation. This can be inferred from occupational studies in which adverse health effects, including hematological abnormalities and neurological effects, have been reported in workers exposed to g -HCH in workplace air (Brassow et al. 1981; Czegledi-Janko and Avar 1970; Kashyap 1986; Samuels and Milby 1971). In addition, a , b , g , and d -HCH have been detected in the blood serum, adipose tissue, and semen of occupationally and environmentally exposed individuals indicating that absorption does take place (Baumann et al. 1980; Czegiedi-Janko and Avar 1970; Kashyap 1986; Nigam et al. 1986; Saxena et al. 1980, 1981a, 1981b). There are no specific studies that have quantified the rate or extent of absorption of the HCH isomers following inhalation exposure. No information is available on the absorption of a , b , g , and d -HCH following inhalation exposure in experimental animals.

2.3.1.2 Oral Exposure

In humans, KCH is absorbed following oral exposure. Many accidental poisonings have occurred in humans as a result of g -HCH ingestion, and high blood concentrations have been demonstrated in a number of acute poisoning cases (Berry et al. 1987; Harris et al. 1969; Khare et al. 1977; Munk and Nantel 1977; Nantel et al. 1977; Powell 1980; Starr and Clifford 1972).

HCH is similarly absorbed following oral exposure in animals. Information concerning the rate of absorption from the gastrointestinal tract can be inferred from studies conducted in mice and rats. These studies indicated that g -HCH is readily absorbed from the gastrointestinal tract (Ahdaya et al. 1981; Turner and Shanks 1980). Ahdaya et al. (1981) demonstrated that half of the administered dose was absorbed from the gastrointestinal tract of fasting mice approximately

14 minutes after administration of radiolabeled g -HCH by stomach tube. Although this study demonstrates the rapid absorption of g -HCH from the gastrointestinal tract, the use of fasted animals prevents an assessment of the effect of stomach contents on the rate of absorption.

Turner and Shanks (1980) studied the rate of absorption of g -HCH from the gastrointestinal tract and intestinal lymphatic system using rat intestinal loop preparations. Prepared loops were injected with g -HCH, and the blood and lymph were sampled for 30 minutes. g -HCH was readily absorbed from the intestine into the blood; however, only a small amount of g -HCH entered the lymphatic system from the intestine.

Absorption of technical-grade HCH following oral exposure has been quantified in rats. The extent of absorption of technical-grade HCH has been estimated to be 95.8% in rats within 4 days following the oral administration of single doses of the substance (Albro and Thomas 1974). Variation of the dosages from 30 to 125 mg/kg had no effect on the percentage of absorption. The overall degree of absorption of technical-grade HCH administered in the feed for 14 days was similar (94.9%), but the average absorption values of a -, b -, g -, and d -HCH were 97.4%, 90.7%, 99.4%, and 91.9%, respectively (Albro and Thomas 1974).

The ready absorption of g -HCH through human skin due to its lipid solubility has been demonstrated in several studies that examined the absorption of g -HCH from an antiscabies lotion (Feldmann and Maibach 1974; Ginsburg et al. 1977; Lange et al. 1981). Maximal blood levels in volunteers and scabies patients were reported within 4-6 hours following whole-body application (Ginsburg et al. 1977; Lange et al. 1981). However, the maximum levels of g -HCH reached in scabies patients were greater than those reported for normal volunteers. Studies involving a single topical application of g -HCH to the forearm, which was left for 24 hours before washing, indicate that at least 9% of the applied dose was absorbed; maximum absorption occurred during the first 12 hours after application of g -HCH to the skin, but absorption continued for at least 5 days (Feldmann and Maibach 1974).

2.3.2.4 Other Routes of Exposure

Studies have demonstrated that g -HCH accumulates in the fatty tissue of pregnant women and can be transferred to the fetus through the placenta and to neonates through the milk (Siddiqui et al. 1981b). Concentrations of g -HCH in human milk have been shown to be approximately five and seven times greater than concentrations in maternal or umbilical cord blood, respectively (Siddiqui et al. 1981b). Data also exist that suggest that the longer the potential exposure to g -HCH, the higher the concentration of g -HCH in the maternal blood system (Saxena et al. 1981a, 1981b). Older women were found to have higher g -HCH levels in the placenta and umbilical cord blood than younger women (Saxena et al. 1983). During pregnancy, higher levels of g -HCH were reported in the fetal blood tissue, uterine muscle, placenta, and amniotic fluid than in maternal adipose tissue. g -HCH levels increased in maternal blood serum during delivery (Polishuk et al. 1977b; Roncevic et al. 1987; Wasserman et al. 1982). Males exposed to HCH in the environment accumulate g -HCH and other HCH isomers in adipose tissue and to a smaller extent in the testes or semen (Szymczynski and Waliszewski 1981, 1983).

2.3.5 Mechanisms of Action

Possible mechanisms of action of HCH on some of the target organs have been described. In the nervous system, Y-HCH is thought to interfere with the gamma-aminobutyric acid (GABA) system by interacting with the GABA-A receptor-chloride channel complex at the picrotoxin binding site.

2.4 RELEVANCE TO PUBLIC HEALTH

Evidence was found in the reviewed literature that HCH isomers are toxic to humans and animals. Human exposure to HCH occurs primarily by occupational exposure, by ingesting HCH in contaminated food or water, or through the misuse of therapeutic lotions containing Y-HCH to control mites or lice. Humans are generally exposed to Y-HCH or to technical-grade HCH, which contains a -, b -, g -, and d -HCH. Technical-grade HCH and a -, b -, and d -HCH are currently unavailable in the United States; therefore, exposure to these isomers is likely to occur only in or near sites at which technical-grade HCH was disposed. Humans can absorb HCH following inhalation, ingestion, or dermal exposure. The possible human health effects associated with exposure to HCH are adverse hematological effects, hepatic effects, renal effects, immunological effects, neurological effects, reproductive effects, and cancer. These effects are strongly dependent on dose, duration of exposure, and route of administration.

Neurological Effects.

In humans, neurological effects including paresthesia of the face and extremities, headaches, vertigo, abnormal EEG patterns, and often seizures and convulsions have been reported in individuals occupationally exposed to g -HCH or in individuals exposed accidentally or intentionally to large amounts of g -HCH by ingestion or dermal application (Czegledi-Janko and Avar 1970; Davies et al. 1983; Harris et al. 1969; Heiberg and Wright 1955; Kashyap 1986; Lee and Groth 1977; Matsuoka 1981; Munk and Nantel 1977; Nantel et al. 1977; Powell 1980; Starr and Clifford 1972; Telch and Jarvis 1982). Acute- and intermediate-duration exposure of animals to high oral or dermal doses of g - or b -HCH affects the central nervous system as evidenced by behavior disorders, decreased nerve velocity, convulsions, seizures, and coma (Albertson et al. 1985; Desi 1974; Hanig et al. 1976; Muller et al. 1981; Tilson et al. 1987; Tusell et al. 1987; Van Velsen et al. 1986). No histological examinations were conducted on the brain or nervous system of animals exposed by any route for any duration. The effects in humans and in animals suggest that exposure of humans to high air concentrations or large oral doses could result in neurotoxic effects.

2.5.2 Biomarkers Used to Characterize Effects Caused by HCH

The individual isomers of HCH can be detected in the blood serum, urine, adipose tissue, and semen of exposed individuals. However, the concentrations measured in these biological tissues have not been exclusively correlated as yet with the degree of adverse health effects observed.

Adverse effects such as neurophysiological and neuropsychological disorders and gastrointestinal disturbances have been reported in workers exposed to HCH during pesticide or fertilizer formulation. Both handlers and nonhandlers complained of paresthesia of the face and extremities, headache, and giddiness; other symptoms included malaise, vomiting, tremors, apprehension, confusion, loss of sleep, impaired memory, and loss of libido. Similar but less severe effects were noted in 19 maintenance workers who visited the plant frequently. Serum HCH levels measured in these workers were 0.004-0.1 ppm c -HCH, 0.02-0.2 ppm b -HCH, 0-0.32 ppm g -HCH, and 0-0.04 ppm d -HCH. Kashyap (1986) also reported higher serum enzyme levels of alkaline phosphatase, lactate dehydrogenase, ornithine carbamyl transferase, gamma-glutamyl transpeptidase, and leucine aminopeptidase and increased IgM in the handlers as compared with the nonhandlers and a control population of 14 workers with no occupational contact with RCH. Czegledi-Janko and Avar (1970) reported that g -HCH blood levels of 0.024-0.16 ppm were associated with clinical symptoms including muscle jerking and variations in EEG in 37 workers exposed to g -HCH in a fertilizer plant.

2.7 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE

A susceptible population will exhibit a different or enhanced response to HCH than will most persons exposed to the same level of HCH in the environment. Reasons include genetic makeup, developmental stage, age, health and nutritional status (including dietary habits that may increase susceptibility, such as inconsistent diets or nutritional deficiencies), and substance exposure history (including smoking). These parameters result in decreased function of the detoxification and excretory processes (mainly hepatic, renal, and respiratory) or the pre-existing compromised function of target organs (including effects or clearance rates and any resulting end-product metabolites). For these reasons we expect the elderly with declining organ function and the youngest of the population with immature and developing organs will generally be more vulnerable to toxic substances than healthy adults. Populations who are at greater risk due to their unusually high exposure are discussed in Section 5.6, Populations With Potentially High Exposure.

Infants, young children, and people with excoriated (peeling) skin are more susceptible to the toxic effects of g -HCH than healthy adult men and women (Ginsburg et al. 1977). The potential hazards of using g -HCH preparations on infants and young children are underscored by the fact that the very young have a large surface area to volume ratio, possibly less efficient hepatic detoxification abilities, and are more likely to lick treated skin (Kramer et al. 1980). Therefore, the use of g -HCH as a scabicide on infants and very young children, especially those that have very little body fat, has been discouraged (Telch and Jarvis 1982).

Pregnant and/or lactating women should not be exposed to -f -HCH (Ginsburg et al. 1977; Kramer et al. 1980; Solomon et al. 1977a). In pregnant women, g -HCH crosses the placenta. HCH and Y-HCH body tissue levels have also been associated with premature labor and spontaneous abortions (Rasmussen 1980; Saxena et al. 1980, 1981a, 1981b; Wassermann et al. 1982).

If however, no causal relationship has been established between blood and tissue levels of g -HCH and premature termination of pregnancy.

People with lowered convulsion thresholds due to epilepsy (treated or untreated), cerebrovascular accidents, or head injuries may be at greater risk of the central nervous system effects of Y-HCH toxicity and may suffer increased risk of or severity of seizures (Kramer et al. 1980; Matsuoka 1981). Those individuals suffering from malnutrition (low protein, low fiber, and low vitamin intake) may be more susceptible than the general public to the toxic effects of the Y-HCH (Rasmussen 1987). Individuals with liver and/or kidney disease may be at risk because of compromised deto3dfication mechanisms in the liver and excretory mechanisms in the kidney. Additionally, individuals with existing or suspected immunodeficiencies may be at risk because HCH isomers may enhance immunosuppression.

2.8 METHODS FOR REDUCING TOXIC EFFECTS

This section will describe clinical practice and research concerning methods for reducing toxic effects of exposure to HCH. However, because some of the treatments discussed may be experimental and unproven, this section should not be used as a guide for treatment of exposures to HCH. When specific exposures have occurred, poison control centers and medical toxicologists should be consulted for medical advice.

2.8.1 Reducing Peak Absorption Following Exposure

When a large amount of HCH has been swallowed, emetics have been used to induce vomiting. One of the problems with inducing vomiting is that the insecticidal form of HCH is often dissolved in an organic solvent, which presents an aspiration hazard. Activated charcoal can also be used to decrease gastrointestinal absorption. To avoid skin absorption, the clothing should be removed, and the skin should be washed (Ellenhorn and Barceloux 1988). There are no known methods for reducing absorption following inhalation exposure.

2.8.2 Reducing Body Burden

The traditional methods of increasing elimination or decreasing distribution (dialysis, diuresis, and hemoperfusion),are not useful because of the high volume of distribution of HCH into adipose tissue (Elienhorn and Barceloux 1988). HCH presumably accumulates in adipose tissue following all routes of exposure.

2.8.3 Interfering with the Mechanism of Action for Toxic Effects

Possible mechanisms of action of HCH on some of the target organs have been described. In the nervous system, g -HCH is thought to interfere with the GABA system by interacting with the GA13A-A receptor-ionophore complex at the picrotoxin binding site (Portig and Schnorr 1988; Rivera et al 1991; Sunol et al. 1988). Thus, the seizures caused by g -HCH can be antagonized by GABA-A mimetics. In the liver, g -HCH is thought to function by interfering with hepatic oxidative capacity and glutathione metabolism (Barros et al. 1988, 1991; Srinivasan and Radhakrishnamurty 1988; Videla et al. 1991). Another possible mechanism for hepatic toxicity is the increased lipid metabolism (Ravinder et al. 1990; Srinivasan and Radhakrishnamurty 1988). It is possible that interfering with these mechanisms can decrease the toxicity of HCH.

2.9 ADEQUACY OF THE DATABASE

Section 104(i)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with the Administrator of EPA and agencies and programs of the Public Health Service) to assess whether adequate information on the health effects of HCH is available. Where adequate information is not available, ATSDR, in conjunction with the National Toxicology Program (NTP), is required to assure the initiation of a program of research designed to determine the health effects (and techniques for developing methods to determine such health effects) of HCH.

Joint teams of scientists from ATSDR, NTP, and EPA have identified the following categories of possible data needs. They are defined as substance-specific informational needs that if met would reduce the uncertainties of human health assessment. This definition should not be interpreted to mean that all data needs discussed in this section must be filled. In the future, the identified data needs will be evaluated and prioritized, and a substance-specific research agenda will be proposed.

2.9.1 Existing Information on Health Effects of HCH

The existing data on health effects of inhalation, oral, and dermal exposure of humans and animals to HCH are summarized in Figure 2-4. The purpose of this figure is to illustrate the existing information concerning the health effects of HC14. Each dot in the figure indicates that one or more studies provide information associated with that particular effect. The dot does not imply anything about the quality of the study or studies. Gaps in this figure should not be interpreted as "data needs." A data need, as defined in ATSDR's Decision Guide for Identifying Substance-Specific Data Needs Related to Toxicological Profiles (ATSDR 1989), is substance-specific information necessary to conduct comprehensive public health assessments. Generally, ATSDR defines a data gap more broadly as any substance-specific information missing from the scientific literature.

Most of the literature reviewed concerning the health effects of inhaled a -, b -, g -, or d -HCH in humans consists of case reports of individuals occupationally exposed or exposed in the home following exposure to a Y-HCH vaporizer. The predominant route of exposure in occupational studies is presumed to be inhalation, although dermal exposure is also likely. The health effects in humans associated with ingested HCH are reported primarily in case studies in which individuals ingested pesticide pellets or therapeutic lotions containing g -HCH used to control scabies. Information concerning the health effects of HCH in humans following dermal exposure is limited to case studies of individuals who have misused therapeutic lotions containing g -HCH used to control scabies and head and body lice. The duration and level of exposure to HCH generally cannot be quantified from the information presented in these reports. In addition, the case study reports in humans are limited because concomitant exposure to other toxic substances or other substances present in the atmosphere may have occurred.

No information was found regarding the health effects of HCH following inhalation exposure in animals. The health effects of a -, b -, g -, or d -HCH following oral exposure have been well documented in a variety of species. Limited information is available concerning the health effects of HCH following dermal exposure. Health effects following chronic dermal exposure to HCH in animals have not been investigated.

g -HCH is the isomer most thoroughly tested in intermediate- and chronic-duration studies. The carcinogenic effects of technical-grade HCH and a -, b -, and g -HCH have been examined, but the carcinogenic potential of d -HCH has not been as well studied.

2.9.2 Identification of Data Needs

Acute-Duration Exposure

Occasional case reports are available for humans who have had adverse health effects, including death, from excessive inhalation exposure from 7-HCH vaporizers (Conley 1952; Loge 1965). When applied dermally, Y-HCH also has been shown to have adverse effects in a few humans (Davis et al. 1992; Fagan et al. 1981; Rauch et al. 1990). Oral exposure to large amounts has resulted in a few human deaths (Storen 1955; Sunder Ram Rao et al. 1988) and adverse neurological effects (Munk and Nantel 1977). The level of exposure in the human studies generally cannot be quantitated because the information is derived from anecdotal case reports. Therefore, there is no reliable information in humans associating dose with effect. Such information might allow investigators to establish thresholds for systemic toxicity due to acute exposure.

No acute inhalation data are available for animals. In order to derive an MRL, more information from this route of exposure is important. An acute oral MRL has been developed from data on neurological effects (Joy et al. 1982). Other acute oral studies in animals have reported death in the rat (Gaines 1960) and mouse (Liu and Morgan 1986), hepatic effects in the mouse (Oesch et al. 1982) and kidney effects in the rat (Srinivasan et al. 1984). Acute dermal studies in rats are also available (Dikshith et al. 1991c; Gaines 1960).

Intermediate-Duration Exposure

Information on human health effects of repeated exposure to HCH is available from studies of occupationally exposed individuals (Kayshap 1986); no information is available on the effects of repeated oral or dermal exposure in humans. The exact duration and level of exposure in the human studies generally cannot be quantified because often this information is not provided in the studies. Such information would allow investigators to determine health effects associated with known levels of exposure. Intermediate-duration oral studies have been performed in animals regarding hematic (Rivett et al. 1978; Van Velsen et al. 1986), hepatic (Desi 1974; Dikshith et al. 1991a; Fitzhugh et al. 1950; Hanada et al. 1973; Ito et al. 1973; Oesch et al. 1982; Ortega et al. 1957; Ravinder et al. 1989; Van Velsen et al. 1986), and renal (Desi 1974; Dikshith et al. 1991a; Fitzhugh et al. 1950; Srinivasan et al. 1984; Van Velsen et al. 1986) effects. Dermal exposure in rats, rabbits, and guinea pigs has also been examined (Dikshith et al. 1973, 1978, 1989b, 1991c). An MRL has been derived for intermediate-duration oral exposure in animals; therefore, further studies using this exposure are probably not useful.

Since no information on inhalation exposure is available, further studies using this route are important to develop an MRL.

Comparative Toxicokinetics - Evidence is available to suggest that both animals and humans absorb HCH and store the isomers primarily in the fat and other body tissues (Chand and Ramachandran 1980; Eichler et al. 1983; Srinivasan and Radhakrishnamurty 1983b). Similar metabolites have been identified in the urine of exposed individuals and treated animals, and in both, the primary route of excretion is the urine (Angerer et al. 1981; Chadwick et al. 1985). Further studies are not necessary at this time.

Methods for Reducing Toxic Effects - There is some information on the mechanism for the toxic effects of HCH on the brain (Abalis et al. 1985; Casida and Lawrence 1985; Lawrence and Casida 1984) and liver (Barros et al. 1988, 1991; Srinivasan and Radhakrishnamurty 1988; Videla et al. 1991). Further studies in these areas might be fruitful in developing methods for reducing toxic effects.

The following studies involving g -HCH are being sponsored by the National Institutes of Health: